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Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Garassino MC, Martelli O, Broggini M, et al, on behalf of the TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 2013; published online July 22. http://dx.doi.org/10.1016/S1470-2045(13)70310-3.

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A randomised trial of erlotinib versus docetaxel as second-line treatment of patients with

advanced non-small cell lung cancer and wild-type epidermal growth factor receptor

(TAILOR)

SUPPLEMENTARY APPENDIX

2

CONTRIBUTORS AS is the Principal Investigator. MCG, MB and VT conceptualised the study. All the TAILOR steering committee members designed the study. IF, ER collected data. ER, IF AND VT did the statistical analysis. GF, AB, FL, LM, MT, RL were the main clinical investigators. MB, SV, FB, MM, MG, CL did the molecular and pathological examinations. GG was the chair of the IDMSC. MCG, VT, MB AND SM developed an early draft, and all investigators reviewed and approved the submitted report. TAILOR STEERING COMMITTEE: AS (Principal Investigator), MCG, GF, Joanna Landi, Angela Spena, FB, MG, Giorgio Gherardi, Fatebenefratelli e Oftalmico Hospital Milano, Italy. MB, Elena Copreni, IF, MM, Davide Poli, ER, VT, IRCCS-Istituto Ricerche Farmacologiche "Mario Negri", Milano, Italy. Marcello Gambacorta, CL, SV, Niguarda Cà Granda Hospital, Milano, Italy. SM, Institute for Cancer Research and Treatment, Candiolo, Italy. RL, Papa Giovanni XXIII Hospital, Bergamo, Italy. OM, S. Giovanni Addolorata Hospital, Roma, Italy. Lorenzo Rosso, Luigi Santambrogio, IRCCS “Ca' Granda” General Hospital, University of Milan, Italy. TAILOR IDMSC GG, (Chair) Lombardi Comprehensive Cancer Center, Washington DC. Roberto D’Amico, Università degli Studi di Modena e Reggio Emilia, Italy. Thomas Fleming, University of Washington, Seattle, WA. Edmondo Terzoli, Istituto Regina Elena, Roma, Italy. INVESTIGATORS: MCG, GF, Sheila Piva, Nicla Maria La Verde, Fatebenefratelli e Oftalmico Hospital Milano, Italy. FL, Bruno Gori, Luciano Stumbo, Vittoria Lapadula, Umberto I Policlinico, Roma, Italy. RL, AB, Lucia Bonomi, Carlo Tondini, Papa Giovanni XXIII Hospital, Bergamo, Italy. LM, Fabrizio Nelli, Maria Agnese Fabbri, Belcolle Hospital, Viterbo, Italy. MT, Claudia Bareggi, Elisa Locatelli, IRCCS Ca’ Granda Ospedale Maggiore Policlinic, Milano, Italy. Ida Pavese, San Pietro Hospital, Roma, Italy. Maria Giuseppina Sarobba, Antonia Arru, Azienda Ospedaliera Universitaria, Sassari, Italy. Roberta Buosi, Oscar Alabiso, Ospedale Maggiore della Carità, Novara, Italy. Alessandro Bertolini, Elisabetta Menatti, Valtellina e Valchiavenna Hospital, Sondrio, Italy. Antonio Russo, Giuseppe Cicero, Sergio Palmeri, Paolo Giaccone Policlinic, Palermo, Italy. Maria Mauri , Olga Martelli , S. Giovanni Addolorata Hospital, Roma, Italy. Andrea Mancuso, San Camillo Forlanini Hospital, Roma, Italy. Antonio Ardizzoia, Isabella Vittimberga, A. Manzoni Hospital, Lecco, Italy. Claudio Graiff, Emanuela Vattemi, Bolzano Central Hospital, Bolzano, Italy. Vittorio Ferrari, Spedali Civili, Brescia, Italy. Enrico Cortesi, Sapienza University,Umberto I Policlinico, Roma, Italy. Luigi Cavanna, G. Saliceto Hospital, Piacenza, Italy. Antonio Pazzolla, S.S. Annunziata Hospital, Sassari, Italy. Daniele Fagnani, Desio e Vimercate Hospital, Vimercate, Italy. Anna Calcagno, Legnano Hospital, Legnano, Italy. Alessandro Del Conte, S. Maria degli Angeli Hospital, Pordenone, Italy. Bruno Massidda, Presidio Monserrato Cagliari Hospital, Cagliari, Italy. Camilla Casi, ASL 7 AltavaldelsaCampostaggia Hospital, Siena, Italy. Franco Spremberg, S. Giovanni Evangelista Hospital, Tivoli, Italy. Cristina Locatelli, San Carlo Borromeo Hospital, Milano, Italy. Emodio Barletta, G. Rummo Hospital, Benevento, Italy. Mario Comandè, Melegnano e Gorgonzola Hospital, Melegnano, Italy. Paolo Foa, San Paolo Polo Hospital, Milano, Italy. Sonia Fatigoni, S. Maria Hospital, Terni, Italy. Andrea De Censi, Galliera Hospitals, Genova, Italy. Massimiliano Cergnul, Santa Maria Hospital, Castellanza, Italy. Giuseppe Valmadre, Morelli Sondalo, Valtellina e Valchiavenna Hospital, Sondalo, Italy. Libero Ciuffreda, San Giovanni Battista Hospital, Torino, Italy. Efisio De Fraia, Armando Businco Hospital, Cagliari, Italy. Giovanna Antonelli, San Vincenzo Hospital, Taormina, Italy. Giuseppe Nastasi, PesentiFenaroli Hospital, Alzano Lombardo, Italy. Giuseppe Grimaldi, Umberto I Hospital, Nocera Inferiore, Italy. Giammaria Fiorentini, S. Giuseppe Antica Sede Hospital, Empoli, Italy. Ida Colantonio, S. Croce e S. Carlo Hospital, Cuneo, Italy. COORDINATION SUPPORT: Joanna Landi, Angela Spena, Aurora Rizzo, Anna Bianchi, Serena Girelli, Fatebenefratelli e Oftalmico Hospital Milano, Italy. Luca Clivio, IRCCS-Istituto Ricerche Farmacologiche "Mario Negri", Milano, Italy. INDEPENDENT STATISTICIANS Stefania Galimberti, Maria Grazia Valsecchi Università degli Studi Milano Bicocca, Milano, Italy. Pinuccia Valagussa, Michelangelo Foundation, Milano, Italy. INDEPENDENT RADIOLOGICAL REVIEW BOARD: Alfonso Marchianò, Michelle Magli, Fondazione IRCSS Istituto Nazionale dei Tumori, Milano, Italy. Role of the funding source The study was sponsored by Agenzia Italiana del Farmaco (AIFA), the Italian Drug Regulatory Agency, which provided financial support without imposing restrictions on the investigators with respect to study design, data collection, analysis and interpretation, and report writing. AIFA approved all the protocol amendments and followed the study conduction. Conflicts of interest MCG and OM and VT declare a consultancy with Eli-Lilly. MCG declares a consultancy with Boehringer Ingelheim. VT and RL declare consultancy with Roche. OM and VT declare consultancy with Amgen. All other authors declare that they have no conflicts of interest.

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SUPPLEMENTARY FIGURE S1: STUDY DESIGN

PD 1:1

NO CROSS

OVER

DOCETAXEL

75 mg/m2 iv

day 1,21

or

35 mg/m2 iv

day 1,8,15

ERLOTINIB

150 mg po , daily

R

NSCLC

Stage IIIB/IV

Second line treatment

Previous platinum based

doublet

EGFR wild - type

KRAS determined

ECOG PS 0 - 2

PD 1:1

NO CROSS

OVER

DOCETAXEL

75 mg/m2 iv

day 1,21

or

35 mg/m2 iv

day 1,8,15

ERLOTINIB

150 mg po , daily

R

NSCLC

Stage IIIB/IV

Second line treatment

Previous platinum based

doublet

EGFR wild - type

KRAS determined

ECOG PS 0 - 2

4

SUPPLEMENTARY FIGURE S2. CHECK FOR ASSUMPTION OF PROPORTIONAL HAZARD

Interaction between variables and log time

Model Overall Survival

(test for interaction)

Progression Free Survival

(test for interaction)

Univariate Chi=0·04 df=1 p=0·85 Chi= 0·43 df=1 p=0·51

Multivariable Chi=14·12 df=10 p=0·17 Chi=11·19 df=10 p=0·34

5

SUPPLEMENTARY TABLE S1- DOCETAXEL DRUG-RELATED ADVERSE EVENTS

AllGrades

N. (%)

Grade 3 N. (%)

Grade 4 N. (%)

χ2Erlotinib

vs Docetaxel χ

2 weekly weeklyDocetaxel vs 3w-Docetaxel

Febrile neutropenia

Erlotinib 0 0 0

WeeklyDocetaxel 0 0 0

3w-Docetaxel 5 (7·9) 1(1·6) 3(4·8)

0·032

0·085

Neutropenia

Erlotinib 3 (2·8) 0 1 (0·9)

WeeklyDocetaxel 6 (14·6) 2 (4·9) 0

3w-Docetaxel 25 (39·7) 7 (11·1) 12(19·1)

<0·0001 0·001

Diarrhea

Erlotinib 32 (29·9) 3 (2·8) 0


3w-Docetaxel 9 (14·3) 0 0

0·323 0·027

Alopecia

Erlotinib 2 (1·9) 0 0


3w-Docetaxel 26 (41·3) 10 (15·9) 3(4·8)

<0·0001 0·016

Asthenia

Erlotinib 40 (37·4) 4 (3·7) 2 (1·9)


3w-Docetaxel 38 (60·3) 5 (7·9) 0

0·199 0·163

Neurological

Erlotinib 5 (4·7) 1 (0·9)* 1 (0·9)

WeeklyDocetaxel 6 (14·6) 5 (12·2)* 0

3w-Docetaxel 11 (17·5) 5 (7·9)* 1 (1·6)

0·013 0·953

Nausea/vomiting

Erlotinib 11 (10·3) 1 (0·9) 0


3w-Docetaxel 14 (22·2) 0 0

0·053 0·139

Dermatological

Erlotinib 62 (57·9) 10 (9·4) 5 (4·7)

WeeklyDocetaxel 1 (2·4) 0 0

3w-Docetaxel 3 (4·8) 0 0

<0·0001 0·447

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SUPPLEMENTARY TABLE S2 - TIMES TO EVALUATION

Arm Evaluation

no. N pts

Median months

Lower quartile

Upper quartile

First 96 1·9 1·6 2·3 Second 32 4·3 3·8 5·5 Third 10 7·2 6·3 7·9 Fourth 4 9·5 8·7 10·5

Docetaxel

Fifth 2 11·2 11·1 11·3

First 100 1·9 1·6 2·3 Second 26 4·4 3·8 5·5 Third 11 7·3 5·8 7·7 Fourth 11 8·6 7·4 9·8

Erlotinib

Fifth 7 11·8 9·8 12·1

7

SUPPLEMENTARY TABLE S3- MULTIVARIABLE ANALYSIS

Multivariate Analysis - OS Multivariate Analysis - PFS

HR 95% CI p-value HR 95% CI p-value

KRAS

(mutated vs wild-type)

1·24

0·87

1·77

0·233

1·01

0·71

1·41

0·977

Histology

(squa/NASvsadenocarcinoma)

0·96

0·67

1·39

0·846

1·11

0·79

1·55

0·559

(others vs adenocarcinoma) 0·57 0·30 1·10 0·094 1·11 0·62 1·98 0·736

Smoking habits

(ex/current vs never-smokers)

0·89

0·59

1·35

0·579

1·06

0·73

1·56

0·756

Sex

(F vs M)

0·75

0·52

1·10

0·144

0·94

0·67

1·31

0·701

ECOG-PS

(2 vs 0,1)

3·32

1·92

5·73

<·0001

3·04

1·78

5·21

<·0001

Best Response

(CR/PR vs adjuvant)

0·84

0·47

1·51

0·567

0·93

0·54

1·61

0·800

(SD vs adjuvant)

0·94

0·51

1·73

0·844

1·18

0·67

2·09

0·559

(PD vs adjuvant)

1·40

0·77

2·56

0·270

1·49

0·85

2·61

0·167

TreatmentArm

(DocetaxelvsErlotinib)

0·73

0·54

1·00

0·049

0·71

0·53

0·95

0·023

Università degli Studi di Milano-Bicocca DIPARTIMENTO DI MEDICINA CLINICA E PREVENZIONE

Edificio U8 – Monza 20052, Via Cadore 48 tel. 02/64488351 – fax 02/64488363 – http://www.dimep.medicina.unimib.it

Monza, 30 May 2011

Statistical revision of the TAILOR study Power analysis After review of the study rationale and design in the light of new external evidence and after consideration of the slow recruitment, power calculations were performed under different plausible scenarios. Study recruitment will continue until the end of 2011 and it is expected to reach a final number of patients between 210 and 230. Power calculations were done for these two sizes, considering different figures for survival probabilities (S – primary endpoint) and for progression free survival probabilities (PFS – secondary endpoint) in the two treatment groups (DOC and ERL) and accounting for no losses to follow-up (for survival, this is a realistic option given that census data will be searched for in order to avoid losses) or for up to 5% losses to follow-up. Calculations were based on the following assumptions: - log-rank test on the following system of hypothesis: H0: SDOC (PFSDOC) = SERL (PFSERL) H1: SDOC (PFSDOC) ≠ SERL (PFSERL)

- two-sided test at = 5% level of significance - recruitment period = 4 years – from end of 2007 to 2011 - (uniform) - minimum period of follow-up = 1 year - randomization ratio = 1:1

Power calculations were based on the method proposed by Lachin e Foulkes (1986). Assumptions on endpoints were based on the results of recent studies that motivated a reformulation of the study rationale. These results are summarized in the table below (in bold relevant figures):

Study Random % patients S PFS

in 2 line Median % 6 m % 12 m Median % 4 m % 6m BR.20 DOC 75 7.0 54 30 2.4 - - (Shepherd, JCO) BSC 4.6 38 20 1.5 - - BR.21 ERL 50 6.7 51 30 2.2 - 23 (Shepherd, NEJM) BSC 4.6 43 22 1.8 - 10 Interest DOC 85 8.0 60 34 2.7 38 18 (Kim, Lancet) GEF 7.6 60 32 2.2 32 19

Legenda: DOC=docetaxel; BSC= Best Supportive Care; ERL=Erlotinib; GEF=Gefitinib



Primary Endpoint: survival (S) – figures at 1 year (Table 1) Highlighted (gray) the result of power calculation for the study hypothesis on the 1-year survival in the two randomized treatment groups: DOC = 34%, ERL = 20% . With 210 subjects (worst scenario) the study will have a power of approximately 80% to detect as statistically significant a difference of 14% in the 1-year survival in the two treatment groups, Number of events required for final analysis after 1 year from stop recruitment will be 199. The 14% difference in 1 year survival corresponds to a hazard ratio of 1.49. Power will be more than 80% if sample size will reach 230 patients (best scenario). As shown in table 1, the study will have comparable levels of power for detecting a 14% difference also for similar scenarios in terms of 1-year survival figures in the two treatment groups (for instance, DOC = 32% and ERL = 18%). Table 1: Power calculation on the primary endpoint. Different scenarios of 1-year survival figures and of levels of losses to follow-up are evaluated.

n=210 ERL (%)

DOC (%) losses fup

(%) 15 18 20 22 25 25 0 60.2 32.7 18.6 9.6 - 5 59.0 31.9 18.1 9.5 -

30 0 88.4 69.8 53.3 36.6 16.9 5 87.5 68.4 52.0 35.6 16.5

32 0 93.8 81.1 67.5 51.4 28.1 5 93.2 79.9 66.1 50.1 27.3

34 0 97.0 89.2 79.3 65.6 41.9 5 96.6 88.2 78.0 64.2 40.7

n=230 ERL (%)

DOC (%) losses fup

(%) 15 18 20 22 25 25 0 64.1 35.2 19.9 10.1 - 5 62.8 34.4 19.4 9.9 -

30 0 91.0 73.6 57.0 39.4 18.0 5 90.2 72.3 56.7 38.3 17.6

32 0 95.6 84.4 71.4 55.0 30.3 5 95.1 83.3 70.0 53.7 29.4

34 0 98.0 91.6 82.7 69.6 45.1 5 97.7 90.8 81.5 68.1 43.8



Secondary Endpoint : progression free survival (PFS) – figures at 6 months (Table 2) Highlighted (gray) the result of power calculation for the study hypothesis on the 6-month progression free survival in the two randomized treatment groups: DOC = 20%, ERL = 10% . With 210 subjects the study will have a 73% power to detect as statistically significant a 10% difference in the progression free survival at 6 months and the power will reach 76% with 230 patients. Table 2: Power calculation on the secondary endpoint. Different scenarios of 6-month progression free survival and of levels of losses to follow-up are evaluated.

n=210 ERL (%)

DOC (%) losses fup

(%) 5 10 15 15 0 89.6 28.8 -

5 89.0 28.3 - 20 0 98.9 72.5 22.1

5 98.8 71.4 21.7 25 0 99.9 94.4 61.3 5 99.9 93.8 60.0

n=230 ERL (%)

DOC (%) persi fup

(%) 5 10 15 15 0 92.1 31.1 -

5 91.6 30.5 - 20 0 99.4 76.2 23.8

5 99.3 75.2 23.3 25 0 99.9 96.0 65.2 5 99.9 95.6 63.9



References Lachin, J. M., and M. A. Foulkes. Evaluation of sample size and power for analysis of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 42: 507–519, 1986. Shepherd F.A., Dancey J. et al. Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy. Journal of Clinical Oncology, 18, 10, 2095-2103, 2000. Shepherd F.A., Pereira J.R. et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. New England Journal of Medicine. 353, 123-132, 2005. Kim, E.S., Hirsh V. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. The Lancet, 372, 9652, 1809-1818, 2008.

