istitutofondazione ricerca piemonte per l’ cura del cancro ... · with her2-positive metastatic...

004-IRCC-10IIS-12 Protocol Version 3.0 - 18 June 2015

________________________________________________________________________________________________

Confidential Page 1 of 87

Istituto per la Ricerca e la Cura del Cancro

Fondazione del Piemonte per l Oncologia

Open-Label, Phase II Study of Trastuzumab in Combination with

Lapatinib or Pertuzumab in Combination with Trastuzumab in Patients

with HER2-positive Metastatic Colorectal Cancer: the HERACLES Trial

(HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification)

IMP Identifiers: Trastuzumab

Lapatinb

Pertuzumab

Protocol Number: 004-IRCC-10IIS-12

EudraCT Number: 2012-002128-33

Protocol Version (Date): V3.0 - 18 June 2015

Sponsor: FPO_IRCC, Candiolo (Torino)

CONFIDENTIAL

This document contains confidential information belonging to Sponsor. Except as may be otherwise agreed

to in writing, by accepting or reviewing these materials, you agree to hold such information in confidence

and not to disclose it to others (except where required by applicable law), nor to use it for unauthorized

purposes. In the event of actual or suspected breach of this obligation Sponsor should be promptly notified.


________________________________________________________________________________________________




SPONSOR SIGNATURE

Paolo Maria Comoglio

Sponsor Representative

22/06/2015

Signature Date

STUDY CHAIR SIGNATURE

Dr. Salvatore Siena

Study Chair

22/06/2015

Signature Date


________________________________________________________________________________________________




PRINCIPAL INVESTIGATOR AGREEMENT

I have read the Protocol entitled Open-Label, Phase II Study of Trastuzumab in Combination with Lapatinib

or Pertuzumab in Combination with Trastuzumab in Patients with HER2-positive Metastatic Colorectal

Cancer: the HERACLES Trial (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification) and I

agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good Clinical

Practice and applicable regulatory requirements. I will provide all study personnel under my supervision with

all information provided by the Sponsor and I will inform them about their responsibilities and obligations.

Principal Investigator

(printed name, Institution, Department and location)

Signature Date


________________________________________________________________________________________________




ADDITIONAL TRIAL PERSONNEL/SITE INFORMATION

Sponsor Fondazione Piemonte Oncologia (FPO),

Strada Provinciale 142 km 32, 10060 Candiolo (To)

Phone: 011-993-3601

Fax: 011-962-1525

E-mail: [email protected]

Sponsor authorized representative

Prof. Paolo Maria Comoglio


Phone: 011-993-3601

Fax: 011-962-1525


Sponsor Medical officer

Dr. Silvia Marsoni


Phone: 011-993-3926

Fax: 011-962-1525


Study Chair Dr. Salvatore Siena

Divisione Oncologia Falck, Ospedale Niguarda Ca

Granda, Piazza Ospedale Maggiore 3, 20162 Milano

Phone: +39-02-6444.2291

Fax: +39-02-6444.2957


Principal Investigators Dr. Andrea Sartore Bianchi

Divisione Oncologia Falck, Ospedale Niguarda Ca

Granda, Piazza Ospedale Maggiore 3, 20162 Milano

Phone: +39-02-6444.2291

Fax: +39-02-6444.2957


Dott. Francesco Leone

Fondazione Piemonte Oncologia (FPO),


Phone: 011-993-3628

Fax: 011-962-1525


Dr. Zagonel Vittorina

IOV, Istituto Oncologico Veneto, Padova

Phone: +39 049 8215953 - 5909

Fax: +39 049 8215890


Dr. Carmine Pinto

Unit Operativa di Oncologia Medica

S. Orsola Malpighi (Bologna)

Phone: 051-6362-204

Fax: 051-6362-207


________________________________________________________________________________________________




E-mail:[email protected]

Dr. Fortunato Ciardiello

Unit operativa complessa Oncologia Medica

AOU Seconda Universit degli studi di Napoli .