Maria Grazia Valsecchi Galimberti Stefania Professor of Medical Statistics Center of Biostatistics for Clinical Epidemiology Department of Clinical Medicine and Prevention University of Milano-Bicocca

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TAILORAIFA TArceva Italian Lung Optimization tRial

Optimization of erlotinib for the treatment

of patients with advanced non small cell

lung cancer: an Italian randomized trial

CLINICAL STUDY PROTOCOL

id2277000 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com

CLINICAL STUDY PROTOCOL

Eudract number 2007-004786-17

Sponsor

A. O. Fatebenefratelli e Oftalmico - Milano

With the Support of AIFA (Agenzia Italiana del Farmaco) - Codice AIFA

FARM6F5JER

Coordinating Ethics Committee

Comitato Etico Indipendente (IEC)

dell�A.O. Fatebenefratelli e Oftalmico � Milano

Principal Investigator Alberto Scanni, MD

A.O. Fatebenefratelli e Oftalmico - Milano

Steering Committee Filippo Bianchi, MD

Massimo Broggini, PhD

Gabriella Farina, MD

Irene Floriani, PhD

Marcello Gambacorta, MD

Marina Chiara Garassino, MD

Giorgio Gherardi, MD

Roberto Labianca, MD

Mirko Marabese, PhD

Silvia Marsoni, MD

Olga Martelli, MD

Lorenzo Rosso, MD

Luigi Santambrogio, MD

Silvio Veronese, PhD

DSMC Roberto D�Amico, PhD

Thomas Fleming, PhD

Giuseppe Giaccone, MD

Edmondo Terzoli, MD

Final version, 20.09.2007

Amendment 1, 02.04.2009

Amendment 2, 30.05.2011

TArceva Italian Lung Optimization tRial

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TAILORAIFA

Clinical Study Protocol

2nd

amendment, 30.05.2011 Page 3 of 66

STUDY CONTACTS

Sponsor A. O. Fatebenefratelli e Oftalmico - Milano

Corso di Porta Nuova, 23

20121 Milano

Principal

Investigator

Alberto Scanni, MD

[email protected]

Coordinating

center

Laboratory of Clinical Trials

Istituto di Ricerche

Farmacologiche �Mario Negri�

Via La Masa, 19-20156 Milano

Tel: +39 02 390141

Fax: +39 02 33200231

Statistician Irene Floriani (final analysis)

Eliana Rulli (interim analysis)

Phone: +39 02 39014695

e-mail: [email protected]

Phone : +39 0239014645

e-mail : [email protected]

Data Manager Elena Copreni Phone: +39 02 39014641


Informatics Davide Poli Phone: +39 02 39014643


Local Monitor Elena Biagioli

Phone: +39 02 39014655


Safety desk Marlen Llerena Phone : + 39 02 39014638


Randomization and e-CRF

http://crc.marionegri.it/trials/tailor

mailto:[email protected]









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TAILORAIFA


2nd


SYNOPSIS

Title TAILORAIFA [TArceva Italian Lung Optimization tRial]

Optimization of erlotinib for the treatment of patients with advanced non-small cell

lung cancer: an Italian randomized trial

Sponsor A. O. Fatebenefratelli e Oftalmico � Milano

Clinical Phase III

Background Erlotinib is registered in all patients affected with NSCLC in second and subsequent

lines with a small benefit. Recent evidence suggest that it should be possible to

select patients according with clinical and biological features. Most of these proofs

are drawn from case series or post hoc analyses and not from properly planned

randomized clinical trials rendering their interpretation controversial. Recent data

suggest that EGFR determined with immunohistochemistry (IHC) or FISH are at the

present time not recommended because they do not reproducibly predict outcome.

Moreover, indirect evidence on subgroup analyses on randomized trial suggest that

chemotherapy might be superior to erlotinib in wild-type EGFR patients.

Study objectives

Primary

To compare the efficacy in terms of OS of erlotinib and docetaxel as second-line

treatment in NSCLC pts without exons 19 or 21 EGFR mutations

Secondary To compare:

Progression free survival

Response rate

Quality of life

To evaluate toxicity, graded according to the NCI-CTAE version 3.0, and the safety

profile, in terms of frequency and nature of serious adverse reactions, of each

treatment arm.

To prospectively assess the prognostic value of K-RAS mutations in patients treated

with a first line platinum containing regimen.

Sub-protocols Other secondary endpoints will be addressed with specific sub-protocols that will

require additional procedures and data. Such sub-protocols will regard the collection

of blood samples, in order to identify different prognosis-related polymorphisms and

to assess their sensitivity and specificity in the detection of EGFR and k-ras

mutations with respect to histological samples.

Study design This is an Italian, multicentre, randomized, open label, phase 3 superiority trial.

In order to define the appropriate population to be entered in the trial, the design is

planned according to three different phases, which follow the journey of patient

disease.

Phase 1: Registration and tissue banking

In this phase pts with NSCLC before or during first line platinum-based

chemotherapy as well as pts recurred after a first line adjuvant platinum-based

chemotherapy will be registered, providing the availability of material for molecular

analysis. Tumour specimens and blood samples will be collected to perform genomic

and immunohistochemical analyses in order to identify the molecular characteristics

of tumour

Phase 2: Randomization of second line therapies

At progression after first line treatment, pts with exons 19 or 21 EGFR mutations will

be electively treated with ERL and followed up, while pts without EGFR mutations will

be randomized to treatment consisting of:

erlotinib 150mg/day until disease progression or unacceptable toxicity developed


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TAILORAIFA


2nd


docetaxel 75 mg/m2 on day 1 every 21 days, (3-weekly schedule) or 35 mg/m

2

on day 1, 8 and 15 every 28 days (weekly schedule), until disease progression or

unacceptable toxicity developed

Phase 3: Clinical assessment and further treatments

During treatment and follow-up phases, clinical assessment of pts will be made on

regular basis, in order to collect the relevant data to compare safety and efficacy.

In case of further progression, all pts may receive a standardized third line therapy

with either pemetrexed, 500 mg/m2 on day 1 every 21 days supplemented by folic

acid and vitamin B12, or gemcitabine (1000 mg/m2 days 1, 8, 15 every 28 days)

or

vinorelbine (30 mg/m2

days 1, 8, 15 every 28 days) depending on the first line

treatment received until disease progression or unacceptable toxicity developed.

Number of patients 750-850 pts are needed to be registered in order to randomise the required number

of 220 pts.

Target population Pts with histologically or cytologically documented, locally advanced or metastatic

NSCLC in second line treatment or relapsed after adjuvant treatment.

Inclusion criteria

Exclusion criteria

Age 18 years or older

Histological or cytological confirmation of NSCLC (may be from initial diagnosis of

NSCLC or subsequent biopsy). Only patients with available tissue samples may be

included in the study

Absence of EGFR mutations of exons 19 or 21 (randomization)

Locally advanced or metastatic NSCLC, not amenable to curative surgery or

radiotherapy

One prior platinum-based at adequate doses and taxane-free regimen and anti

EGFR axis drug free. Platinum-based regimen containing other agents (i.e.

bevacizumab, ixapebilone, etc) not targeting the EGFR axis (i.e.

cetuximab) are allowed. Pts who initially presented with early stage disease but

subsequently progressed or recurred are eligible if they received full dose

platinum-based taxane-free adjuvant or neoadjuvant chemotherapy at full

cytotoxic doses or platinum therapy as part of a

chemotherapy/radiotherapy regimen. They will not be eligible if they have only

received platinum at a radio sensitizing dosage (prior surgery and/or localized

irradiation are allowed)

Measurable (uni-dimensional) disease by RECIST in a lesion not previously

irradiated or non-measurable disease

ECOG-PS 0-2

ANC greater than 1.5 x 109/L and platelets greater than 100 x 10

9/L

Bilirubin level either normal or <1.5xULN

AST (SGOT) and ALT (SGPT) <2.5xULN (≤5 x ULN if liver metastases are

present)

Serum creatinine <1.5xULN

Effective contraception for both, male and female pts, if the risk of conception

exists

Recovery from all acute toxicities of prior therapies

Provision of written informed consent to the analysis of biological markers

(registration)

Provision of written informed consent to enter the randomized part of the study

(randomization)

Prior therapy with an experimental agent whose primary mechanism of action is

inhibition of EGFR or its associated tyrosine kinase

Prior chemotherapy with taxanes

Newly diagnosed CNS metastases that have not yet been treated with surgery


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TAILORAIFA


2nd


and/or radiation. Pts with previously diagnosed and treated CNS metastases or

spinal cord compression may be considered if they have evidence of clinically SD

(no steroid therapy or steroid dose being tapered) for at least 28 days

Less than 14 days since completion of prior radiotherapy or persistence of any

radiotherapy related toxicity

Any unresolved chronic toxicity from previous anticancer therapy that, in the

opinion of the investigator, makes it inappropriate for the patient to be enrolled in

the study

Known severe hypersensitivity to erlotinib or any of the excipients of this product

Known hypersensitivity to docetaxel, polysorbate 80 or other drugs formulated

with polysorbate 80, or any of the excipients of docetaxel

Other co-existing malignancies or malignancies diagnosed within the last 5 years

with the exception of basal cell carcinoma or cervical cancer in situ

Unable to swallow tablets

Any evidence of clinically active interstitial lung disease (patients with chronic,

stable, radiographic changes who are asymptomatic or patients with

uncomplicated progressive lymphangitic carcinomatosis need not be excluded)

As judged by the investigator, any evidence of severe or uncontrolled systemic

disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic or renal

disease)

As judged by the investigator, any inflammatory changes of the surface of

the eye

Evidence of any other significant clinical disorder or laboratory finding

that makes it undesirable for the patient to participate in the study

Pregnancy

Breast feeding

Length of study This is an event driven study. The study will continue until 199 deaths have

occurred.

The patient accrual period is planned for approximately 48 months. To assess OS,

all pts will be followed for up to 12 months after the last patient is randomized.

Therefore the maximum estimated study duration will be approximately 60 months.

Treatment regimens

Second line therapy Pts with EGFR 19-21 mutations will receive:

erlotinib 150 mg/day until disease progression.

Pts without EGFR 19-21 mutations will be randomized to receive:

erlotinib 150 mg/day or

docetaxel 75 mg/m2 on day 1 every 21 days (3-weekly schedule) or 35 mg/m

2

on day 1, 8 and 15 every 28 days (weekly schedule)

until disease progression or unacceptable toxicity developed.

Third line therapy At further progression of disease, at discretion of the investigators pts will receive a

standardized third line therapy either with pemetrexed 500 mg/m2 on day 1 every

21 days, supplemented by folic acid and vitamin B12, or gemcitabine (1000 mg/m2

days 1, 8, 15 every 28 days) or vinorelbine (30 mg/m

2 days 1, 8, 15 every 28 days)

depending on the previous first line treatment administered. Treatment will continue


Patient assignment After registration only pts without 19-21 EGFR mutations and fulfilling all the

inclusion/exclusion criteria can be entered into the randomized part of the study.

Allocation to treatment will be centrally performed with 1:1 ratio using a biased-coin

minimization procedure having centre, stage (progressed vs. recurred), prior first

line chemotherapy (containing vinorelbine vs. containing gemcitabine vs.

containing pemetrexed vs. containing other drugs not targeting the EGFR axis),


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ECOG-PS (0-1 vs. 2) and adequacy of histological sample (optimal vs. suboptimal)

as stratification variables.

Pts with 19-21 EGFR mutations will be entered in the non randomized part of the

trial.

Endpoints

Efficacy

OS is defined as the time from the date of randomization to the date of death

from any cause. Subjects who were not reported as having died at the time of the

analysis will be censored at the date they were last known to be alive

PFS is defined as the time from the date of randomization up to the date of first

progression, second primary malignancy or death from any cause, whichever

comes first. Subjects who have not progressed or died while on study will be

censored at the last disease assessment date

Response will be assessed by RECIST

Quality of life will be assessed by QLQ-C30 and QLQ-LC13 questionnaires

Safety Toxicity, graded according to the NCI-CTAE version 3.0

Frequency and nature of serious adverse reactions

Premature withdrawals

Statistical method

Sample size

considerations

According to recently published data, it is reasonable to hypothesize that DOC may

reduce mortality by 33% (HR 0.67) with respect to ERL. This effect translates in an

increased probability of surviving at 1 year from 20% with ERL to 34% with DOC.

In order to detect with a 80% power such an effect at the significance level of 5%,

two-sided, 199 events must be observed overall.

Based on these assumptions, with a uniform accrual of 48 months, a minimum

follow-up for each patient of 12 months, a 5% lost to f-up pts, the total number of

required pts is approximately 220.

Statistical analysis Efficacy will be analysed on an intention-to-treat strategy, therefore all randomized

patients without major protocol violations will be included in the analysis according

to the randomization arm.

All patients who have received at least one dose of the trial medication and had at

least one safety follow-up, whether withdrawn prematurely or not, will be included in

the safety analysis. The safety parameters will be analyzed and presented according

to the therapy the patient received.

Major violations in the eligibility criteria and study conduction will be evaluated on a

case by case basis in a pre-analysis meeting in order to define the population to be

analysed.

CONSORT rules will be applied to describe study flow and protocol deviations.

All time to event curves will be drawn by the Kaplan-Meier method. All comparisons

between arms will be performed by long-rank test. Statistical significance of

difference will also be tested by a multivariable Cox�s model including stratification

variables and clinical-biological features as covariates. Results will be presented as

hazard ratios (HRs) and their 95% confidence intervals (95% CIs).


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ABBREVIATIONS

ADR Adverse drug reaction

AE Adverse event

ALT Alanine transferase

ANC Absolute neutrophil count

AST Aspartate aminotransferase

BAC Bronchioloalveolar carcinoma

BL Baseline

BSA Body surface area

CI Confidence interval

CNS Central nervous system

CR Complete response

CrCl Creatinine clearance

CRF Case report form

CSF Colony stimulating factor

CT Computed tomography

DCF Data clarification form

DOC Docetaxel

EC Ethics Committee

ECG Electrocardiogram

ECOG-PS Eastern Cooperative Oncology Group - performance status

EGFR Epidermal growth factor receptor

EGFR+ EGFR protein expression

EGFR- No EGFR protein expression

ERL Erlotinib

FISH Fluorescent in situ hybridisation

FISH+ High EGFR copy number

FISH- Low EGFR copy number

G-CSF Granulocite colony stimulating factor

GEF Gefitinib

GEM Gemcitabine

HR Hazard ratio

ICH International Conference on Harmonisation

IEC/IRB Ethics committee/institutional review board

IHC Immunohistochemical

ILD Interstitial lung disease

INR International normalised ratio

Im Intramuscular

Iv Intravenous

K-ras+ Presence of K-ras gene mutation


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K-ras- Absence of K-ras gene mutation

L Liter

LD Longest diameter

LDH Lactate dehydrogenase

NCIC-CTG National Cancer Institute of Canada Clinical Trials Group

NCI-CTCAE National Cancer Institute Common Toxicity Criteria for Adverse Events

NSAID Nonsteroidal anti-inflammatory drugs

NSCLC Non small cell lung cancer

OS Overall survival

PCR Polymerase chain reaction

PD Progressive disease

PEM Pemetrexed

PFS Progression free survival

Po Per os

PR Partial response

Pts Patients

QoL Quality of life

RECIST Response evaluation criteria in solid tumors

RR Response rate

SAE Serious adverse event

SD Stable disease

SNP Single nucleotide polymorphism

SUSAR

TNM

Suspected Unexpected Serious Adverse Reaction

Classification of malignant tumor

TKI Tyrosine kinase inhibitor

ULN Upper limit of normal

VNB Vinorelbine

WBC White blood cell


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CONTENTS

STUDY CONTACTS ...................................................................................................................... 3

SYNOPSIS .................................................................................................................................. 4

ABBREVIATIONS ........................................................................................................................ 8

1. BACKGROUND AND RATIONALE ........................................................................................... 14

1.1. Introduction .................................................................................................................... 14

1.1.1. Chemotherapy treatment .............................................................................................. 14 1.1.2. Erlotinib ...................................................................................................................... 14 1.2. Rationale of the study ...................................................................................................... 15

2. STUDY OBJECTIVES.............................................................................................................. 17

2.1. Primary .......................................................................................................................... 17

2.2. Secondary ...................................................................................................................... 17

3. STUDY DESIGN ..................................................................................................................... 17

3.1. Overview of study design .................................................................................................. 17

3.2. Number of centers ........................................................................................................... 18

3.3. Number of patients .......................................................................................................... 18

3.4. Study duration ................................................................................................................ 18

4. PATIENT SELECTION CRITERIA ............................................................................................ 19

4.1. Target population ............................................................................................................ 19

4.2. Inclusion criteria .............................................................................................................. 19

4.3. Exclusion criteria ............................................................................................................. 20

5. PATIENT ENROLLMENT ........................................................................................................ 21

5.1. Registration .................................................................................................................... 21

5.2. Randomization ................................................................................................................ 21

6. TREATMENT PLAN ................................................................................................................ 22

6.1. Body surface area calculation ............................................................................................ 22

6.2. Erlotinib administration .................................................................................................... 22

6.3. Erlotinib dose adjustments ................................................................................................ 23

6.3.1. Erlotinib dose adjustments due to diarrhoea .................................................................... 23 6.3.2. Erlotinib dose adjustments due to rash ........................................................................... 24 6.4. Erlotinib administration warnings and precautions ............................................................... 25

6.5. Ophthalmologic disorders caused by erlotinib ...................................................................... 25

6.6. Interstitial lung disease-like events caused by erlotinib ........................................................ 26

6.7. Docetaxel administration .................................................................................................. 26


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6.8. Docetaxel dose adjustments ............................................................................................. 26

6.8.1. Docetaxel dose adjustments due to haematological toxicity ............................................... 26 6.8.2. Docetaxel dose adjustments due to non haematological toxicity ........................................ 27 6.9. Pemetrexed administration ............................................................................................... 28

6.10. Pemetrexed dose adjustments .......................................................................................... 29

6.10.1. Pemetrexed dose adjustments due to haematological toxicity ........................................... 29 6.10.2. Pemetrexed dose adjustments due to non haematological toxicity ..................................... 29 6.11. Pemetrexed treatment delays due to insufficient folic acid or vitamin B12 supplementation ...... 30

6.12. Vinorelbine administration ................................................................................................ 30

6.13. Vinorelbine dose adjustments............................................................................................ 31

6.13.1. Vinorelbine dose adjustments due to haematological toxicity ............................................. 31 6.13.2. Vinorelbine dose adjustments due to non haematological toxicity ....................................... 31 6.14. Gemcitabine administration .............................................................................................. 32

6.15. Gemcitabine dose adjustments .......................................................................................... 32

6.15.1. Gemcitabine dose adjustments due to haematological toxicity .......................................... 32 6.16. Concomitant therapies ..................................................................................................... 33

7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP .......................................... 34