Phone: 081-5666-745

Fax: 081-5666-732


Contract Research Organization (CRO)

CLIOSS Srl

V.le Pasteur, 10

20014 Nerviano (MI), ITALY

Pharmacovigilance (SAE Reporting) Fondazione del Piemonte per lOncologia

Dr. Cosimo Martino


Phone: 011-993-3842

Fax: 011-993-3318


Central laboratories for Pharmacogenomics

(body fluids, tissue samples)

Istituto di Anatomia Patologica Ospedale Niguarda Ca

Granda,

Dr. Emanuele Valtorta

Piazza Ospedale Maggiore 3, 20162 Milano

Phone: 02-6444-2702

Fax:02-6444-2102


Laboratorio di Genetica Molecolare Istituto per la Ricerca

e la Cura del Cancro, Candiolo

Prof. Alberto Bardelli

S.P. 142 Km 3.95 Candiolo (TO)

Phone: 011-993-3235

Fax: 011-962-1525


Laboratorio di Biochimica Clinica

Piano Terra - Padiglione 9

Dr. Laura Farioli, Dr. Simonetta Granata

Ospedale Niguarda Ca Granda

Piazza Ospedale Maggiore 3, 20162 Milano

Phone + 39 02 6444 2428/2559

Fax: + 39 02 6444 2901

E-mail: [email protected] ;

[email protected]
mailto:[email protected]:[email protected]


________________________________________________________________________________________________




TABLE OF CONTENTS

1 SYNOPSIS ............................................................................................................................................................. 9

2 SCHEDULE OF EVENTS ..................................................................................................................................... 15

3 ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................................................................... 19

4 BACKGROUND INFORMATION ...................................................................................................................... 21

LAPATINIB ..................................................................................................................................................................... 21 TRASTUZUMAB .............................................................................................................................................................. 22 PERTUZUMAB ................................................................................................................................................................ 22

5 STUDY RATIONALE ............................................................................................................................................ 23

6 STUDY OBJECTIVES........................................................................................................................................... 23

6.1 PRIMARY OBJECTIVE ......................................................................................................................................... 23 6.2 SECONDARY OBJECTIVE(S) ................................................................................................................................ 23 6.3 EXPLORATORY OBJECTIVE(S) ............................................................................................................................ 23

7 STUDY ENDPOINTS ............................................................................................................................................ 24

7.1 PRIMARY ENDPOINT .......................................................................................................................................... 24 7.2 SECONDARY ENDPOINT(S) ................................................................................................................................. 24 7.3 EXPLORATORY ENDPOINT(S) ............................................................................................................................. 24

8 STUDY DESIGN .................................................................................................................................................... 24

9 STUDY POPULATION ......................................................................................................................................... 24

9.1 SUBJECT SELECTION .......................................................................................................................................... 24 9.1.1 Subject Inclusion Criteria ......................................................................................................................... 25 9.1.2 Subject Exclusion Criteria ........................................................................................................................ 25

9.2 SCREENING FAILURES ........................................................................................................................................ 26 9.3 REPLACEMENTS ................................................................................................................................................. 26

10 ENROLLMENT PROCEDURES ..................................................................................................................... 26

11 STUDY TREATMENT ...................................................................................................................................... 27

11.1 DESCRIPTION OF INVESTIGATIONAL PRODUCT (S) ............................................................................................. 27 11.1.1 Lapatinib ................................................................................................................................................... 27 11.1.2 Trastuzumab.............................................................................................................................................. 27 11.1.3 Pertuzumab ............................................................................................................................................... 27

11.2 DRUG PREPARATION .......................................................................................................................................... 27 11.2.1 Instructions for trastuzumab reconstitution .............................................................................................. 27 11.2.2 Instructions for pertuzumab reconstitution ............................................................................................... 28

11.3 TREATMENT DOSE AND SCHEDULE ................................................................................................................... 28 11.4 DURATION OF TREATMENT ................................................................................................................................ 30 11.5 DRUG ACCOUNTABILITY ................................................................................................................................... 30 11.6 SAFETY PROFILE OF INVESTIGATIONAL PRODUCTS ........................................................................................... 31

11.6.1 Lapatinib Warnings and Precautions ....................................................................................................... 31 11.6.2 Trastuzumab Warnings and Precautions .................................................................................................. 32 11.6.3 Pertuzumab Warnings and Precautions.................................................................................................... 33

11.7 TREATMENT INTERRUPTION AND DOSE MODIFICATIONS GUIDELINE IN CASE OF ADVERSE EVENT .................... 34 11.7.1 Dose Reductions ....................................................................................................................................... 34 11.7.2 Dose Delay and Dose reduction in case of Drug Related Toxicity ........................................................... 34


________________________________________________________________________________________________




11.7.3 Infusion-Associated Symptoms and Allergic Reactions ................................................................................. 36 11.7.4 Incomplete Loading Dose of Trastuzumab and Pertuzumab .................................................................... 36 11.7.5 Continuation/discontinuation study treatment based on LVEF assessment ............................................. 37 11.7.6 Liver Chemistry Stopping Criteria ............................................................................................................ 38 11.7.7 Liver Chemistry Follow-up Criteria ........................................................................................................ 39 11.7.8 Management of Diarrhoea ........................................................................................................................ 40 11.7.9 Management of Dermatological events .................................................................................................... 40

11.8 CONCOMITANT MEDICATIONS AND OTHER THERAPY ....................................................................................... 41

12 SUBJECT WITHDRAWAL FROM STUDY PARTICIPATION ................................................................. 43

13 TREATMENT ASSESSMENT ......................................................................................................................... 43

13.1 SCREENING EVALUATIONS ................................................................................................................................ 43 13.2 ON STUDY EVALUATIONS.................................................................................................................................. 44 13.3 OFF TREATMENT EVALUATIONS ........................................................................................................................ 45 13.4 FOLLOW-UP EVALUATIONS ............................................................................................................................... 45 13.5 DETAILS OF INDIVIDUAL ASSESSMENTS ............................................................................................................ 45 13.6 PHARMACOGENOMICS STUDIES ......................................................................................................................... 46

14 SAFETY ASSESSMENTS ................................................................................................................................. 47

14.1 PRE-EXISTING CONDITION.................................................................................................................................. 47 14.2 ADVERSE EVENT ASSESSMENT .......................................................................................................................... 47 14.2 ADVERSE EVENT REPORTING PERIOD ............................................................................................................... 49 14.3 REPORTING PROCEDURES FOR ADVERSE EVENT ................................................................................................ 50 14.4 RECORDING ADVERSE EVENTS IN THE CASE REPORT FORMS ............................................................................ 51 14.5 CAUSALITY ASSESSMENT AND GRADING OF ADVERSE EVENT SEVERITY ......................................................... 51 14.6 PREGNANCY REPORTING ................................................................................................................................... 52 14.7 OVERDOSE ......................................................................................................................................................... 52 14.8 FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS .............................................................................................. 53

15 EFFICACY ASSESSMENTS ............................................................................................................................ 53

15.1 DEFINITION OF EFFICACY PARAMETERS ............................................................................................................. 53

16 STATISTICAL METHODS .............................................................................................................................. 53

16.1 SAMPLE SIZE CALCULATION .............................................................................................................................. 53 16.2 STUDY POPULATION .......................................................................................................................................... 53 16.3 ANALYSIS .......................................................................................................................................................... 54

16.3.1 Study Conduct and Subject Disposition ......................................................................................................... 54 16.3.2 Baseline Characteristics and treatment Group Comparability ..................................................................... 54 16.3.3 Treatment Analysis ........................................................................................................................................ 54 16.3.4 Safety Analysis ............................................................................................................................................... 54 16.3.5 Pharmacogenomics Analysis (or any other ancillary analysis if applicable) ................................................ 55 16.3.6 Efficacy Analysis ............................................................................................................................................ 55

17 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................ 55

17.1 MONITORING ..................................................................................................................................................... 55 17.2 AUDITING .......................................................................................................................................................... 56 17.3 LABORATORY REQUIREMENTS .......................................................................................................................... 56

18 DATA HANDLING AND RECORD KEEPING ............................................................................................. 56

18.1 CASE REPORT FORM (CRF) ........................................................................................................................... 56 18.2 DATA HANDLING ............................................................................................................................................... 56 18.3 RECORD RETENTION .......................................................................................................................................... 57


________________________________________________________________________________________________




19 ETHICAL CONSIDERATION ......................................................................................................................... 57

19.1 INSTITUTIONAL REVIEW BOARD(IRB)/ INDEPENDENT ETHICS COMMITTEE (IEC) AND COMPETENT AUTHORITY (CA) 57 19.2 ETHICAL CONDUCT OF THE TRIAL ...................................................................................................................... 57 19.3 INFORMED CONSENT ......................................................................................................................................... 57

20. STUDY DISCONTINUATION CRITERIA .................................................................................................... 58

21 LIABILITY AND INSURANCE ....................................................................................................................... 58

22 CONFIDENTIALITY OF INFORMATION AND PUBLICATION OF RESULTS ................................... 59

23 REFERENCES ................................................................................................................................................... 59