7.1. Registration .................................................................................................................... 34

7.1.1. Patients with a new diagnosis of NSCLC .......................................................................... 34 7.1.2. Patients relapsed or progressed after first line treatment .................................................. 35 7.2. Before randomization ....................................................................................................... 35

7.3. During second line treatment ........................................................................................... 37

7.3.1. Pts with 19-21 EGFR mutations ..................................................................................... 37 7.3.2. Erlotinib arm ............................................................................................................... 37 7.3.3. 3-weekly docetaxel ...................................................................................................... 39 7.3.4. Weekly docetaxel ......................................................................................................... 40 7.4. During third line treatment ............................................................................................... 42

7.5. During follow-up .............................................................................................................. 44

8. BIOLOGICAL EVALUATION ................................................................................................... 45

8.1. Specimen handling .......................................................................................................... 45

8.1.1. Patients entering the study at diagnosis .......................................................................... 45 8.1.2. Patients entering the study at relapse ............................................................................. 46 8.2. Minimal criteria for inclusion in the study ............................................................................ 47

8.2.1. Histological specimens .................................................................................................. 47 8.2.2. Cytological specimens .................................................................................................. 47 8.3. Analysis performed on tissues ........................................................................................... 48

8.3.1. Determination of mutational status of EGFR and K-ras genes ............................................ 48 8.3.2. Immunohistochemistry for p-AKT, DDR1, FGFR ............................................................... 49 8.3.3. Copy number determination of c-MET and FGFR1 genes ................................................... 49 8.3.4. EML4-ALK translocation ................................................................................................ 49 8.3.5. Analysis performed on blood ......................................................................................... 50


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9. ASSESSMENT OF RESPONSE ................................................................................................. 51

9.1. Definition of measurable and non-measurable ..................................................................... 51

9.2. Baseline documentation of �target� and �non-target� lesions ................................................. 52

9.3. Evaluation of best overall response .................................................................................... 52

9.4. Confirmation and review of response ................................................................................. 53

9.5. Reporting of results ......................................................................................................... 53

10. QOL ASSESSMENT .............................................................................................................. 53

10.1. Operative Procedures ....................................................................................................... 54

10.2. QoL timing ...................................................................................................................... 54

11. REMOVAL AND REPLACEMENT OF PATIENTS ...................................................................... 54

11.1. Replacement of patients ................................................................................................... 55

12. REGISTRATION/RANDOMIZATION PROCEDURE ................................................................ 55

12.1. Registration .................................................................................................................... 55

12.2. Randomization ................................................................................................................ 55

13. SAFETY DATA COLLECTION, RECORDING AND REPORTING ................................................ 56

13.1. Definitions ...................................................................................................................... 56

13.1.1. Adverse event ............................................................................................................. 56 13.1.2. Serious adverse event .................................................................................................. 56 13.2. Reporting of procedures for all adverse events .................................................................... 58

13.3. Serious adverse event reporting procedures ........................................................................ 59

14. STATISTICAL CONSIDERATIONS ........................................................................................ 59

14.1. Definition of endpoints ..................................................................................................... 59

14.1.1. Efficacy/activity ........................................................................................................... 59 14.1.2. Safety ........................................................................................................................ 60 14.2. Sample size .................................................................................................................... 60

14.3. Efficacy analyses ............................................................................................................. 60

14.4. Response rate ................................................................................................................. 61

14.5. Safety analyses ............................................................................................................... 61

14.6. Quality of life .................................................................................................................. 61

14.7. Interim analyses .............................................................................................................. 62

15. INDEPENDENT DATA & SAFETY MONITORING COMMITTEE ................................................ 63

16. DATA COLLECTING AND MONITORING ............................................................................... 63

17. ETHICS AND GOOD CLINICAL PRACTICE ............................................................................ 63

17.1. Patient protection ............................................................................................................ 64

17.2. Informed consent ............................................................................................................ 64

18. TRIAL SPONSORSHIP AND FINANCING .............................................................................. 64


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19. PUBLICATION POLICY ........................................................................................................ 65

20. REFERENCES ...................................................................................................................... 65


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1. BACKGROUND AND RATIONALE

1.1. Introduction

Non small cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide and the

development of more effective therapies remains challenging. Approximately 70% of NSCLC patients

(pts) presents with advanced (stage IIIb-IV) disease [1]. Despite the recent therapeutic progress the

median survival of advanced disease rarely exceeds 8 months and less than 30% of pts is still alive at

one year. Also the prognosis of those pts previously treated with curative intent remains poor and more

than 60% of them recurres. Approximately 60% of pts can receive a second line treatment, but disease

control is limited and median time to progression is less than 3 months.

1.1.1. Chemotherapy treatment

The chemotherapy most common regimens for naïve pts consist of platinum agents (cisplatin or

carboplatin) combined with gemcitabine (GEM), paclitaxel, docetaxel (DOC) or vinorelbine (VNB) and with

similar, although modest, efficacy [2]. Second line chemotherapy has demonstrated only modest

improvement in overall survival (OS) over best supportive care. At present, drugs approved as second

line include DOC, pemetrexed (PEM) and erlotinib (ERL). DOC [3] is the most extensively investigated

drug and demonstrated objective tumour response rate (RR) ranging from 14% to 22% and a median

survival ranging from 7 months to 11 months. Moreover, "3-weekly" (75 mg/m2) and "weekly" (35 mg/

m2) schedules seem to be equivalent [4] with different toxicity and quality of life (QoL) in some items.

Single agent PEM showed a RR of 8.9% to 23% and a median OS ranging between 5.7 months and 10

months. DOC and PEM resulted in clinically equivalent efficacy, but different toxicity profile. The

progression free survival (PFS) was 2.9 months for both treatments, whereas OS was 7.9 and 8.3,

respectively [5].

1.1.2. Erlotinib

The development of agents that target the epidermal growth factor receptor (EGFR) signal transduction

pathways has provided a novel class of therapeutic agents. ERL, an orally active, selective EGFR tyrosine

kinase inhibitor (TKI) recently approved in NSCLC pre-treated pts and gefitinib (GEF) are the most

studied agents of this class of compounds. The use of single agent ERL after failure with chemotherapy is

supported by the results of a recently completed phase 3 study (BR.21), an international trial conducted

by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). The RR was 8.9% in the ERL

group and less than 1% in the placebo group (p<0.001); respectively. Median PFS were 2.2 months and

1.8 months [Hazard Ratio (HR): 0.61, p<0.001] while median OS were 6.7 months and 4.7 months,

respectively (HR: 0.70; p<0.001), in favour of ERL. Five percent of pts interrupted for unexpected

toxicity. Subgroups analysis showed that the magnitude of the benefit was higher in females, in

adenocarcinomas, in never smokers and Asiatic ethnicity [6].

If the use of single agent ERL after failure of at least one prior chemotherapy regimen has been

demonstrated, TALENT [7] and TRIBUTE [8] trials failed to demonstrate any benefit in adding ERL to

chemotherapy in NSCLC pts.


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Results of a large trial comparing GEF and DOC have been recently presented [9]. The study was

designed as a non-inferiority trial in terms of OS between the two arms and was emended following the

emergence of biomarkers data, in order to find a superiority in pts with high EGFR copy number (FISH+).

Final results showed a non inferiority of GEF against DOC in terms of OS (7.6 vs. 8.0 months, HR: 1.02,

95% confidence interval (95% CI) 0.90-1.15) and PFS (HR: 1.4, 95% CI 0.93-1.18). Superiority of GEF

was not detected in FISH+ pts (HR 1.09, 95% CI 0.78-1.51).

1.2. Rationale of the study

In the period between 2008 and 2011, several evidence appeared in published paper or presented

abstract changing the previous scenario that was the basis of the first design of the TAILOR trial.

One large phase III trial, the Iressa Pan-Asia Study [IPASS] trial [10,11], three smaller phase III

randomized controlled trials [12-14] using PFS as the primary endpoint, and one small phase III trial with

OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis

of the recent ASCO Provisional Clinical Option (PCO) [15]. This PCO is authoritatively offering clinical

direction and potentially practice-changing data from major studies. First statement is that on the basis

of five phase III RCTs, patients with advanced NSCLC of the lung who are being considered for first-line

therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI)

should have their tumour tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy

is the appropriate first-line therapy. Despite this PCO is limited to mutation testing, it is commenting that

at present FISH and IHC testing for EGFR at the present time are not recommended because the do not

reproducibly predict outcome.

While the situation of EGFR mutated patients appears clear, also if OS results are negative as result of

the cross-over treatment, it is of crucial importance to understand whether patients with wild type tumors

should be treated at relapse or progression with an anti EGFR drug or with chemotherapy.

Surprising is the information on the TKIs performance in wt EGFR patients reported in the four most

recently published trials [10, 16-18]. The molecularly profiled fraction is ranging only from 10 to 38% of

the randomized population, as shown in the table below, and only post-hoc analyses are done. Although

driving inferences from such a low percentage of the enrolled population can carry a high risk of a

selection bias, several considerations can be made by scrutinizing those data.

Data on PFS were reported by two studies, both suggesting a superiority of chemotherapy, although with

a statistically significant result only in the IPASS trial [10]. OS was reported in three trials with

inconsistent, not statistically significant results. However, the presence of unplanned cross-over

treatments at progression makes these results misleading.

In conclusion, while several papers describe in depth the right approach in the 10% represented by the

mutated population, it continues to remain unclear how to manage the remaining majority of patients at

relapse or progression. However, considering the above mentioned methodological limits, the available

evidence seems to suggest a superiority of chemotherapy on TKIs.

Moreover, in this period a consistent literature appeared also on possible mechanisms of primary or

acquired resistance to TKIs. In particular K-ras seems more a prognostic factor than a negative factor,


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instead the presence of c-met amplification, T790 mutation, Her 2 mutation, BRAF mutation, PIK3CA,

AKT1, MAP2K1 mutation, IGFR1 overexpression and EML4/ALK translocation seem to confer resistance to

ERL and gefitinib [19, 20]. These gene alteration are generally mutually exclusive on the principle of

oncogene addiction. Moreover, it seems that squamocellular histology is more resistant to TKIs than

others and our original hypothesis is that in this process two driver mutations, FGFR1 and DDR1 might be


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implicated. It is important also to underline also that all these mutations are �druggable�, this means that

understanding the résistance mechanisms to TKIs is not only important to exclude patients from a

treatment, but it may open a new scenario of therapies for these patients.

2. STUDY OBJECTIVES

2.1. Primary

The primary aim of the study is to to compare the efficacy in terms of OS of ERL and DOC as second-line

treatment in NSCLC pts without exon 19 or 21 EGFR mutations.

2.2. Secondary

To compare:

- Progression free survival (PFS)

- Response rate (RR, see section 14.1.1 for definition)

- Quality of life (QoL).

To provide insights on the prevalence of biological markers, their inter-correlation and their association

with basic clinical variables (histotype, gender, age, smoking habit).

To evaluate toxicity, graded according to the NCI-CTAE version 3.0, and the safety profile, in terms of

frequency and nature of serious adverse reactions, of each treatment arm.

To improve the knowledge on the resistance mechanisms to TKIs.

To prospectively assess the prognostic value of K-RAS mutations in patients treated with a first line

platinum containing regimen.

Other secondary analyses, such as collection of blood samples, in order to identify different prognosis-

related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and k-ras

mutations with respect to histological samples, will be addressed with specific sub protocols that will

require additional procedures and data.

3. STUDY DESIGN

3.1. Overview of study design

This is an Italian, multicentre, randomized, open label, phase 3 superiority trial. In order to define the

appropriate population to be entered in the trial, the design is planned according to three different

phases, which follow the journey of patient disease.

Phase 1: Registration and tissue banking

In this phase pts with NSCLC before or during first line platinum-based taxane free chemotherapy as well

as pts recurred after a first line adjuvant platinum-based taxane free chemotherapy will be registered,

providing the availability of material for molecular analysis. Tumour specimens and blood sample will be


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collected to perform genomic, ICH and proteomic analyses in order to identify the molecular

characteristics of tumour.

Phase 2: Randomization of second line therapies

At progression after first line treatment, pts with EGFR mutations of exons 19 or 21 will be electively

treated with ERL and followed up, while pts without EGFR mutations will be randomized to treatment

consisting of:

erlotinib 150 mg/day


2 on day 1, 8 and 15

every 28 days (weekly schedule)


Allocation to treatment will be centrally performed with 1:1 ratio using a biased-coin minimization

procedure having centre, stage (progressed vs. recurred), prior first line chemotherapy (containing VNB

vs. containing GEM vs. containing PEM vs. containing other drugs not targeting the EGFR axis), adequacy

of histological sample (optimal vs. sub-optimal), ECOG PS (0-1 vs. 2), as stratification variables.

Access to random system will be allowed by phone or via web.

Phase 3: Clinical assessment and further treatments

During treatment and follow-up phase clinical assessment of pts will be made on regular basis, in order to

collect the relevant data to compare safety and efficacy. The study endpoints are defined in section 14.1.

In case of further progression, pts treated with a platinum-based first line chemotherapy with VNB or

GEM will receive a standardized third line therapy with PEM, 500 mg/m2 on day 1 every 21 days

supplemented by folic acid and vitamin B12, while pts treated with a platinum-based first line

chemotherapy with PEM will receive either GEM (1000 mg/m2 days 1, 8, 15 every 28 days)

or VNB (30

mg/m2

days 1, 8, 15 every 28 days) until disease progression or unacceptable toxicity developed.

3.2. Number of centers

Approximately 100 Italian centres will participate in this study.

3.3. Number of patients

750-850 pts needed to be registered in order to randomise the required number of 220 pts. Please refer

to section 14.2 for justification of sample size.

3.4. Study duration

This is an event driven study. The study will continue until 199 deaths have occurred.


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The patient accrual period is planned for approximately 48 months. To assess OS, all pts will be followed

for up to 12 months after the last patient is randomized. The maximum estimated study duration is

approximately 60 months.

STUDY FLOW-CHART

4. PATIENT SELECTION CRITERIA

4.1. Target population

Pts with histologically documented, locally advanced or metastatic NSCLC in second line treatment or

recurred or relapsed after adjuvant treatment.

4.2. Inclusion criteria

For inclusion in the study, pts must fulfil all of the following criteria:

Age 18 years or older

REGISTRATION AND TISSUE SECOND LINE TREATMENT THIRD LINE THERAPY

POSITIVITY

for EGFR 19-21 mutations

NEGATIVITY

for EGFR 19-21 mutations

erlotinib 150 mg po, daily dose

R

docetaxel 75mg/m2 iv on day 1

every 21 days or docetaxel

35mg/m2 iv on days 1,8,15 every

28 days until disease

progression or unacceptable

toxicity developed.

erlotinib 150 mg po,

daily dose

P

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G

R

E

S

S

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N

PEM 500mg/m2 on day 1 every

21 days, supplemented by folinic

acid and vitamin B12 or

VNB 30 mg/m2 days 1, 8, 15,

every 28 days or

GEM 1000 mg/m2 days 1, 8, 15,

every 28 days

if judged by the investigator,

until disease progression or

unacceptable toxicity developed

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G

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S

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N

TARGET POPULATION

Pts with histologically or

cytologically documented,

locally advanced or metastatic

or recurred/relapsed after

adjuvant treatment NSCLC

previously treated with

platinum based taxan free

regimens

RANDOMIZATION

With a 1 : 1 ratio using a biased-

coin minimization procedure

having

- centre

- stage (relapsed vs. progressed)

- prior chemotherapy (GEM vs.

VNB vs. PEM vs. others)

- ECOG-PS (0-1 vs. 2)

- Adequacy of histological sample

(yes vs. no)

as stratification factors

PRIMARY ENDPOINT

overall survival

SECONDARY ENDPOINTS

Progression free survival

Toxicity and safety

Response rate

Quality of life


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Histological or cytological confirmation of NSCLC (may be from initial diagnosis of NSCLC or

subsequent biopsy). Only patients with available tissue samples may be included in the study (see

major details in section 8 for the minimum sample characteristics)

Absence of EGFR mutations of exons 19 or 21 (randomization)

Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy

One prior platinum-based at adequate doses and taxane-free regimen and anti EGFR axis drug free.

Platinum-based regimen containing other agents (i.e. bevacizumab, ixapebilone etc) not targeting the

EGFR axis (i.e. cetuximab) are allowed. Pts who initially presented with early stage disease but

subsequently progressed or recurred are eligible if they received full dose platinum-based taxane free

adjuvant or neoadjuvant chemotherapy at full cytotoxic doses or platinum therapy as part of a

chemotherapy/radiotherapy regimen. They will not be eligible if they have only received platinum at a

radio sensitizing dosage (prior surgery and/or localized irradiation are allowed)

Measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) in a lesion not

previously irradiated or non-measurable disease

Eastern Cooperative Oncology Group - performance status (ECOG-PS) 0-2

Absolute neutrophil count (ANC) > 1.5 x 109/liter (L) and platelets > 100 x 10

9/L

Bilirubin level either normal or <1.5 x ULN

AST (SGOT) and ALT (SGPT) <2.5 x ULN (≤ 5 x ULN if liver metastases are present)

Serum creatinine <1.5 x ULN

Effective contraception for both, male and female pts, if the risk of conception exists

Recovery from all acute toxicities of prior therapies

Provision of written informed consent to the analysis of biological markers (registration)

Provision of written informed consent to enter the randomized part of the study (randomization)

4.3. Exclusion criteria

Any of the following is regarded as a criterion for exclusion from the study:

Prior therapy with an experimental agent whose primary mechanism of action is inhibition of EGFR or

its associated tyrosine kinase

Prior therapy with taxanes

Newly diagnosed central nervous system (CNS) metastases that have not yet been treated with

surgery and/or radiation. Pts with previously diagnosed and treated CNS metastases or spinal cord

compression may be considered if they have evidence of clinically stable disease (SD) (no steroid

therapy or steroid dose being tapered) for at least 28 days

Less than 14 days since completion of prior radiotherapy or persistence of any radiotherapy related

toxicity

Any unresolved chronic toxicity from previous anticancer therapy that, in the opinion of the

investigator, makes it inappropriate for the patient to be enrolled in the study


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Known severe hypersensitivity to erlotinib or any of the excipients of this product

Known hypersensitivity to DOC, polysorbate 80 or other drugs formulated with polysorbate 80, or any

of the excipients of DOC

Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception

of basal cell carcinoma or cervical cancer in situ

Unable to swallow tablets

Any evidence of clinically active interstitial lung disease (ILD) (patients with chronic, stable,

radiographic changes who are asymptomatic or patients with uncomplicated progressive lymphangitic

carcinomatosis need not be excluded)

As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g.,

unstable or uncompensated respiratory, cardiac, hepatic or renal disease)

As judged by the investigator, any inflammatory changes of the surface of the eye

Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for

the patient to participate in the study

Pregnancy

Breast feeding

5. PATIENT ENROLLMENT

Patient enrollment can be done in two steps: registration and randomization.

5.1. Registration

Pts with a recent diagnosis of NSCLC, as well as those relapsed after surgery or from the end of adjuvant

treatment can be registered, in order to provide tissue specimens and to allow EGFR and K-ras mutation

detection. All pts with a new diagnosis of locally advanced or metastatic NSCLC should preferentially be

registered at this time in order to allow all the biological evaluations.

Before registration eligible pts must provide his/her informed consent to the analysis of biological

markers.

An eligibility screening form documenting the patient fulfilment of the eligibility criteria is to be completed

by the investigator before registration.

5.2. Randomization

After registration only pts without 19-21 EGFR mutations and fulfilling all the inclusion/exclusion criteria

can be entered into the randomized part of the study. Pts with 19-21 EGFR mutations will be entered in

the non randomized part of the trial.

Before randomization eligible patients must provide his/her informed consent to participate.


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6. TREATMENT PLAN

As second line therapy, pts with EGFR 19-21 mutations will receive erlotinib 150 mg/day until disease

progression or unacceptable toxicity developed, while pts without EGFR 19-21 mutations will be

randomized to receive:

erlotinib 150 mg/day

or


2 on day 1, 8 and 15

every 28 days (weekly schedule),


At further progression of disease, at discretion of the investigators pts will receive a standardized third

line therapy with PEM, 500 mg/m2 on day 1 every 21 days, supplemented by folic acid and vitamin B12,

until disease progression or unacceptable toxicity developed, while pts treated as first line with platinum-

based chemotherapy with PEM will receive either GEM (1000 mg/m2 days 1, 8, 15 every 28 days)

or VNB

(30 mg/m2

days 1, 8, 15 every 28 days), until disease progression or unacceptable toxicity developed.

6.1. Body surface area calculation

The actual dose of DOC and PEM to be administered, will be determined by calculating the body surface

area (BSA) at the beginning of each cycle, this principle applies to individuals whose calculated surface

area is 2.2 m2 or less. In those rare cases where a patient surface area is greater than 2.2, the actual

surface area or 2.2 may be used.

6.2. Erlotinib administration

ERL will be administered at the starting dose of 150 mg/day. ERL is to be taken, preferably in the

morning, with up to 200 ml of water. On visit days, study drug will be taken in the clinic as instructed by

the study nurse or the investigator. Drug should be taken at least 1 hour before or 2 hours after the

ingestion of any food or other medication.

Pts who are unable to swallow tablets may grind the tablets provided that the tablet powder (after

grinding) is collected quantitatively (by e.g. grinding in a mortar and collecting the whole powder) for

administration. This powder can then be mixed with marmalade or jelly (in order to mask the taste).

ERL will be administered on an outpatient basis. Doses should be taken at the same time each day.

If the patient vomits after taking the tablets, the dose is replaced only if the tablets can actually be seen

and counted.

If a patient misses a dose normally taken in the morning, the patient may take the dose any time during

the same day. However the missed dose should not be taken on a subsequent day. Pts will be instructed

to notify study site personnel of missed doses.


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ADMINISTRATION OF ERLOTINIB

Drug Dose Time

Erlotinib 150 mg per os (po), daily

dose

Daily dose should be taken in the morning at least 1 hour before or 2

hours after the ingestion of any food or other medication

6.3. Erlotinib dose adjustments

Interruption and/or reduction of dosing for adverse events (AEs) may take place at any time during the

study. In the event of any non�dose-limiting toxicity that is not controlled by optimal supportive care, or

not tolerated due to symptomatology, disfigurement, or interference with normal daily activities,

regardless of severity, the daily dose of ERL will be decreased according to the schedule displayed below.

ERLOTINIB DOSE LEVEL REDUCTIONS

Starting dose Dose at first reduction Dose at second reduction

150 mg 100 mg 50 mg

Within 2 weeks following a dose reduction, ERL related toxicity must improve by at least one National

Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) grade and be NCI-CTCAE

grade ≤2, or further dose reduction by one level will be required. Dosing may be interrupted for a

maximum of 2 weeks, if clinically indicated and if the toxicity is not controlled by optimal supportive

medication. Once a patient has had a dose reduction for toxicity, the dose will not be re-escalated except

in the case of ERL related rash. In the event of a rash, dose can be re-escalated when rash is ≤ grade 2.

6.3.1. Erlotinib dose adjustments due to diarrhoea

Diarrhoea occurres in around 50% of pts, who receive ERL, is usually transient and, in most cases, can

be managed with loperamide. The recommended regimen is 4 mg loperamide at onset of symptoms,

followed by 2 mg every 2�4 hours, until the patient has remained free from diarrhoea for 12 hours. Pts

with diarrhoea that are unresponsive to loperamide, or those with associated dehydration, may require

dose reduction or interruption. Appropriate rehydration should be provided (particularly important for

elderly pts, who can rapidly become dehydrated, even with mild diarrhoea).

GUIDELINES FOR MANAGEMENT OF ERLOTINIB RELATED DIARRHOEA

Grade Study drug dosage

modification

Guideline for management

Grade 1 None Consider loperamide (4 mg at first onset, followed by 2 mg every 2-4 hours

until diarrhoea free for 12 hours) and appropriate rehydration

Grade 2 Interrupt Loperamide (4 mg at first onset, followed by 2 mg every 2-4 hours until

diarrhoea free for 12 hours) and appropriate rehydration

Grade 3 Interrupt Interrupt and give appropriate reyhdration, monitor electrolyte balance and

renal function until resolution to grade ≤ 1; restart at reduced dose

Grade 4 Discontinue study


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6.3.2. Erlotinib dose adjustments due to rash

A patient may develop several kinds of dermatological events (including rash) while being treated with

ERL. It is important to recognise that the rash typically seen during treatment with ERL is pathologically

and aetiologically distinct from acne (including steroid-induced acne) and therefore should be managed

differently. In clinical trials, rash was the most common side effect reported with ERL, in about 75% of

pts. Typically, the rash develops about 7�10 days after the start of treatment, and affects skin areas

above the waist. In most pts, the rash is mild (grade 1 or 2). For example, in the pivotal phase III trial

(BR.21), only 8% of pts had grade 3 rash, and less than 1% had grade 4 rash [6]. Mild or moderate rash

may be managed using topical emollients and corticosteroids, but in a few pts, the rash may be severe

enough to warrant dose reduction or withdrawal. There are also many reports of rash resolving

spontaneously (without treatment) and reappearing later (during the same treatment regimen).

Management of rash without secondary infections:

Consider using topical corticosteroids early in pts with mild rash (e.g. clobetasol propionate)

Analgesics may be of benefit: consider using before reducing the dose of ERL

Topical retinoids and other acne medications (e.g. benzoyl peroxide) are NOT recommended; their

skin-drying effects may exacerbate the rash

Evaluate treatment effectiveness after 1 week and continue for another week; discontinue if no

improvement after 2 weeks

Use topical agents cautiously, especially for severe rash: efficacy may be restricted if penetration of

deep layers of skin is poor

Systemic agents should be used with care as they may adversely affect beneficial processes in the

tumour

Consider using intranasal mupirocin applied once daily to each nostril to prevent secondary infection.

Management of rash with secondary infections:

Consider using topical antibiotics such as clindamycin

Short course of oral antibiotics; consider tetracyclines for their weak anti-inflammatory effects

If staphylococcus aureus infection is confirmed, or impetigo is diagnosed, consider topical mupirocin

If antibiotic resistance is suspected, culture to determine the infective bacterial strain and treat

accordingly.

GUIDELINES FOR MANAGEMENT OF ERLOTINIB RELATED RASH

Grade Study drug dosage modification

Grade 1 None

Grade 2 None

Grade 3 Dose reduction; dose can be re-escalated when rash is grade 2

Grade 4 Discontinue study


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Pts who require an interruption in dosing of >2 weeks (due to any ERL related AE not manageable with

optimal supportive medication) will discontinue ERL treatment and be taken off study. The reasons for

missed doses or ERL discontinuation must be recorded on the case report form (CRF).

Pts for whom ERL therapy is interrupted for <2 weeks for reasons other than ERL related AEs may restart

ERL therapy if the investigator agrees it is in the best interest of the patient to re-challenge and the

patient meets the following criteria to restart ERL therapy:

ECOG-PS must be 0�1, AND

ocular toxicity must improve to NCI-CTCAE Grade ≤ 1 (if appropriate).

6.4. Erlotinib administration warnings and precautions

ERL is protein bound (92% to 95% in humans) and metabolized by hepatic cytochromes CYP3A4 and

CYP1A2 and pulmonary cytochrome CYP1A1. Therefore, a potential for drug-drug interaction exists when

ERL is co-administered with drugs that are highly protein bound or that are CYP3A4 or CYP1A2

inhibitors/inducers. Substances that are potent inhibitors of CYP3A4 activity (e.g., ketoconazole)

decrease ERL metabolism and increase ERL plasma concentrations. This increase may be clinically

relevant as adverse experiences are related to dose and exposure. Therefore, for this study, caution

should be used when administering CYP3A4 inhibitors to patients who are on study drug.

Substances that are potent inducers of CYP3A4 activity (e.g., rifampin, phenytoin) increase ERL

metabolism and significantly decrease ERL plasma concentrations. This decrease in exposure may be

clinically relevant, as preclinical studies suggest that higher concentrations are more efficacious in vivo

animal tumour models. However, the relationship between exposure and efficacy in cancer pts has not

been adequately studied. Therefore, for this study, caution should be used when administering CYP3A4

inducers to pts who are on study drug. International normalised ratio (INR) elevations and/or bleeding

events have been reported in some cancer pts taking warfarin while on ERL. During this study, pts taking

warfarin or other coumarin-derived anticoagulants should be monitored as clinically indicated for changes

in prothrombin time or INR.

6.5. Ophthalmologic disorders caused by erlotinib

Based on results of Phase I studies in normal volunteers and the toxicological results in dogs dosed at 50

mg/kg/day, frequent ophthalmologic examinations were included in initial Phase I and II studies. Based

on the clinical experience to date and the rarity of significant ophthalmologic findings, these examinations

have been reduced or eliminated in more recent studies unless clinically indicated for ocular symptoms.

Infrequent occurrences of conjunctivitis and keratitis with associated facial rash have been observed

during ERL treatment. Isolated reports of corneal ulceration, uveitis, and orbital cellulites have been

reported in pts receiving ERL therapy, mostly as complications of mucocutaneous inflammation. However,

pts developing eye symptoms should promptly undergo ophthalmologic examination.


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6.6. Interstitial lung disease-like events caused by erlotinib

In the event of acute onset of new or progressive, unexplained pulmonary symptoms such as dyspnoea,

cough, and fever, ERL therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed,

ERL should be discontinued and appropriate treatment and close follow-up instituted as necessary.

6.7. Docetaxel administration

ADMINISTRATION OF 3-WEEKLY SCHEDULE DOCETAXEL

Drug Dose Time

Docetaxel 75 mg/m2 intravenous (iv) infusion Administered in either 0.9% sodium chloride or 5% dextrose

solution (the final concentration should be between 0.3 and 0.74

mg/mL), over 1 hour on day 1 every 21 days, until disease

progression or unacceptable toxicity developed.

Dexamethasone 8 mg iv or intramuscular (im),

every 12 hour or equivalent regimen

(-24, -12, 0, +12, +24, +36)

For 3 days starting the day before to each dose of DOC, unless

clinical contraindications exist, to reduce the severity of fluid

retention and hypersensitivity reactions

ADMINISTRATION OF WEEKLY SCHEDULE DOCETAXEL

Drug Dose Time

Docetaxel 35 mg/m2 iv infusion

Administered in either 0.9% sodium chloride or 5% dextrose

solution (the final concentration should be between 0.3 and

0.74 mg/mL), over 1 hour on day 1, 8, 15 every 28 days, until

disease progression or unacceptable toxicity developed.

Dexamethasone 8 mg iv or im, every 12 hours or

equivalent regimen (-12, 0, +12)

For 3 times starting 12 hours before to each dose of DOC,

unless clinical contraindications exist, to reduce the severity of

fluid retention and hypersensitivity reactions

6.8. Docetaxel dose adjustments

Any patient who requires a DOC dose reduction will continue to receive a reduced dose for the remainder

of the study. Any patient with two prior dose reductions who experiences a toxicity that would cause a

third dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42

days from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related

toxicity. A patient who cannot be administered study drug for 42 days from the time of last treatment

must be discontinued from study therapy unless continuation is approved by study coordinator.

6.8.1. Docetaxel dose adjustments due to haematological toxicity

6.8.1.1. 3-weekly schedule

Dose adjustments at the start of a subsequent course of therapy will be based on platelet and neutrophil

ANC nadir (lowest value) counts from the preceding cycle of therapy. ANC must be >1.5 x 109/L and

platelets >100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow time for

recovery. Upon recovery, if treatment is resumed, it must be according to the guidelines reported in the

table below.


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ADJUSTMENTS OF 3-WEEKLY SCHEDULE DOCETAXEL DOSE FOR HAEMATOLOGICAL TOXIC EFFECTS

Platelets ( 109/L) Nadir ANC ( 10

9/L) Nadir Percent of Previous Dose

≥25 And ≥0.5 100%

≥25 And <0.5 for <7 days AND no fever 100%

≥25 And <0.5 for >7 days OR fever 75%

<25 And 0.5 75%

<25 And <0.5 for <7 days AND no fever 75%

<25 And <0.5 for >7 days OR fever 50%

6.8.1.2. Weekly schedule

It is possible only one dose reduction from 35 to 30 mg/m2 to discretion of physician, the start of a

subsequent course of therapy will be based on platelet and neutrophil value: ANC must be >1.5 x 109/L

and platelets >100 x 109/L prior to the start of any dose, in absence of other toxicity of grade 2, 3 or 4

(excluding alopecia). Treatment may be delayed for up to 42 days from day 1 of the current cycle to

allow a patient sufficient time to recover from study drug-related toxicity. A patient who cannot be

administered study drug for 42 days from the time of last treatment must be discontinued from study

therapy unless continuation is approved by study coordinator.

6.8.2. Docetaxel dose adjustments due to non haematological toxicity

6.8.2.1. 3-weekly schedule

For most grade 3 or 4 non haematological toxicities, including severe or cumulative cutaneous reactions,

but excluding grade 3 nausea or vomiting, treatment should be delayed until resolution of toxicity to the

patient�s original baseline grade. Treatment should resume at 75% of the previous dose level if deemed

appropriate by the treating physician [Do not forget to report any inpatient hospitalization as a serious

adverse event (SAE)]. If after two dose reductions, the patient still experiences grade 3 or 4 non

haematological toxicity (excluding grade 3 nausea and vomiting), discontinue the patient from study

therapy. Discontinue the patient if grade 4 vomiting occurs despite antiemetics and 2 dose reductions.

Exceptions to this dose adjustment scheme for non haematological toxicities are the following:

Clinically significant effusions

For pts who develop clinically significant pleural or peritoneal effusions (on the basis of symptoms or

clinical examination) during therapy, consideration should be given to draining the effusion prior to

dosing. However, if, in the investigator�s opinion, the effusion represents progression of disease,

patient should be discontinued from study therapy.

Fluid retention

Pts may be treated for symptomatic oedema (grade 2 or higher) with diuretics at the investigator

discretion. Spironolactone at a starting dose of 25 mg three times daily plus furosemide 20 � 40 mg

as needed is recommended.


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If fluid retention is grade 3 or 4, treatment should be delayed until resolution of toxicity to the

patient�s original baseline grade. Treatment should resume at 75% of the previous dose level if

deemed appropriate by the treating physician.

Grade 3 or 4 peripheral neuropathy

Pts who experience grade 3 or 4 peripheral neuropathy must stop receiving DOC. Pts will then enter

post-study follow.

Hypersensitivity reactions

If, despite the dexamethasone treatment regimen, patients experience hypersensitivity reactions,

treatment should be as indicated below.

MANAGEMENT OF HYPERSENSITIVITY REACTIONS FOR PATIENTS RECEIVING DOCETAXEL

Mild symptoms:

Localized cutaneous reaction such as

mild pruritus, flushing, rash

Consider decreasing the rate of infusion until recovery of symptoms; stay at

bedside. Then, complete DOC infusion at the initial planned rate.

Moderate symptoms:

Any symptom not listed as mild or

severe such as generalized pruritus,

flushing, rash, dyspnea, hypotension

with systolic blood pressure >80 mm

Hg.

Stop DOC infusion, give iv dexamethasone 10 mg and/or iv diphenhydramine

50 mg; resume DOC infusion after recovery of symptoms.

Severe symptoms such as

bronchospasm, generalized urticaria,

systolic blood pressure 80 mmHg,

angioedema.

Stop DOC infusion, give iv diphenhydramine 50 mg and/or epinephrine as

needed. Whenever possible, resume DOC infusion within 3 hours after

recovery, or reinfuse the patient within 72 hours, pretreating ½ hour prior to

infusion with dexamethasone 10 mg iv and/or diphenhydramine 50 mg iv. If

severe reaction recurs despite additional premedication, discontinue the

patient from study drug therapy.

Anaphylaxis (grade 4 reaction) No further study drug therapy

6.8.2.2. Weekly schedule

See section 6.8.2.1.

6.9. Pemetrexed administration


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ADMINISTRATION OF PEMETREXED

Drug Dose Time

Pemetrexed 500 mg/m2 iv infusion Administered in 0.9% sodium chloride approximately 100 mL

over 10 minutes (8 � 15 minutes) on day 1 of a 21-day cycle

Folic acid 1. 350 � 600 g folic acid

2. A multivitamin containing

folic acid in the range of 350

g to 600 g is acceptable if

option 1 is not available.

3. A dose of folic acid between

600 g and 1000 g is

acceptable only if neither

option 1 nor option 2 is

available.