24 APPENDIX 59


________________________________________________________________________________________________




1 SYNOPSIS

Protocol Title: Open-Label, Phase II Study of Trastuzumab in Combination with Lapatinib or

Pertuzumab in Combination with Trastuzumab in Patients with HER2-positive

Metastatic Colorectal Cancer: the HERACLES Trial (HER2 Amplification for

Colo-rectaL Cancer Enhanced Stratification)

Protocol Number:

IMPS: Lapatinib

Oral formulation

250 mg tablets

Glaxo Smith Kline

Trastuzumab

i.v. formulation

440 or 150 mg/vial

Roche

Pertuzumab

i.v. formulation

30 mg/mL

Roche

Participating countries Italy

List of study centres Ospedale Niguarda Ca Granda, Milano; FPO, Fondazione Piemonte Oncologia,

Candiolo, Torino, IOV, Istituto Oncologico Veneto, Padova; Policlinico S. Orsola

Malpighi, Bologna, Universit Federico II, Napoli.

Background Information and

Study Rationale

Metastatic colorectal carcinoma (mCRC) is the second or third most common

cancer in developed countries and remains a nearly universally fatal disease;

despite the treatment advances made in the last decade, the 5-year survival for

patients with mCRC remains indeed only 10%1. The development monoclonal

antibodies (moAbs) directed against the epidermal growth factor receptor (EGFR)

has provided additional therapeutic options for patients with mCRC progressing

through chemotherapy, and may increase the efficacy of chemotherapy when

given in combination2. Response rates in the range of 13%-17% are achievable by

EGFR-targeted moAbs in tumours without mutations in codon 12 or 13 of the

KRAS gene, whereas only 0%-1.2% of the KRAS mutant tumours respond to this

therapy3. Nevertheless, even in KRAS wild-type CRCs, about 40% of the

previously untreated and about 60%-70% of the previously treated do not respond

to anti-EGFR treatment4. Additional detection of NRAS, BRAF,and PIK3CA exon

20 mutations and loss of PTEN protein may further enhance selection of patients

but elucidation of other mechanism(s) by which tumor cell resistance is acquired

in this setting and identification of druggable molecular targets to overcome

resistance are clearly a priority of clinical research, since there are no other

available therapeutic options for patients progressing during or after standard

medical therapies.

In a recent study by our group, we exploited direct transfer xenografts of mCRC

surgical specimens in mice (xenopatients) to discover novel determinants of

therapeutic response and new druggable driver oncoproteins6. This approach,

combining the flexibility of preclinical analysis with the informative value of

population-based studies, led to the identification of HER2 amplification as an

additional molecular marker of resistance to EGFR-targeted therapy with

cetuximab in xenopatients harbouring mCRC tumors for which other known

molecular alterations conferring resistance were excluded, i.e., KRAS, NRAS,


________________________________________________________________________________________________




BRAF, and PIK3CA mutations. In this defined subset, HER2 amplification was

detected in 4 of 11 cases (36%), suggesting a greater frequency of HER2

amplification in cetuximab-resistant cases and its progressive enrichment along

with refinement of genetic selection. Indeed, data from literature show that HER2

amplification occurs in a small percentage (2%-3%) of genetically unselected

colorectal cancers7, 8, 9

, but its incidence increases in KRAS wild-type colorectal

cancer patients that displayed de novo resistance to anti-EGFR therapies (13.6%)

and possibly rises to a summit in KRAS/NRAS/BRAF/PIK3CA WT tumors

resistant to EGFR-targeted therapies6.

A proof-of-concept, multi-arm study in HER2-amplified xenopatients revealed

that combinations of the dual small molecule EGFR/HER2 inhibitor lapatinib and

the anti-HER2 moAb trastuzumab or lapatinib and the HER-dimerization inhibitor

moAb pertuzumab induced overt, long-lasting tumor regressions, while

monotherapy with lapatinib led to disease stabilization and either monotherapy

trastuzumab or pertuzumab were ineffective6. The combination of pertuzumab and

trastuzumab has also a strong rationale for treatment of HER2-amplified tumors,

since recent clinical observations have demonstrated that combining these two

moAbs together yields synergistic results in HER2 positive breast cancers that

progressed during prior trastuzumab therapy19

, suggesting a cooperative

mechanism of inhibition. Currently, the latter combination is also being explored

in our xenopatients platform (Trusolino, personal communication).

Based on these findings, the combinations of trastuzumab and lapatinib or

pertuzumab and trastuzumab appear to have a sounded rationale for the treatment

of those mCRC harbouring amplification of the HER2 oncogene. This hypothesis-

driven trial will test whether these two distinct anti-HER2 therapy combinations

would produce a response rate 30% in chemorefractory mCRC patients, for

whom further effective treatment remains an unmet clinical need. Safe doses for

both trastuzumab combinations have been already established in the clinic for

gastric and breast cancer in different clinical settings. The combination of

pertuzumab and trastuzumab has been tested in breast cancer patients (pertuzumab

840 mg/loading dose, followed by 420 mg q3wks, plus trastuzumab 4 mg/kg

loading dose, then 2 mg/kg weekly or 8 mg/kg loading dose, then 6 mg/kg

q3wks19

.

Primary Objective Define the antitumor activity of the anti-HER2 combinations of lapatinib +

trastuzumab and pertuzumab + trastuzumab given to two separate, sequential

cohorts of patients with chemo-refractory advanced disease and HER2 amplified

tumours.

Secondary Objective(s) 1. Define the safety profile of the two combinations

2. Define the Progression Free Survival (PFS)

Exploratory Objectives 1. To determine whether selected tumor biomarkers evaluated in tumor specimens,

including but not limited to mutations of effectors downstream of HER-family

receptors (such as KRAS, BRAF and PIK3CA) or related tyrosine kinase

receptors, have association with response/resistance to experimental treatment

2. To determine whether selected tumor biomarkers as evaluated from circulating

tumor DNA, including but not limited to mutations of effectors downstream of

HER-family receptors (KRAS, BRAF, and PIK3CA) or related tyrosine kinase

receptors, evolve during tumor progression


________________________________________________________________________________________________




Primary Endpoint Objective Response Rate according to RECIST 1.1 criteria

Secondary Endpoint(s) 1. Description of the frequency and severity of Adverse Events based on the NCI CTCAE V4.0

2. PFS

Exploratory Endpoints 1. Correlation between selected tumor biomarkers evaluated in tumor specimens (including but not limited to mutations of effectors downstream of HER-family

receptors - such as KRAS, BRAF, and PIK3CA, or related tyrosine kinase

receptors), and tumor response/resistance to experimental treatment

2. Comparison of tumor biomarkers status in blood samples collected before start

of treatment, with that collected during treatment and after progression

Study Design This is a Phase II multi-center 2-sequential cohorts trial, designed to assess the

objective response rate of the anti HER2 monoclonal antibody trastuzumab, used

in combination with either the small molecule tyrosine kinase inhibitor lapatinib

(Cohort A) or the monoclonal antibody pertuzumab (Cohort B), in advanced

disease CRC patients harbouring an amplified HER2 tumor (SISH).

Treatment Cohort A:

- lapatinib 1000 mg daily per os

- trastuzumab 4 mg/kg iv load, followed by 2 mg/kg iv weekly

Cohort B:

- pertuzumab 840 mg/kg iv load, followed by 420 mg/kg iv Q3weeks

- trastuzumab 8 mg/kg iv load, followed by 6 mg/kg on day 1 of each

subsequent 3 week cycle

Treatment Duration Patients enrolled in both cohorts will receive study medication until disease

progression, unacceptable toxicity, withdrawal of consent or death, whichever

come first.

Supportive Therapy N.A.

Efficacy Assessments Objective tumor response in target and non-target lesions will be assessed

according to RECIST 1.1 criteria.

Tumor response will be assessed starting on week 8 and every 8 weeks thereafter.

Tumor response MUST be confirmed 4 + 1week from first assessment of

response.

Safety Assessments Frequency and severity of Adverse Events will be recorded according to the NCI

CTCAE V4.0.

Pharmacogenomics

Assessments

Tumor specimens (primary tumor and/or metastases) must be available in a

mandatory manner for all patients for evaluation of HER2 status (as per inclusion

criteria) and evaluation of selected tumor biomarkers including but not limited to

mutations of effectors downstream of HER-family receptors (such as KRAS,

BRAF and PIK3CA) or related tyrosine kinase receptors, with the aim of

evaluating their potential association with response/resistance to experimental

treatment.

All patients will undergo a blood test for retrieving circulating tumor DNA


________________________________________________________________________________________________




(ctDNA) at selected time-points before and during treatment for determining

whether the status of selected tumor biomarkers, including but not limited to

molecular alterations of effectors downstream of HER-family receptors or related

tyrosine kinase receptors (such as mutations of KRAS, BRAF and PIK3CA)

evolve during tumor progression by comparing different ctDNA samples. Blood

samples will be also analysed for determination of circulating serum levels of the

extra-cellular domain of HER2 (HER2 ECD) as a non invasive surrogate measure

of changes in tumor HER2 during treatment.