Oral dose daily beginning approximately 1-2 weeks prior to the

first dose of PEM, and continuing daily until 3 weeks after the

last dose of PEM.

Vitamin B12 1000 µg im injection Approximately 1 � 2 weeks prior to the first dose of PEM, and

approximately every 9 weeks until 3 weeks after the last dose

of PEM.

Dexamethasone 4 mg, orally twice per day or

equivalent (-24, -12, 0, +12,

+24, +36)

Should be taken on the day before, the day of, and the day

after each dose of PEM, unless clinical contraindications exist.

Higher or additional doses are permitted for reasons (eg,

antiemetic prophylaxis).

6.10. Pemetrexed dose adjustments

Any patient who requires a PEM dose reduction will continue to receive a reduced dose for the remainder

of the study. Any patient with two prior dose reductions who experiences a toxicity that would cause a

third dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42

days from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related

toxicity. A patient who cannot be administered study drug for 42 days from the time of last treatment

must be discontinued from study therapy unless continuation is approved by study coordinator.

6.10.1. Pemetrexed dose adjustments due to haematological toxicity


nadir (lowest value) counts from the preceding cycle of therapy. ANC must be >1.5 x 109/L and platelets

>100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow time for recovery.

Upon recovery, if treatment is resumed, it must be according to the guidelines reported below.

DOSE ADJUSTMENTS FOR PEMETREXED BASED ON NADIR HEMATOLOGICAL VALUES FOR PRECEDING CYCLE



≥50 and ≥0.5 100%

≥50 and <0.5 75%

<50 and Any 50%

6.10.2. emetrexed dose adjustments due to non haematological toxicity

Clinically significant effusions


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For pts who develop clinically significant pleural or peritoneal effusions (on the basis of symptoms or

clinical examination) during therapy, consideration should be given to draining the effusion prior to

dosing. However, if, in the investigator opinion, the effusion represents progression of disease,

patient should be discontinued from study therapy.

Diarrhoea, mucositis, and other non haematological toxicities

In the event of diarrhoea requiring hospitalization (or of at least grade 3), treatment should be

delayed until diarrhoea has resolved before proceeding. Treatment should be resumed at 75% of the

previous dose level. For other non haematological effects greater than or equal to grade 3 (with the

exception of grade 3 transaminase elevations, nausea, or vomiting), treatment should be delayed

until resolution to less than or equal to the patient original baseline grade before proceeding.

Treatment should resume at 75% of the previous dose level if deemed appropriate by the treating

physician. (Do not forget to report any inpatient hospitalization as a SAE). Relevant dose adjustments

in case of mucositis are reported in the table below.

DOSE MODIFICATIONS FOR PEMETREXED FOR MUCOSITIS

NCI-CTCAE grade Percent of previous dose

Grade 0-2 100%

Grade 3-4 50%

Recurrence of grade 3 or 4 after treatment at 2 dose reductions Discontinue patient from study therapy

Creatinine clearance (CrCl)

If a patient develops a CrCl <45 mL/min, the next cycle will not begin until CrCl is 45 mL/min. Re-

testing is recommended at weekly intervals but will be conducted at the investigator discretion. If a

patient CrCl has not returned to 45 mL/min within 42 days of the last dose of PEM, the patient must

be discontinued from study therapy unless continuation is approved by study coordinator.

6.11. Pemetrexed treatment delays due to insufficient folic acid or vitamin B12

supplementation

Delay the first dose of PEM until the patient has taken folic acid for at least 5 of the 7 days immediately

preceding the first dose of PEM, and until the vitamin B12 injection has been administered. Delay

subsequent doses of PEM until the patient has taken folic acid for at least 14 of the 21 days before day 1

of the cycle.

6.12. Vinorelbine administration


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ADMINISTRATION OF VINORELBINE

Drug Dose Time

Vinorelbine 30 mg/m2 iv infusion* Administered in 0.9% sodium chloride or 5% glucose

approximately in 20-50mL in 6-10 minutes on days 1, 8, 15

every 28 days

* Suggested doses to be modified by the investigator on the basis of toxicities in previous lines of treatment

6.13. Vinorelbine dose adjustments

Any patient who requires a VNB dose reduction will continue to receive a reduced dose for the remainder

of the study. Any pts with two prior dose reductions who experiences a toxicity that would cause a third

dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42 days

from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related

toxicity. A pts who cannot be administered study drug for 42 days from the time of last treatment must


6.13.1. Vinorelbine dose adjustments due to haematological toxicity

DOSE ADJUSTMENTS FOR VINORELBINE BASED ON NADIR HEMATOLOGICAL VALUES FOR PRECEDING CYCLE



≥100 and ≥1.0 100%

50-100 and 0.5-1.0 75%

<50 and Any do not administer

6.13.2. Vinorelbine dose adjustments due to non haematological toxicity

The most common adverse events is stipsis, that rarely may induce also a paraliticus ileus.

Other adverse events are vomit, diarrohea, peripheral neurotoxicity, arthralgia, fever, mialgia, alopecia.

In the event of stipsis or paraliticus ileus requiring hospitalization (or of at least grade 3), treatment

should be delayed until stipsis has resolved before proceeding. Treatment should be resumed at 75% of

the previous dose level. For other non haematological effects greater than or equal to grade 3 (with the

exception of grade 3 transaminase elevations, nausea, or vomiting), treatment should be delayed until

resolution to less than or equal to the patient original baseline grade before proceeding. Treatment

should resume at 75% of the previous dose level if deemed appropriate by the treating physician. (Do

not forget to report any inpatient hospitalization as a SAE). Relevant dose adjustments in case of stipsis

are reported in the table below.


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DOSE MODIFICATIONS FOR VINORELBINE FOR STIPSIS

NCI-CTCAE grade Percent of previous dose

Grade 0-2 100%

Grade 3-4 50%

Recurrence of grade 3 or 4 after treatment at 2 dose reductions Discontinue patient from study therapy

6.14. Gemcitabine administration

ADMINISTRATION OF GEMCITABINE

Drug Dose Time

Gemcitabine 1000 mg/m2 iv infusion* Administered in 0.9% sodium chloride approximately 250 mL

over 30 minutes on days 1, 8, 15 every 28 days

Dexamethasone 4 mg, orally twice per day Higher or additional doses are permitted for reasons (eg,

antiemetic prophylaxis).

* Suggested doses to be modified by the investigator on the basis of toxicities in previous lines of treatment

6.15. Gemcitabine dose adjustments

Any pts who requires a GEM dose reduction will continue to receive a reduced dose for the remainder of

the study. Any pts with two prior dose reductions who experiences a toxicity that would cause a third

dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42 days

from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related

toxicity. A pts who cannot be administered study drug for 42 days from the time of last treatment must


6.15.1. Gemcitabine dose adjustments due to haematological toxicity


nadir (lowest value) counts from the preceding cycle of therapy. ANC must be >1.5 x 109/L and platelets

>100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow time for recovery.

Upon recovery, if treatment is resumed, it must be according to the guidelines reported below.

DOSE ADJUSTMENTS FOR GEMCITABINE BASED ON NADIR HEMATOLOGICAL VALUES FOR PRECEDING CYCLE



≥100 and 1.0 100%

50-100 and 0.5-1.0 75%

<50 and Any do not administer


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6.16. Concomitant therapies

Pts are allowed to receive full supportive care therapies concomitantly during the study. No other

chemotherapy, immunotherapy, hormonal cancer therapy, surgery for cancer, or experimental

medications, will be permitted while the patients are receiving study therapy. Palliative radiation therapy

is permitted for irradiating small areas of painful metastasis that cannot be managed adequately using

systemic or local analgesics. Any disease progression requiring other forms of specific anti-tumoral

therapy will be cause for early discontinuation of study therapy. The following concomitant therapies

warrant special attention:

Colony stimulating factors (CSFs)

Routine use of CSFs is not permitted during this study. Patients should not receive prophylactic

granulocyte colony stimulating factors (G-CSFs) in any cycle. G-CSFs should be considered only for

patients who have ANC <0.5 109/L, neutropenic fever, or documented infections while neutropenic.

Duration of uncomplicated neutropenia before initiation of G-CSF treatment is left to the investigator

discretion. G-CSF must be discontinued at least 24 hours prior to the start of the next cycle of

chemotherapy. If a patient develops hematological toxicities, chemotherapy dose reduction and

acute treatment of neutropenia are recommended, rather than chemotherapy dose maintenance and

pre-emptive treatment with G-CSFs.

Use of erythropoietin is allowed.

Use of stimulators of thrombopoiesis is not allowed

Nonsteroidal anti-inflammatory drugs (NSAIDs) (PEM only)

Pts taking NSAIDs or salicylates will not take the NSAID or salicylate 2 days before, the day of, and 2

days after receiving PEM. If a patient is taking an NSAID or salicylate with a long half-life (e.g.,

naproxen, piroxicam, diflunisal, or nabumetone), it should not be taken 5 days before, the day of,

and 2 days after receiving PEM

Diarrhea therapy

In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: hydration,

octreotide, and antidiarrheals. If diarrhea is severe (requiring intravenous hydration) associated with

fever or severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Pts with

severe diarrhea (requiring intravenous hydration) associated with severe nausea or vomiting should

be managed according to local standard procedures for iv hydration and correction of electrolyte

imbalances. (Do not forget to report any in-patient hospitalization as a SAE)

Febrile neutropenia therapy

Patients experiencing febrile neutropenia, especially with diarrhea, should be managed according to

local standard procedures, with the urgent initiation of intravenous antibiotic therapy

Antiemetic therapy

Antiemetic therapy should be administered according to standard local practice


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Radiotherapy

If palliative radiotherapy will be judged necessary, the patient should be fully assessed for possible

progression. Because of possible interactions between cytotoxics and radiation in the study, it is

advised that palliative radiotherapy should not be given until at least one week after any previous

chemotherapy treatment, and subsequent chemotherapy should not be given until one week after the

end of radiation. As well, large single-dose radiotherapy (i.e. > 800 cGy) should not be used in this

study

Pregnancy

Fertile women must be instructed to avoid pregnancy. In case of pregnancy, ERL or chemotherapy

must be stopped. The investigator should counsel the patient; discuss the risks of continuing with the

pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until

conclusion of the pregnancy

Other subsequent therapy

No chemotherapy other than that planned in the study design, or immunotherapy or experimental

medications will be permitted when patients have progressed after second-line treatment, third line

treatment, will be PEM or VNB or GEM depending on first line treatment (see section 6 �treatment

plan�) or the pts will enter in the follow-up phase.

7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP

7.1. Registration

7.1.1. Patients with a new diagnosis of NSCLC

All pts referring to the centre with a new diagnosis of locally advanced or metastatic NSCLC should

preferentially be registered at this time in order to allow all the biological evaluations.

Before registration, results of the following assessments, performed at the time of diagnosis must be

available:

Demographics, medical history including diagnosis of lung cancer and prior response therapy

History of smoking habit

Physical examination including ECOG-PS. In the physical examination, particular care should be taken

with the cardiovascular treatment. A careful baseline evaluation should be done in such pts and they

can be considered eligible on the basis of an individual risk/benefit assessment by the investigator

with the patient

Existing signs, symptoms and toxicity evaluation

Concomitant medications

Laboratory assessment: white blood cell (WBC) count with granulocyte, lymphocyte and monocyte

counts, platelet count, haemoglobin, calcium, sodium, potassium, albumin, uric acid, glucose, blood

urea nitrogen, creatinine, alkaline phosphatase, aspartate aminotransferase (AST), alanine

aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), gamma-GT, PT, PTT


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Tumour stage (TNM)

Radiology test assessment including: computer tomography (CT) scan of brain, chest and upper

abdomen, bone scan, plain chest X-ray. Other investigation(s) to document all sites of disease.

Written informed consent to allow the biological investigations on blood and tissue and written consent

to the management of personal data.

At the time of registration the blood sample is needed in order to perform pharmacogenomic analyses.

7.1.2. Patients relapsed or progressed after first line treatment

Pts relapsed after adjuvant treatment taxane free may be registered.

Pts progressed after first line platinum based, taxane free may be registered too, if this procedure has

not already done at diagnosis of NSCLC. For these category of pts it is important, providing that they are

eligible, to promptly send tissue and blood samples in order to avoid any delay in the detection of EGFR

19-21 mutations.

At the time of registration the blood sample is needed in order to perform pharmacogenomic analyses

REGISTRATION ASSESSMENTS

Procedure and Investigation Timing

History and Physical exam ECOG-PS, existing sign and symptoms, tumor stage (TNM) Within 14 days prior to

registration Diagnosis Pathological diagnosis of NSCLC

Smoking habit Number of cigarettes/day, duration of smoke

Haematology and

Biochemistry

White blood cell (WBC) count with granulocyte,

lymphocyte and monocyte counts, platelets count,

haemoglobin, calcium, sodium, potassium, albumin, uric

acid, glucose, blood urea nitrogen, creatinine, alkaline

phosphatase, aspartate aminotransferase (AST), alanine

aminotransferase (ALT), total bilirubin, lactate

dehydrogenase (LDH), gamma-GT, PT, PTT

Within 21 days prior to

registration

Biomarker samples Biopsy and blood samples

Radiology CT scan of brain, chest and upper abdomen, bone scan,

plain chest X-ray. Other investigation(s) to document all

sites of disease

Informed consent for

biopsy and blood samples

Before any registration

procedure

7.2. Before randomization

Pts in which

- EGFR 19-21 mutations have been demonstrated will be treated with erlotinib

- EGFR 19-21 mutations have not been demonstrated can be randomized

All pts, irrespectively from their EGFR mutation status, will be monitored in the same way, according to

sections 7.3, 7.4 and 7.5.


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An eligibility screening form documenting the patient fulfilment of the eligibility criteria is to be completed

by the investigator before randomization.

Furthermore, before randomization, results of the following assessments, performed within a time

window of two or three weeks, must be available:

Demographics, medical history including diagnosis of lung cancer and prior response therapy

Physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (body

temperature, blood pressure and pulse). In the physical examination, particular care should be taken

with the cardiovascular treatment. A careful baseline evaluation should be done in such patients and

they can be considered eligible on the basis of an individual risk/benefit assessment by the

investigator with the patient


History of smoking habit


Laboratory assessment: WBC count with granulocyte, lymphocyte and monocyte counts, platelet

count, hemoglobin, calcium, sodium, potassium, albumin, uric acid, glucose, blood urea nitrogen,

creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH, gamma-GT and PT, PTT and CEA.

Additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results

must be reported in the CRF and should be explained by clinical assessment and investigation

Clinical tumour measurement (see section 9)

Radiology test assessment including : CT scan of brain, chest and upper abdomen, bone scan, plain

chest X-ray. Other investigation(s) to document all sites of disease. Baseline and subsequent

examinations must be performed using identical techniques

QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC13

Written informed consent must be obtained prior the patient undergoing any study specific procedures


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AT RANDOMIZATION

Procedure and Investigation Timing

History and Physical

exam*

Height, weight, BSA, ECOG-PS, body temperature, blood

pressure, pulse, existing sign and symptoms, concomitant

medications, medical history, response to prior therapy, clinical

tumour measurement


randomization.

Hematology* Hemoglobin, WBC, granulocyte lymphocyte and monocyte

counts, platelet count

Biochemistry* Serum bilirubin, alkaline phosphatase, AST, ALT, serum

creatinine, sodium, potassium, LDH, calcium, albumin, uric

acid, glucose, urea nitrogen, gamma GT, calculated PT, PTT,

CEA

Radiology* CT scan of brain, chest and upper abdomen, bone scan, plain

chest X-ray. Other investigation(s) to document all sites of

disease

Baseline and subsequent examinations must be performed

using identical techniques.


randomization.

To be performed only if

registration was made

more than 30 days

before.

Other Pregnancy test

Electrocardiogram (ECG)


randomization

Biomarker sample Status of EGFR and K-ras mutations Before start therapy

Toxicity Baseline evaluation (to document symptoms on entering study) Within 14 days prior to

randomization

Quality of Life EORTC QLQ - C 30 and EORTC QLQ � LC 13 Within 7 days prior to

randomization

Informed consent

signature

Before any study

procedure

*To be performed only if registration was made more than 30 days before

7.3. During second line treatment

7.3.1. Pts with 19-21 EGFR mutations

Pts with EGFR mutations will be treated with ERL and prospectively followed-up according to what

planned for randomized pts, as described in section 7.3.2.

7.3.2. Erlotinib arm

For baseline (BL) visit see section 7.2.

In this arm the dose of ERL is 150 mg daily, until disease progression.

Written informed consent must be obtained prior the patient undergoing any study specific procedures.

Before each cycles, every 28 days, is necessary to perform:

medical history and prior response therapy

Physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (blood pressure

and pulse). In the physical examination, particular care should be taken with the cardiovascular

treatment



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Chemistry assessment within 4 days prior to each cycle: calcium, sodium, potassium, albumin, uric

acid, glucose, blood urea nitrogen, creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH,

gamma-GT and CEA

For haematology weekly within 4 days prior to each cycle: WBC count with granulocyte, lymphocyte

and monocyte counts, platelet count, haemoglobin



QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC13 must be administered prior to each cycle

After every 2 cycles is necessary a radiological and clinical revaluation:


Radiology test assessment including: CT scan of brain, chest and upper abdomen, plain chest X-ray

(bone scan to discretion of investigator). Other investigation(s) to document all sites of disease and

examinations must be performed using identical baseline techniques

It is suggested a ECG control before radiology tumour assessment.

The schedule of events described in the table below should be followed.

ASSESSMENTS DURING SECOND LINE TREATMENT � ERLOTINIB ARM

BL During Therapy

Cycle/Visit 0 1 2 3 4 5- etc.

Day in a cycle 1 → → 28 1 → → 28 1 → → 28 1 → → 28 1 → → 28

Informed consent X

Physical exam X X X X X X

Medical history X X X X X

Response to prior therapy X

ECG X X X

Blood pressure and pulse X X X X X

BSA X X X X X

Concomitant medications X X X X X

ECOG-PS X X X X X

QLQ�C30,QLQ-LC13 X X X X X

Tumor assessment (palpable) X X X X X

Radiology tests X X X

Chemistry X X X X X

Hematology X X X X X

NCI-CTCAE grading X X X X X

CRF X X X X X X

ERL therapy X X X X X X X X X X X X X X X X X X X X

Tissue sample X

Blood samples X


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7.3.3. 3-weekly docetaxel

For BL visit see section 7.2.

In this arm docetaxel schedule is 75 mg/m2 iv on day 1 every 21 days, until disease progression or

unacceptable toxicity developed.

Written informed consent must be obtained prior the patient undergoing any study specific procedures.

Before each cycles is necessary to perform this control:




treatment





gamma-GT and CEA

For haematology within 3 days prior to each infusion: WBC count with granulocyte, lymphocyte and

monocyte counts, platelet count, hemoglobin. It is strongly suggested to control WBC value weekly



QoL assessment by EORTC QLQ-C 30 and EORTC QLQ�LC13 must be administered prior to each cycle






It is suggested an ECG control before radiology tumour assessment


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ASSESSMENTS DURING SECOND LINE TREATMENT � 3-WEEKLY DOCETAXEL ARM

BL During Therapy

Cycle/Visit 0 1 2 3 4 5 6-etc.

Day in a Cycle 1 8 15 1 8 15 1 8 15 1 8 15 1 8 15 1 8 1

5

Inform Informed consent X

Physical examination X X X X X X X

Medical history X X X X X X


ECG X X X

Blood pressure and pulse X X X X X X

BSA X X X X X X

Concomitant medication X X X X X X

ECOG-PS X X X X X X

QLQ�C30, QLQ-LC13 X X X X X X

Tumor assessment

(palpable)

X X X X X X

Radiology test tumor X X X

Chemistry X X X X X X

Hematology X X X X X X X X X X X X X X X X X X

NCI-CTCAE grading X X X X X X

CRF X X X X X X X

DOC therapy X X X X X X

Tissue sample X

Blood samples X

7.3.4. Weekly docetaxel

In this arm docetaxel schedule is 35 mg/m2 iv on day 1, 8 and 15 every 28 days, until disease

progression or unacceptable toxicity developed. Written informed consent must be obtained prior the

patient undergoing any study specific procedures.





treatment





gamma-GT and CEA


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For hematology weekly within 3 days prior to each infusion: WBC count with granulocyte, lymphocyte

and monocyte counts, platelet count, hemoglobin. It is suggested to control WBC value weekly



QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC 13 must be administered prior to each cycle

Complete additional measurements weekly





examinations must be performed using identical baseline techniques. It is suggested an ECG control

before radiology tumour assessment

ASSESSMENTS DURING SECOND LINE TREATMENT � WEEKLY DOCETAXEL ARM

BL During Therapy

Cycle/Visit 0 1 2 3 4-etc.

Day in a Cycle 1 8 15 21 1 8 15 21 1 8 15 21 1 8 15 21

Informed consent X

Physical exam X X X X X

Medical history X X X X


ECG X X X

Blood pressure and pulse X X X X

BSA X X X X

Concomitant medication X X X X

ECOG-PS X X X X

QLQ�C30, QLQ-LC13 X X X X X

Tumor assess (palpable) X X X X X


Chemistry X X X X

Hematology X X X X X X X X X X X X X X X X

NCI-CTCAE grading X X X X

CRF X X X X

DOC therapy X X X X X X X X X X X X

Tissue sample X

Blood samples X


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7.4. During third line treatment

After progression to the second line therapy, both pts with 19-21 EGFR mutations, included in the

randomized part of the study, and those with 19-21 EGFR mutations, treated with ERL, if judged by the

investigator, may receive a third line therapy.

Pts treated with a platinum-based first line chemotherapy with VNB or GEM will receive a standardized

third line therapy with PEM, 500 mg/m2 on day 1 every 21 days supplemented by folic acid and vitamin

B12, while pts treated with a platinum-based first line chemotherapy with PEM will receive either GEM

(1000 mg/m2 days 1, 8, 15 every 28 days)

or VNB (30 mg/m

2 days 1, 8, 15 every 28 days) until disease

progression or unacceptable toxicity developed.



physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (blood pressure


treatment

existing signs, symptoms and toxicity evaluation

concomitant medications

chemistry assessment within 4 days prior to each cycle: calcium, sodium, potassium, albumin, uric


gamma-GT and CEA

for hematology within 3 days prior to each infusion: WBC count with granulocyte, lymphocyte and

monocyte counts, platelet count, hemoglobin. It is strongly suggested to control WBC value weekly.

additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results

must be reported in the CRF and should be explained by clinical assessment and investigation.

QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC13 must be administered prior to each cycle

Complete additional measurements weekly






It is suggested a ECG control before radiology tumour assessment

Vitaminic supplementation (only for PEM): folic acid po daily beginning approximately 1-2 weeks prior

to first dose of PEM and continuing daily until 3 weeks after the last dose of PEM or vitamin B12 given

as an intramuscular injection approximately 1 to 2 weeks prior to first dose of PEM and repeated

approximately every 9 weeks until 3 weeks after the last dose of PEM.


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ASSESSMENTS DURING PEMETREXED THIRD LINE TREATMENT

BL During Therapy

Cycle/Visit 0 1 2 3 4 5 6-etc.

Day in a Cycle 1 8 15 1 8 15 1 8 15 1 8 15 1 8 15 1 8 15

Physical exam X X X X X X X



ECG X X X

Blood pressure, pulse X X X X X X

BSA X X X X X X


ECOG-PS X X X X X X

QLQ�C30, QLC-LC 13 X X X X X X

Tumor assessment (palpable) X X X X X X



Hematology X X X X X X X X X X X X X X X X X X X


CRF X X X X X X X

Folic acid X X X X X X X X X X X X X X X X X X X

Vitamin B12 X X X

PEM therapy X X X X X X

ASSESSMENTS DURING VINORELBINE OR GEMCITABINE THIRD LINE TREATMENT

BL During Therapy

Cycle/Visit 0 1 2 3 4 5

Day in a Cycle 1 8 15 21 1 8 15 21 1 8 15 21 1 8 15 21 1 8 15 21

Physical exam X X X X X X

Medical history X X X X X


ECG X X

Blood pressure, pulse X X X X X

BSA X X X X X

Concomitant medication X X X X X

ECOG-PS X X X X X

QLQ�C30, QLC-LC 13 X X X X X

Tumor assessment

(palpable)

X X X X X

Radiology tests X X

Chemistry X X X X X

Hematology X X X X X X X X X X X X X X X X

NCI-CTCAE grading X X X X X

CRF X X X X X X

VNB or GEM therapy X X X X X X X X X X X X X X X


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7.5. During follow-up

The patient that enter in follow-up are:

- those not suitable of third line after therapy with ERL or DOC

- pts that finished third line chemotherapy.

After each patient discontinues study therapy, the investigator should make every effort to continue to

evaluate the patient for delayed toxicity by clinical and laboratory evaluations as clinically indicated.

Every attempt should be made to obtain haematology and chemistry approximately 30 days after the last

dose of DOC or ERL or PEM or VNB or GEM. The pts must be followed approximately every 30 days until

toxicity resolves.

To obtain data on tumour responses, assessments of disease status will be made at regular intervals

throughout study therapy and until the patient is live. The timing of the assessment in post-therapy

follow-up will therefore be approximately every 3 months. Assessments will consist of clinical evaluation

(physical exam, medical history, blood pressure, pulse, BSA, PS, evaluation of toxicity), a plain x-ray and

CT same method used during study therapy to quantitatively assess tumor, chemistry, haematology, and

ECG.

After progression until death is necessary only clinical evaluation (physical exam, medical history, blood

pressure, pulse, BSA, PS, evaluation of toxicity).

During this post-therapy follow-up, information will be collected regarding date of disease progression or

death, and any additional supportive therapy or radiotherapy. Each patient�s assessments will continue

until death .

The QLQ�C30 and QLQ�LC13 should be completed at the time the patient discontinues from study

therapy. They should also be completed at any revaluation: every 3 months.

ASSESSMENTS DURING FOLLOW-UP

Months after last dose of drug 3 6 9 12 15 18-etc

Physical examination X X X X X X


ECG X X X X X X

Blood pressure, pulse X X X X X X

BSA X X X X X X


ECOG-PS X X X X X X

QLQ�C 30, QLQ-LC13 X X X X X X

Tumor assessment (palpable) X X X X X X

Radiology tests X X X X X X


Hematology X X X X X X


CRF X X X X X X


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8. BIOLOGICAL EVALUATION

8.1. Specimen handling

8.1.1. Patients entering the study at diagnosis

Paraffin blocks and stained slides

Once the diagnosis of NSCLC of the lung is made, the physician in charge of the contributing centre

contacts the pathologist in order to organize the specimen submission. In particular, the samples

(paraffin block and stained slide) should be sealed within a proper container to avoid damages. They

should be sent along with the clinical report and a copy of the original diagnosis.

Collection is scheduled through TNT courier every two weeks. Whenever possible each centre should

select the time and the day of the week most appropriate for the picking up. This date is then generally

kept fixed unless special needs are required by the centre. In this case the person in charge for the

centre should contact the Istituto di Ricerche Farmacologiche �Mario Negri� (Massimo Broggini

[email protected], or Marabese Mirko, [email protected]) who will notify the

courier of the requested changes.

TNT courier will pick up the material directly at the centre and will deliver it to the Pathology Department

of Fatebenefratelli Hospital in Milan (S.C. di Anatomia e Istologia Patologica, Ospedale Fatebenefratelli e

Oftalmico, Corso di Porta Nuova 23, 20121, Milano; Tel. 02-63632581;

[email protected]).

Each sample will be reviewed by the referring pathologist in order to confirm the diagnosis as well as to

verify specimen representativity and minimal criteria for enrolment in the study protocol. Diagnostic

confirmation may require additional immunostaining. Additional paraffin sections will be cut from the

paraffin block and sent to the Pathology Department, Niguarda Cà Granda Hospital, Milano, and to the

Mario Negri Pharmacological Institute for further biomolecular determinations. A minimal number of

sections will be retained at Pathology Department of the Fatebenefratelli Hospital which will act as the

central archive for the study.

Blood samples

Heparinized blood (3-5 ml) collected in plastic tubes must be stored at -20°c at each centre facility.

Blood collection from the TNT courier is scheduled every two-three months.

Each participating centre should notify the collection centre (Massimo Broggini

[email protected], or Marabese Mirko, [email protected]) if they do not have

the possibility to pack the samples with dry ice for the shipment. In this case a special delivery system

will be activated.

Blood samples will be delivered to the Laboratory of Molecular Pharmacology of the Istituto di Ricerche

Farmacologiche �Mario Negri�, Milan where DNA will be extracted from each sample.

mailto:[email protected],

mailto:[email protected])




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8.1.2. Patients entering the study at relapse

It is expected that in a limited number of cases a quick determination of the mutational status of EGFR is

needed to proceed with the treatment stratification. These cases will therefore follow a fast track

procedure.

Paraffin blocks and stained slides

The physician in charge of the contributing centre should contact immediately the coordinating people at

the Istituto di Ricerche Farmacologiche �Mario Negri� (Massimo Broggini

[email protected], or Marabese Mirko, [email protected]) who will organise a

quick delivery of the specimen from the participating centre to the Pathology Department of

Fatebenefratelli Hospital in Milan (S.C. di Anatomia e Istologia Patologica, Ospedale Fatebenefratelli e

Oftalmico, C.so di Porta Nuova 23 20121, Milano; tel. 0263632581; [email protected]).

Each sample will be managed as for the procedures reported in section 8.1. Mutational status of the EGFR

will be determined in a short time to allow a quick determination of the treatment modalities necessary

for the patient.

Blood samples

Since analysis of mutations and polymorphisms in blood do not determine treatment modalities, this

material is treated exactly in the same way as reported in section 8.1.

FLOW CHART FOR THE BIOLOGICAL DETERMINATIONS

PATIENTS ENTERING THE STUDY AT DIAGNOSIS

Paraffin block/stainedslides

Stored at room temperature

Heparinized bloodStored at -20°C

Every two weeksE-mail message

to the Collection centrewhich organisesthe picking up of the material from

the centre.Pas

ticip

atin

gce

ntre

Paraffin block

/stained slides

Heparinizedblood

FbfSections

forbiological

studies

FBF FISH ANALYSIS

OSP NIGUARDADNA EXTRACTIONRAS AND EGFR MUT

molecularpharmacologymario negri institute

DNA EXTRACTIONEGFR MUT

DETECTION IN BLOOD

DNAPOLYMORPHISMS

PATIENTS ENTERING THE STUDY AT DIAGNOSIS


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DETECTION IN BLOOD

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RANDOMISATION




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8.2. Minimal criteria for inclusion in the study

Specimens to be evaluated in the study will consist only of histological and/or cytological tumour

samples.

8.2.1. Histological specimens

- Samples should consist of tissue fragments from the primary tumour, or from any metastatic site of

disease, obtained by incisional or excisional biopsies, or by major surgical procedures. Following removal

the tissue should be immediately immersed in 10% buffered formalin, fixed for 12-48 hours at room

temperature, and embedded in paraffin as routine. It is strictly required that the paraffin be melted at

60 °C for 30-60 minutes.

- The paraffin block containing the tumour sample should be submitted with: a) a copy of the original

pathology report, b) a haematoxylin-eosin stained histological slide

- The paraffin block should contain enough tumour tissue as to allow additional cutting of at least 20 new

and representative 4 micron-thick paraffin sections; in particular, the neoplastic area should measure at

least 2mm2

on the tissue section. Tissue necrosis and/or artefacts should not obscure more than 30% of

the sample which should consist of a representative area of the tumour. Paraffin sections can be sent as

a substitute of the paraffin block provided that they fulfil the above requisites. The submitting pathologist

is encouraged to send additional slides with ancillary stains or immunostains that helped reaching the

primary diagnosis; evaluation of these slides by the referring pathologist is of help to reducing the extent

of the paraffin block sectioning of the residual material. These additional slides will be returned

immediately by express courier.

8.2.2. Cytological specimens

- Samples should be taken from the primary tumour and/or from any metastatic site of disease.

PATIENTS ENTERING THE STUDY AFTER RELAPSE




to the Colection centre which organisesthe picking up of the material from

the centre.

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FBF FISH ANALYSIS




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CONTACT IMMEDIATELYTHE COLLECTION CENTRE FOR

FAST TRACK DELIVERY AND MUTATION ANALYSIS

PATIENTS ENTERING THE STUDY AFTER RELAPSE




to the Colection centre which organisesthe picking up of the material from

the centre.

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Heparinizedblood

FbfSections

for biological

studies

FBF FISH ANALYSIS




DETECTION IN BLOOD

DNAPOLYMORPHISMS

RANDOMISATION

CONTACT IMMEDIATELYTHE COLLECTION CENTRE FOR

FAST TRACK DELIVERY AND MUTATION ANALYSIS


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- The following types of cytological specimens are suitable for the study: a) paraffin cell block sample

prepared from a serosal effusion fixed in 10% buffered formalin for 2-24 hours; b) paraffin cell block

sample prepared from needle rinsing following multiple passes by fine-needle (22 G) aspiration biopsy

and fixed in 10% buffered formalin for 2-24 hours; c) paraffin block of a solid core obtained by a 20 G

and 19 G cutting needle fixed in 10% buffered formalin for 2-24 hours. It is strictly required that the

paraffin be melted at 60 °C for 30-60 minutes. Other cytological preparations such as smears cannot

be considered for evaluation in the study.

- The paraffin cell block containing the tumour sample should be submitted with: a) a copy of the original

pathology report, b) a haematoxylin-eosin stained histological slide

- The paraffin cell block should contain enough tumour cellular component to allow additional cutting of at

least 20 new and representative 4 micron-thick paraffin sections. Tissue necrosis and/or artefacts should

not obscure more than 30% of the sample. Paraffin sections cannot be sent as a substitute of the paraffin

block. The submitting pathologist is encouraged to send additional slides with ancillary stains or

immunostains that helped reaching the primary diagnosis; evaluation of these slides by the referring

pathologist is of help to reduce the extent of the paraffin block sectioning of the residual material. These

additional slides will be returned immediately by express courier.

8.3. Analysis performed on tissues

8.3.1. Determination of mutational status of EGFR and K-ras genes

Formalin-fixed paraffin embedded tumour samples will be tested for the presence of EGFR exon 18-21

mutations and in the exon 2-4 of K-ras gene. DNA extraction will be performed on histological tumour

specimens, by using standard phenol-chloroform procedure, after macro/microdissection in order to

recovery most of cancer cells and to reduce the contamination by normal ones. DNA preparations will be

verified for their concentration and quality by spectrophotometric measurement.

Genomic DNA will be amplified by polymerase chain reaction (PCR) using high-fidelity Taq polymerase

and specific primers encompassing intronic regions for EGFR exon 18-21 and K-ras exon 2-4. PCR

products will then be analysed electrophoretically on agarose gel and automate bi-directional sequencing

will be performed using Big Dye Terminator chemistry (Applied Biosystems) and a 3130xl Genetic

Analyzer (Applied Biosystems) according to the manufacturer�s instructions. Sequences will then be

automatically compared with wild-type EGFR and K-ras gene profiles by appropriate software analysis

(SeqScape) in order to assess the presence of possible mutations.

Moreover, RFLP PCR for EGFR exon 19 and 21 will be performed on cases turned out negative at

sequencing to further confirm the absence of mutations. In order to define the presence of deletions in

the exon 19 of EGFR gene, an assay based on the difference in length analysis of fluorescently labelled

PCR products will be used, while for exon 21 the Sau96I restriction enzyme will be used to identify the

presence of L858R (T>G) point mutation. In both procedures digested and undigested fluorescently

labelled PCR products will be analysed by capillary electrophoresis.

In a small number of patients for which the material received will not be sufficient to precisely determine

the mutational status, a potentially more sensitive analysis will be applied. For these cases, Scorpion

primers, which are used in PCR for detection of fluorescent products, coupled with Amplified Refractory


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Mutation System (ARMS) will be used in a real time PCR-based method to detect EGFR and K-RAS

mutations. According to the literature this method is highly sensitive since it is supposed to detect

mutations in tumour DNA even if they are very sparse in relation to normal DNA possibly present. The

analysis will be performed using commercially available standardised kits (DxS, Manchester, UK).

Amplification reactions, using high fidelity taq polymerase, will be analysed on a 7900HT Fast real time

PCR system.

Whenever the material will be sufficient to be further processed, mutations in other genes relevant for

the signalling cascade associated with EGFR and K-RAS will be determined. The genomic regions that will

be analysed are: exon 15 of B-RAF gene, exon 20 of HER2 gene, and exons 9 and 20 of PIK3CA gene.

8.3.2. Immunohistochemistry for p-AKT, DDR1, FGFR

Tissue specimens embedded in paraffin are cut into sections of 4-6 ìm, collected on slides and then air-

dried. Sections are rehydrated through an ethanol scale. They are subjected to heat-induced epitope

retrieval procedure by microwaving for 15 minutes in a citrate buffer pH 6.0 then allowed to cool at room

temperature for additional 15 minutes. Incubations with primary specific anti-DDR1, anti-pAKT, anti-

FGFR monoclonal antibody solution, secondary biotinilated antibody and avidin-biotin complex are

performed by using an automated staining system (Benchmark XT, Ventana Medical Systems). Following

counterstaining the slides are examined under a routine light microscope.

8.3.3. Copy number determination of c-MET and FGFR1 genes

DNA extraction will be performed on histological tumour specimens, by using standard phenol-chloroform

procedure, after macro/microdissection in order to recovery most of cancer cells and to reduce the

contamination by normal ones. DNA preparations will be verified for their concentration and quality by

spectrophotometric measurement.

Genomic DNA will be used to determine the copy number and hence amplification of c-MET and FGFR1

genes using TaqMan® Real-Time PCR Assays on a 7900HT Fast real time PCR system. Analysis of the

results obtianed by Real Time PCR and determination of the number of copies of c-MET gene will be

performed using dedicated softwares available with the TaqMan assay.

8.3.4. EML4-ALK translocation

The EML4-ALK fusion protein results from a small inversion within the short arm of chromosome 2 in

which the N-terminal portion of echinoderm microtubule-associated protein-like 4 (EML4) is fused with

the intracellular kinase domain of anaplastic lymphoma kinase (ALK). ALK gene rearrangements will be

investigated by FISH analysis on tissue sections using a break-apart probe to ALK (Vysis) and cases will

be considered positive when tumor cells show a split signal in more than 20% of the cells.


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8.3.5. Analysis performed on blood

Evidence presented in a limited number of samples reported a good correlation between the detection of

EGFR and K-RAS mutations in the tumour tissue and in the circulating DNA extracted from total blood.

This would represent a valid alternative for the detection of mutations in those patients where the tumour

material is not available and, more generally, as a non-invasive method for the detection of genetic

alterations present in the tumour.

The possibility to detect mutations in circulating DNA needs however further confirmation and the present

study addresses this point by evaluating in approximately 300 patients (2035% of total accrual), the

presence of mutations in EGFR and K-RAS.

Analysis of EGFR and k-RAS mutations in circulating DNA will be performed for all the patients for which a

mutation in the tumour sample has been detected and in the same number of mutation-negative

samples.

Sample preparation and processing

DNA is extracted from total heparinized blood using Qiamp Blood kit from Qiagen and eluted in water.

Scorpion primers, which are used in PCR for detection of fluorescent products, coupled with Amplified

Refractory Mutation System (ARMS) will be used in a real time PCR-based method to detect single base

mutations. This method allows the detection of mutations in tumour DNA even if these are present in

small amounts relative to normal DNA. Specific alterations of EGFR and k-RAS will be evaluated. The

analysis will be performed using standardised kits available from dxs, Manchester, UK.

Amplification reactions, using high fidelity taq polymerase, will be analysed on a 7900HT Fast real time

PCR system.

Determination of single nucleotide polymorphism (SNP) in genes potentially relevant for the response to

erlotinib

Changes in a single nucleotide either inside or outside the coding region of several genes are known to be

associated to a differential response to treatment with anticancer agents.

These single changes, even if not associated to change in protein structure could lead to a differential

stability of the gene product. The search for SNPs potentially associated to ERL response is an attractive

possibility offered by this study along with the analysis of mutations and or amplification of EGFR and K-

ras genes.

The genes selected for this biological analysis are the EGF gene, the cyclin D gene, in the p53 degrading

gene mdm2, and in the DNA repair gene XPD. For these four genes genetic variance has been associated

to differential response to treatment in different tumour types. The possibility to analyse in a large

number of patients (as offered by the study) the relation between genetic variance in these genes and

response to ERL is likely to give useful information for the selection of patients to be treated.


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Sample preparation and processing

Genomic DNA will be extracted using commercially available preparative columns (Qiagen, Promega)

from total blood and purified DNA will be checked for purity and quantified by spectrophotometer

analysis. Analysis of polymorphisms will be performed using TaqMan SNP Genotyping assays. For each

analysis 10 ng of genomic DNA will be amplified using the TaqMan Universal PCR Master Mix

supplemented with the TaqMan SNP Genotyping assay of interest.

Genotyping will be conducted using the ABI PRISM 7900HT sequence detection

system (Applied

Biosystems) according to the manufacturer's protocol.

SNPs present in the Cyclin D gene (A870G), in the EGF gene (A61G), in XPD (312), in mdm2 (309) and

in K-RAS gene (3377) will be investigated.

The results obtained will be evaluated either as independent factors or as variables linked to the assays

performed in the tumoral tissue.

9. ASSESSMENT OF RESPONSE

Objective response will be categorized according to RECIST criteria�for a quick reference see

http://ctep.cancer.gov/guidelines/recist.html.

Objective response will be recorded both for first-line and second-line treatment.

Radiological examinations performed to assess and describe progression during or after first-line

treatment can be used as the baseline for the assessment of response to second line treatment. It is

strongly recommended that the interval between the date of radiological examinations and the date of

start of second line treatment is no longer than 6 weeks.

9.1. Definition of measurable and non-measurable

Measurable disease - the presence of at least one measurable lesion. If the measurable disease is

restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.

Measurable lesions - lesions that can be accurately measured in at least one dimension with longest

diameter 20 mm using conventional techniques or 10 mm with spiral CT scan.

Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm with

conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal disease,

ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic

lesions, and also abdominal masses that are not confirmed and followed by imaging techniques.

Please note that:

all measurements should be taken and recorded in metric notation, using a ruler or calipers;

the same method of assessment and the same technique should be used to characterize each identified

and reported lesion at baseline and during follow-up;

clinical lesions can be considered measurable only when they are superficial (e.g., skin nodules and

palpable lymph nodes).

http://ctep.cancer.gov/guidelines/recist.html.


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9.2. Baseline documentation of �target� and �non-target� lesions

All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative

of all involved organs should be identified as target lesions and recorded and measured at baseline.

Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their

suitability for accurate repeated measurements (either by imaging techniques or clinically).

A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline

sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumour.

All other lesions (or sites of disease) should be identified as non-target lesions and should also be

recorded at baseline. Measurements of these lesions are not required, but the presence or absence of

each should be noted throughout follow-up.

EVALUATION OF TARGET LESIONS

Defined response as: If there is:

Complete Response (CR): Disappearance of all target lesions

Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the

baseline sum LD

Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the

smallest sum LD recorded since the treatment started or the appearance of one or more

new lesions

SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,

taking as reference the smallest sum LD since the treatment started

EVALUATION OF NON TARGET LESIONS

Defined response as: If there is:

CR: Disappearance of all non-target lesions and normalization of tumor marker level

PR: At least a 30% decrease in the sum of the LD of target lesions, taking as reference the

baseline sum LD

NonCR/nonPD: Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker

level above the normal limits

PD: Appearance of one or more new lesions and/or unequivocal progression of existing non-

target lesions

9.3. Evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease

progression/recurrence (taking as reference for PD the smallest measurements recorded since the

treatment started). In general, the patient's best response assignment will depend on the achievement of

both measurement and confirmation criteria.


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EVALUATION OF NON TARGET LESIONS

Target lesions Non-target lesions New lesions Overall response

CR CR No CR

CR Incomplete response/SD No PR

PR Non PD No PR

SD Non PD No SD

PD Any Yes or No PD

Any PD Yes or No PD

Any Any Yes PD

Symptomatic deterioration may occur in some patients. In this situation, disease progression is evident in

the patient�s clinical symptoms, but is not supported by the tumour measurements. Or, the disease

progression is so evident that the investigator may elect not to perform further disease assessments. In

such cases, the determination of clinical progression is based on symptomatic deterioration. These

determinations should be a rare exception as every effort should be made to document the objective

disease progression.

9.4. Confirmation and review of response

Confirmation and review of objective response, to avoid overestimating the observed response rate, are

not required in this study, because response rate is only a secondary end-point.

9.5. Reporting of results

All pts included in the study must be assessed for response to treatment, even if they are ineligible. Each

patient will be assigned one of the following categories: 1) CR, 2) PR, 3) SD, 4) PD, 5) early death from

malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 8) unknown

(not assessable, insufficient data).

All pts will be included in the analysis of the response rate. Pts in response categories 3-8 will be

considered as failing to respond to treatment.

10. QOL ASSESSMENT

The EORTC QLQ-C30 [21], version 3.0, includes 30 questions, 28 with 4-category response, and 2 with

a 7-point scale for response. This questionnaire explores 5 multi-item functional subscales: physical, role,

emotional, social and cognitive functioning; three multi-item symptom scales: fatigue, pain, and emesis;

a global health status subscale; and six single items: financial impact and symptoms such as dyspnoea,

sleep disturbance, appetite, diarrhoea, and constipation.

The EORTC QLQ-LC13 [22] includes 12 questions with 4-category response exploring symptoms induced

by lung cancer and 1 question regarding the use of analgesics, with a binary response (no/yes) and, if

the latter response is yes, a further question on analgesic efficacy.


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10.1. Operative Procedures

- QoL questionnaires must be compiled by the pts

- QoL questionnaires must be compiled before clinical visit and before receiving treatment

10.2. QoL timing

- at baseline: before any study procedures AND within 2 weeks prior to randomization

- during treatment: before each cycle following the first during second and third line therapy

A cover sheet must be compiled by clinical assistants or physicians for all QoL questionnaires, annotating

eventual reasons for lack of questionnaires or lack of specific responses, or whether assistance was

required.

11. REMOVAL AND REPLACEMENT OF PATIENTS

Pts have the right to withdraw fully or partially from the study at any time and for any reason without

prejudice to his or her future medical care by the physician or at the institution.

Withdrawal of full consent for a study means that the patient does not wish to receive further

investigational treatment and does not wish to or is unable to continue further study participation. Any

patient may withdraw full consent to participate in the study at any time during the study. The

investigator will discuss with the patient the most appropriate way to withdraw to ensure the patient

health. Any patient who withdraws full consent to participate in the study will be removed from further

treatment and/or study observation immediately upon the date of request.

Withdrawal of partial consent means that the patient does not wish to take investigational product any

longer but is still willing to collaborate in providing further data by continuing on study (e.g., participate

in all subsequent study visits or procedures).

Pts may decline to continue receiving investigational product at any time during the study. These pts, as

well as those who have stopped receiving investigational products for other reasons (e.g., investigator

concern) should continue the schedule of study observations.

Reasons for removal from investigational product might include:

voluntary discontinuation by the patient who is at any time free to discontinue their participation in

the study, without prejudice to further treatment

safety reasons (e.g., AEs) as judged by the investigators

severe non-compliance to the protocol as judged by the investigator (unless the patient is benefiting

from protocol therapy)

incorrect enrolment or randomization of the patient (unless the patient is benefiting from protocol

therapy)


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radiological, objective progression of disease. If an investigator believes that a patient has convincing

evidence of �clinical progression� (for example worsening of PS that is clearly cancer related) but,

despite adequate imaging, it is not possible to document objective radiological progression, the

patient should be discussed with the investigators and a decision on discontinuation of study therapy

made on a case-by-case basis

Death

Patient lost to follow-up

An excessive rate of withdrawals can render the study uninterpretable; therefore, unnecessary

withdrawal of pts should be avoided. Should a patient decide to withdraw, all efforts will be made to

complete and report the observations as thoroughly as possible.

The investigator should contact the patient either by telephone or through a personal visit or a

responsible relative must be contacted to determine as completely as possible the reason for the

withdrawal. A complete final evaluation at the time of the patient�s withdrawal should be made with an

explanation of why the patient is withdrawing from the study. If the reason for removal of a patient from

the study is an adverse event, this must be reported as a SAE.

11.1. Replacement of patients

Pts who are removed or withdrawn from study following randomization will not be replaced.

12. REGISTRATION/RANDOMIZATION PROCEDURE

12.1. Registration

Once having received a copy of the site�s written independent ethics committee/institutional review board

(IEC/IRB) approval of the protocol, the coordinating center will provide each investigator of the site with

a personal username and a password.

Before registration eligible pts must provide his/her informed consent to the analysis of biological

markers. A validated system will be used accessible 24 hours a day at this address:

http://crc.marionegri.it/trials/tailor (Remember that the system is case sensitive, therefore username

and password should be entered always in compliance with the first capital/small letters format: e.g.

�ABC� is different from �abc�).

All registered pts will receive a unique patient identification number before any study specific procedures

are performed. This number will be used to identify pts throughout the clinical study and must be used on

all study documentation related to that subject. The patient identification number must remain constant

throughout the entire clinical study; it must not be changed at the time of randomization.

12.2. Randomization

After obtained informed consent to participate, eligible pts can be randomized. At that moment,

information regarding relevant demographic characteristics and stratification factors must be available



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and all randomization web page form should be completely filled in. The same system used for

registration will be used for random assignments of treatment groups.

At the end of the randomization process, the randomization web page can be printed. This document is

the notification form of patient randomization to be archived in the study folder. This printing operation is

important because this is the only opportunity to obtain the random notification form during the

randomization process. If this operation fails or has been omitted, please contact the Coordinating Centre

of the Istituto di Ricerche Farmacologiche �Mario Negri� to obtain a copy of the random notification form.

13. SAFETY DATA COLLECTION, RECORDING AND REPORTING

13.1. Definitions

13.1.1. Adverse event

An AE is defined in the International Conference on Harmonisation (ICH) Guideline for Good Clinical

Practice as � any untoward medical occurrence in a patient or clinical investigation subject administered a

pharmaceutical product and that does not necessarily have a causal relationship with this treatment�

(ICH E6 1.2).

This definition of AE is broadened in this study to include any worsening of a pre-existing medical

condition. Worsening indicates that the pre-existing medical condition has increased in severity,

frequency or duration of the condition or an association with significantly worse outcomes.

The term adverse event also applies to laboratory findings or results of other diagnostic procedures that

are considered to be clinically relevant (eg, that required unscheduled diagnostic procedures or treatment

measures, or result in withdrawal from the study.)

Surgical procedures themselves are not adverse events; they are therapeutic measures for conditions

that require surgery.

The investigator is responsible for reviewing laboratory test results and determining whether an abnormal

value in an individual study patient represents a change from values before the study. In general,

abnormal laboratory findings without clinical significance (based on the investigator�s judgement) should

not be recorded as AEs; however, laboratory value changes requiring therapy or adjustment in prior

therapy are considered AEs.

An adverse drug reaction (ADR) occurring in a clinical study is any untoward medical occurrence in a

patient or clinical investigation subject that is possibly or probably causally related to the administration

of a pharmaceutical product. Such ADRs are a subset of the adverse events defined above.

13.1.2. Serious adverse event

A SAE is defined as an adverse event that:

is fatal

is life threatening

requires in-patient hospitalisation or prolongation of existing hospitalization


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results in persistent or significant disability or incapacity

is a congenital anomaly or birth defect

is any other significant medical hazard

�Life-threatening" means that the patient was at immediate risk of death from event as it occurred. It

does not include an event that, had it occurred in a more serious form, might have been life threatening

(i.e. asymptomatic febrile neutropenia).

�Requires in patient hospitalisation or prolongation of existing hospitalisation" should be defined as

hospital admission required for treatment of the adverse event or occurred as a consequence of the

event. Hospital admission for scheduled elective surgery would not be a serious adverse event.

�Important medical events� are those which may not resulted in death or be immediately life-threatening

or result in patient hospitalisation, but may jeopardize patients and may require intervention to prevent

one of the other serious outcomes listed above. Examples of such events are intensive treatment in an

emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result

in hospitalisation; development of drug dependency. A second malignancy or drug over dosage or abuse

may be considered serious by this criterion.

All adverse events, which do not meet any of the criteria for serious should be, regarded as non-serious

adverse events.

Events NOT considered to be SAEs are hospitalizations for:

- routine treatment or monitoring of the studied indication, not associated with any deterioration in

condition

- treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen

- admission to a hospital or other institution for general care, not associated with any deterioration in

condition

- treatment on emergency, outpatient basis for an event not fulfilling any of the definitions of serious

given above and not resulting in hospital admission.

REMARK:

1) In this study death due to progression of disease will NOT be considered as an SAE and must therefore

NOT be reported as SAE.

2) Progression of a patient's underlying condition leading to one of the above should not be reported as a

serious adverse event.

Deaths occurring between the randomization and 30 days following the last infusion must be reported to

the Sponsor within 24 hours, as a SAE, regardless of the relation to study drug(s). Deaths occurring

during the study follow-up period (i.e. later than 30 days after the last infusion) need only to be reported

as serious adverse event if it is thought that there is a possible relation to the study drug(s) (possible,

probable). All deaths should be reported on the death report form section of the CRF regardless of cause.

A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any suspected adverse reactions related to

an investigational medicinal product (IMP) that are both unexpected and serious.


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13.2. Reporting of procedures for all adverse events

The investigator is responsible for ensuring that all AEs (as defined in section 13.1 and as further

specified below) observed by the investigator or reported by patients are collected and recorded in the

appropriate section of CRF. These AEs will include the following:

All SAEs (as defined in section 13.1.2) that occur after the patient has signed the informed consent

form

All non SAEs (as defined in section 13.1.1) that occur after randomization to investigational drugs.

The following AE attributes must be assigned by the investigator: adverse event diagnosis or

syndrome(s) (if known, signs or symptoms if not known); event description (with detail appropriate to

the event); dates of onset and resolution; severity; assessment of relatedness to investigational drugs;

and action taken. The investigator may be asked to provide follow-up information, discharge summaries,

and extracts from medical records or CRFs.

The assessment of causality is made by the investigator using the following definitions:

Relationship Description

Unrelated There is no evidence of any causal relationship

Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within

a reasonable time after administration of the trial medication). There is another reasonable

explanation for the event (e.g. the patient�s clinical condition, other concomitant treatments).

Possible There is some evidence to suggest a causal relationship (e.g. because the event occurs within a

reasonable time after administration of the trial medication). However, the influence of other

factors may have contributed to the event (e.g. the patient�s clinical condition, other concomitant

treatments).

Probable There is evidence to suggest a causal relationship and the influence of other factors is unlikely.

Definitely There is clear evidence to suggest a causal relationship and other possible contributing factors can

be ruled out.

Not assessable There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship.

NCI-CTCAE version 3.0 will be used to grade AEs.

Medically significant AEs considered related to the investigational drugs by the investigator or the sponsor

will be followed until resolved or considered stable.

It will be left to the investigator�s clinical judgement to determine whether an AE is related and of

sufficient severity to require the patient�s removal from treatment or from the study. A patient may also

voluntary withdraw from treatment due to what he or she perceives as an intolerable AE. If either of

these situations arises, the patient should be strongly encouraged to undergo an end-of-study

assessment and be under medical supervision until symptoms cease or the condition becomes stable.


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13.3. Serious adverse event reporting procedures

SAEs must be collected and recorded at least throughout the study period, beginning with the date of

registration through 30 days after the end of the treatment phase.

All SAEs occurring after the patient has been registered must be reported to the Coordinating center

within 1 working day of discovery or notification of the event. Initial SAE information and all amendments

or additions must be recorded on a SAE report form on e-CRF. Please fax or e-mail the report to:

Marlen Llerena

Laboratory of Clinical Trials

Istituto di Ricerche Farmacologiche �Mario Negri�

Phone: +39 02 39014638

Fax: +39 02 33200231


SAEs occurring after conclusion of the study AND thought to be possibly related to investigation drugs will

be collected and reported within 1 working day of discovery or notification of the event.

Determination of expectedness will be based on the investigator� brochure for investigational drugs. It

should be recognized that SAEs and SADRs which have not been previously documented in the

Investigators� Brochure, or which occur in a more severe form than anticipated (i.e. they are

�unexpected�), are subject to rapid reporting to the Regulatory Authorities by the sponsor/promoter. This

also applies to reports from spontaneous sources and from any type of clinical or epidemiological

investigation, independent of design or purpose. The source of the report (investigation, spontaneous,

other) should always be specified.

If a patient is permanently withdrawn from the study because of a SAE, this information must be included

in the initial or follow-up SAE report form as well as the end of study CRF.

The sponsor will send the report to national authorities, Ethics Committees and investigators as

appropriate, according to local regulations.

To enable the Safety Desk/sponsor to comply with regulatory reporting requirements, completed

documentation of any reported serious adverse events or serious adverse drug reactions must be

returned within 10 calendar days of the initial report. If the completed form is not received within this

deadline, the safety desk will make a written request to the investigator.

Any question concerning SAE or SADR reporting can be directed to the Safety Desk.

14. STATISTICAL CONSIDERATIONS

14.1. Definition of endpoints

14.1.1. Efficacy/activity

OS is defined as the time from the date of randomization to the date of death from any cause.

Subjects who were not reported as having died at the time of the analysis will be censored at the date

they were last known to be alive.



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PFS is defined as the time from the date of randomization up to the date of first progression, second

primary malignancy or death from any cause, whichever comes first. Subjects who have not

progressed or died at the time of the analysis will be censored at the last disease assessment date

RR is defined as the proportion of randomized patients who will experience a complete or partial best

response according to RECIST criteria. Patients who will never achieve a CR or PR will be defined as

non-responders

QoL, assessed through EORTC QLQ-C30 and EORTC QLQ-LC13

14.1.2. Safety

Toxicity, graded according to the NCI-CTAE version 3.0

Frequency and nature of serious adverse reactions (SADRs)

Premature withdrawals

14.2. Sample size

According to the results of previous trials [10, 16-17], it is reasonable to hypothesize that DOC may

reduce mortality by 33% (HR 0.67) with respect to ERL. This effect translates in an increased probability

of surviving at 1 year from 20% with ERL to 34% with DOC. In order to detect with a 80% power such

an effect at the significance level of 5%, two-sided, 199 events must be observed overall.

Based on these assumptions, with a uniform accrual of 48 months, a minimum follow-up for each patient

of 12 months, a 5% lost to f-up pts, the total number of required pts is approximately 220.

As for PFS a difference of the same magnitude can be anticipated. Therefore, also for this secondary

endpoint, a comparison analysis between ERL and DOC will be performed at the occurrence of 199

events.

14.3. Efficacy analyses

Efficacy analysis will be performed on an intention to treat basis, therefore all randomized pts without

major protocol violations will be included in the analysis according to the randomization arm. Major

violations in the eligibility criteria and study conduction will be evaluated on a case by case basis in a

pre-analysis meeting in order to define the population to be analysed. CONSORT rules will be applied to

describe study flow and protocol deviations.

All time to event curves will be drawn with the Kaplan-Meier method. All comparisons between arms will

be performed by long-rank test. Statistical significance of difference will also be tested by a multivariable

Cox�s model including stratification variables and clinical/biological features as covariates. Results will be

presented as HRs and their 95% CIs.


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14.4. Response rate

Only patients with at least one target lesion will be considered eligible for response assessment.

Behaviour of patients with non target lesions only will be described.

Response rates in the two arms will be described with their 95% CIs and will be compared with chi-

square test in a 2x2 contingency table (responders/non-responders x treatment arms).

14.5. Safety analyses

All safety parameters will be presented and analysed in terms of listings and summary tables. The

analyses, will be conducted on the safety population, including all patients who received at least one

cycle of treatment. Patients will be assigned to treatment groups based on what they actually received.

The assessment of safety will be mainly based on toxicity and the frequency and nature of SADRs.

For each patient and for each type of toxicity, the worst degree ever suffered during second-line

treatment will be used for the analysis.

Two sets of statistical analyses will be performed to compare toxicity between the two arms. In the first

set the whole pattern of toxicity (all grades) will be considered for each item; analysis will be done by a

linear rank test. In the second set toxicity will be defined as severe (mostly including grade 3 or higher)

and not severe (mostly including grades up to 2) and analysis will be performed by Fisher�s exact test. In

both cases exact tests will be applied because it is foreseeable that (although the large sample size)

there will be uncommon toxic effects that will affect a small number of patients.

For each treatment arm, the number and percentage of patients having any SADR, will be presented.

Other information collected (e.g. severity or suspected relationship to study medication) will be listed as

appropriate.

The evaluation of number of cycles given, the modification of dose and reasons for ending the treatment

will be tabulated and described for each treatment arm.

14.6. Quality of life

QoL will be compared between the two arms only during the second line phase of treatment.

EORTC questionnaires will be managed according to standard rules for their analysis reported in the

EORTC manuals and the Guidelines of the Quality of Life Committee of National Cancer Institute of

Canada Cancer Treatment Group [23].

The pattern of missing data will be analyzed under different frames: rate of patients completing baseline

assessments and the assessments at designated time points over the total number of patients eligible

and entered onto the trial, rate of patients completing assessments at designated time points while

enrolled onto the study over the total number completing assessment at baseline, and rate of patients

completing assessments at designated time points over the number of patients still enrolled onto the

study that were expected to complete questionnaires at each of those time points.

Missing values will be described Multi-item scales are computed by calculating the mean raw scores of

single items and transforming them linearly so that all scales range from 0 to 100. For single items, only


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linear transformation is performed. For functioning scales (i.e. those exploring physical, role, emotional,

cognitive and social functioning and global health status), the higher the value the better the level of

function; for symptoms scales and items, the higher the value the worse the severity of symptoms.

Change scores (ie, differences from baseline) will be calculated and described at 3, 6 and 9 weeks for

each domain or symptom and within each arm.

The best response from baseline will be calculated for each domain or symptom as follows. A change

score of at least 10 points from baseline is defined as clinically relevant [23]. For each domain patients

will be considered improved if they will report a score >10 points better than baseline at any time of QoL

assessment. Conversely, patients will be considered worsened if they reported a score <10 points worse

than baseline at any time of QoL assessment without any improvement. Patients whose scores will be in

between 10-point changes from baseline at every QoL assessment will be considered to be stable. An

exact linear rank test will be used to test whether the two study arms will have the same underlying

multinomial distribution of the ordered QoL response. Because of the natural ordering of the response

categories (improved, stable, or worsened), multivariate analysis (including treatment arm and

stratification factors as covariates) will be performed by fitting a continuation ratio logistic regression

model for ordinal outcomes [24].

14.7. Interim analyses

After two years from the beginning of the study, and then on annual basis, interim analyses will be

conducted. In principle, no formal stopping rule will be applied, unless otherwise suggested by the DSMC.

Furthermore, the assumptions of the sample size calculation will be verified and if necessary adequate

sample size will be recalculated.

Safety reports will be drawn on annual basis.

In order to take into account the suggestions of the DSMC:

- an external statistician was asked to reformulate, if deemed necessary, the primary hypothesis of the

study. This led to the changes provided by the second amendment to the study protocol;

- since the decision to change the primary aim of the study was attributable only to evidences external

to the study, and not driven by the interim analysis results, it was not considered necessary to adjust

the overall type I error in order to make allowance for multiple analyses performed.

After the achievement of the required number of pts, the DSMC will be periodically informed on the

study progress in terms of data quality and number of events occurred;

- a statistician in charge of the interim analyses and not involved as a member of the Steering

Committee was identified.


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15. INDEPENDENT DATA & SAFETY MONITORING COMMITTEE

A DSMC will evaluate the results of interim analyses. Two expert clinicians and two statisticians, who are

not involved in the study and have no conflict of interest with respect of study results, will compose the

DSMC.

The role of the DSMC is to look at the data from an ethical standpoint, the safety, rights and well being of

the trial participants being paramount.

Specific tasks of DSMC are:

Evaluation of all the aspects concerning the study progress (i.e.: accrual rate, protocol compliance,

event rate)

Evaluation of treatment toxicity

Evaluation of efficacy data of interim analysis. It will be presented [unblinded] by the study

statistician to the DSMC. The DSMC may also ask for any additional information, if considered

appropriate

Drawing of a report to the Steering Committee summarising recommendations for study prosecution

and possible protocol modification.

16. DATA COLLECTING AND MONITORING

Data will be reported on the e-CRF connecting to: http://crc.marionegri.it/trials/tailor.

A data validation plan will be used in order to check the consistency, completeness and accuracy of the

data entered and data clarification forms (DCFs) will be sent to the investigators. Those DCFs must be

answered by the investigator (or an authorized staff member).

Each participating investigator will be responsible for ensuring data quality. Each reported information will

be systematically checked for consistency, completeness and accuracy by the Coordinating Data Centre

that will issue DCFs in case of inconsistent data.

Local quality control will be provided by coordinating center, which will be responsible of monitoring all

participating centres.

17. ETHICS AND GOOD CLINICAL PRACTICE

The responsible Investigator will ensure that this study is conducted in compliance with the protocol,

following the instructions and procedures described in it, adhering to the principles of Good Clinical

Practice and with current local legislation and in accordance with:

ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996

Directive 2001/20/EEC of the European Parliament and of the Council

Declaration of Helsinki concerning medical research in humans (Helsinki 1964, amended Tokyo 1975,

Venice 1983, Hong Kong 1989, Somerset West 1996 and Edinburgh)

http://crc.marionegri.it/trials/tailor.


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17.1. Patient protection

The names of pts will not be recorded. A sequential identification number will be automatically attributed

to each patient registered in the trials. This number will identify the patient and must be included on all

CRFs.

In order to avoid identification errors, patient initials (maximum of 4 letters) and date of birth will also be

reported on the CRFs. Investigators will guarantee that all persons involved in this study will respect the

confidentiality of any information concerning the trial subject.

All parties involved in this clinical trial will maintain the strict confidentiality to assure that neither the

person nor the family privacy of the patient participating in the trial is violated; appropriate measures

shall be taken to avoid the access of non-authorized persons to the trial data. The processing of the

personal data of patients taking part in the trial, and in particular regarding data concerning consent,

shall comply with local law on the privacy (Legge delega 127/2001) and with the European Directive on

the Privacy of data (95/46/EC).

17.2. Informed consent

The investigator must explain to each patient (or legally authorised representative) the nature of the

study, its purpose, the procedures involved, the expected duration, the potential risks and benefits

involved and any discomfort it may entail. Each patient must be informed that participation in the study

is voluntary and that she/he may withdraw from the study at any time and that withdrawal of consent

will not affect her/his subsequent medical treatment or relationship with treating physician. The informed

consent will be given by means of standard written statement, using non-technical language. The patient

should read and consider the statement before signing and dating it, and should be given a copy of the

signed document. If the subject cannot read or sign the document, oral presentation may be made or

signature given by the subject�s legally appointed representative, if witnessed by a person not involved in

the study, mentioning that the patient could not read or sign documents. No patient can enter the study

before her informed consent has been obtained. The informed consent is part of the protocol and must be

submitted by the investigator to the local ECs.

18. TRIAL SPONSORSHIP AND FINANCING

The study is sponsored by Ospedale Fatebenefratelli Oftalmico, Milano which plays the role of not-for-

profit Sponsor.

The trial is financially supported by the AIFA with a grant for independent clinical researches (grant no.

FARM6F5JER). All study drugs are already included in the Italian national formulary and reimbursed by

the Italian National Health System.

No funds will be provided to ECs in accordance to the D.Lgs 24-06-2003 and DM 17-12-2004

Results derived from the trial are property of the Dipartimento di Oncologia, Ospedale Fatebenefratelli

Oftalmico, Milano which shares it with all participating investigators.


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19. PUBLICATION POLICY

Publications will be decided by the Steering Committee of the study. Other co-authors to be reported in

the front page will be selected on the basis of the specific contribution or the number of enrolled patients

and on the consistency, completeness and accuracy of the data. All papers will report the statement ��

on behalf of the TAILORAIFA Investigators�, as well as those investigators, who mostly contributed to

study recruitment. Furthermore, all manuscripts will include an appropriate acknowledgment section,

mentioning all investigators who have contributed to the trial, as well as supporting bodies.

Rules for abstract presentation will be the same as for extended papers.

20. REFERENCES

1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin Oncol 51: 15-

36, 2001

2. Schiller JH, Harrington D, Belani CP Comparison of four chemotherapy regimens for advanced NSCLC.

N Engl J Med 346: 92-98, 2002

3. Shepherd F, Dancey J, Ramlau R et al: Prospective randomized trial of docetaxel versus best

supportive care in patients with non small cell lung cancer previously treated with platinum based

chemotherapy. J Clin Oncol 18: 2095-2103, 2000

4. Schuette W, Nagel S, Blankenburg et al: Phase III study of second-line Chemotherapy for advanced

Non-Small- Cell Lung Cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol 23: 8389-

8395, 2005

5. Hanna N, Shepherd F, Fossella F et al Randomized phase III trial of pemetrexed versus docetaxel in

pts with non small cell lung cancer previously treated with chemotherapy J Clin Oncol 2004

6. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung

cancer. N Engl J Med 2005; 353:123-32

7. Gatzemeier U, Pluzanska A, Szczesna A, et al. Results of a phase III trial of erlotinib (OSI-774)

combined with cisplatin and GEM (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J

Clin Oncol 2004; 22: 7010

8. Herbst RS, Preger D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774)

combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin

Oncol 2005; 23: 5892-9

9. Doulillard JY, Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non

small cell lung cancer pre treated with platinum-based chemotherapy: a randomized, apen-label phase

III study (INTEREST) Journal of Thoracic Oncology Vol 2 number 8 August 2007

10. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary

adenocarcinoma. N Engl J Med 361:947-957, 2009

11. Yang CH, Fukuoka M, Mok TS, et al: Final overall survival (OS) results from a phase III, randomised,

openlabel, first-line study of gefitinib (G) v carboplatin/paclitaxel (C/P) in clinically selected patients with

advanced nonsmall cell lung cancer (NSCLC) in Asia (IPASS). Ann Oncol 21:viii1-viii2, 2010 (suppl 8)


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12. Lee JS, Park K, Kim SW: A randomized phase III study of gefitinib versus standard chemotherapy

(gemcitabine plus cisplatin) as a first-line treatment for neversmokers with advanced or metastatic

adenocarcinoma of the lung. 13th World Conference on Lung Cancer, San Francisco, July 31-August 4,

2009 (abstr PRS.4)

13. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for non-small-cell lung cancer

with mutated EGFR. N Engl J Med 362:2380-2388, 2010

14. Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin plus docetaxel in patients with

nonsmall-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405):

An open label, randomised phase 3 trial. Lancet Oncol 11:121-128, 2010

15. VL Keedy, STemin, M Somerfield, MB Beasley, American Society of Clinical Oncology Provisional

Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced

Non�Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy J Clin Oncol

29;15, 2011

16. Kim ES, Hirsch V, Mok T, et al: Gefitinib versus docetaxel in previously treated non-small-cell lung

cancer (INTEREST): A randomised phase III trial. Lancet 372:1809-1818, 2008

17. Ciuleanu T, Stelmakh L, Cicenas S et al, Erlotinib versus docetaxel or pemetrexed as second line

therapy in patients with advanced Non Small Cell Lung Cancer and poor prognosis: efficacy and safety

results from phase III TITAN study ASCO Proceedings Multidisciplinary Thoracic Symposium Chicago 2010

18. Maruyama R, Nishiwaki Y, Tamura T et al: Phase III Study, V-15-32, of Gefitinib Versus Docetaxel in

Previously Treated Japanese Patients With Non�Small-Cell Lung Cancer J Clin Oncol 26: 4244-4252, 2008

19. Ji H. Mechanistic insights into acquired drug resistance in epidermal growth factor receptor mutation-

targeted lung cancer therapy. Cancer Sci. 2010 Sep;101(9):1933-8

20. Pao W, Girard N.New driver mutations in non-small-cell lung cancer Lancet Oncol. 2011

Feb;12(2):175-80

21. Aaronson NK, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a

quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85: 365-

376, 1993

22. Bergman B, et al. The EORTC QLQ-LC13: a modular supplement to the EORTC core quality of life

questionnaire (QLQ C30) for use in lung cancer clinical trials. Eur J Cancer 30A: 630-642, 1994

23. Osoba D, Bezjak A, Brundage M, et al. Analysis and interpretation of health-related quality-of-life

data from clinical trials: basic approach of the National Cancer Institute of Canada Clinical Trials Group.

Eur J cancer 41; (2): 280-7, 2005

24. Armstrong BG, Sloan M. Ordinal regression models for epidemiologic data. Am J Epidemiol 129: 191-

204, 1989

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