Sample Size For each cohort the sample size has been calculated basing on the Fleming & Hern

single stage design, and under the following identical assumptions:

1. Standard proportion of eligible patients which would respond to a

chemotherapy (H0) = 10%

2. Minimum required proportion of patients expected to respond to the

combination (H1) = 30%

Given =0.05 and power=0.85, 27 patient (N) are required in each trial cohort

(Part A 27 + Part B 27 = 54 patients overall).

Each combination (A or B) will be considered positive if at least 6 responses/27

patients are observed.

In March 2015, HERACLES met the primary endpoint, since we observed 8

responses in the first 23 evaluable patients (1CR+7PR).

In May 2015 we have enrolled the 27th patient required to complete cohort A, but

in the screening procedures we found other 6 potentially eligible HER2 amplified

patients. We plan to extend cohort A enrollment from 27 to 33 patient for ethical

reason, in order to not deprive these patients of a potential effective and very well

tolerated treatment.

Under the same statistical assumptions, extending the cohort A sample size from

27 to 33 will require 7/33 instead of 6/27 OR in order to declare the study

positive; as of June 2015 we already have 8 OR the study will be positive in any

case.

Inclusion Criteria

(valid for Cohorts A & B)

Subjects must meet all the following inclusion criteria to be eligible for enrolment

into the study:

1. Histological/confirmed adenocarcinoma of the colon or rectum with

metastatic disease not amenable to salvage surgery

2. Pathology mandatory requirements:

a. the original tumour specimen must be KRAS WT and SISH/FISH positive or IHC 3+ positive in more than 50% cells.

Note: for immunohistochemistry a positive staining (3+) is defined as an

intense membrane staining which can be circumpherential, basolateral,

or lateral of the tumor cells.

b. the original paraffin block or a minimum of 15 polarized unstained

slides from the original paraffin block must be made available to the

Pathology Core within 15 days from registration.


________________________________________________________________________________________________




3. Age 18.

4. ECOG PS 0-1.

5. Measurable disease as defined by RECIST 1.1 criteria.

6. Progression (PD) while on treatment, or within 6 months from therapy with

approved standard drugs.

7. Unless otherwise contraindicated patients should have received and failed

the following previous therapies for mCRC: fluoropirimidines, oxaliplatin,

irinotecan, cetuximab or panitumumab containing regimens. Bevacizumab is

allowed.

8. Adequate haematological function as defined by: ANC 1.5 x 109/L, platelet

count 100 x 109/L, haemoglobin 10 g/dL.

9. Adequate renal function, as defined by: creatinine 1.5 x UNL.

10. Adequate hepatobiliary function, as defined by the following baseline liver

function tests:

o total serum bilirubin 1.5 upper normal limit (UNL)

o alanine aminotransferase (ALT), aspartate aminotransferase (AST)

2.5xUNL

o alkaline phosphatase (AP) 2.5xUNL; if total alkaline phosphatase (AP)

> 2.5xUNL, alkaline phosphatase liver fraction must be 2.5xUNL

11. Adequate contraception for all fertile patients.

12. Negative pregnancy test.

Exclusion criteria

(valid for Cohorts A & B)

Subjects meeting any of the following criteria must not be enrolled in the study:

1. Radiotherapy 4 weeks prior to enrolment

2. Other chemotherapy or biological therapy treatment 4 weeks prior to

enrolment

3. Symptomatic brain metastases

4. Active infection

5. Gastro-intestinal abnormalities, inability to take oral medication, any

condition affecting absorption

6. Impaired cardiac function including any of the following: uncontrolled

hypertension (systolic >150 mmHg and/or diastolic > 100 mmHg) or

clinically significant (ie active) cardiovascular disease: cerebrovascular

accident/stroke or myocardial infarction within 6 months prior to first study

medication; unstable angina; chronic heart failure (CHF) of New York Heart

Association (NYHA) Grade II or higher; or serious cardiac arrhythmia

requiring medication, baseline Left Ventricular Ejection Fraction (LVEF)

55% measured by echocardiography (ECHO)

7. Major surgery in the two weeks prior to entering the clinical trial

8. Concurrent treatment with any other anti-cancer therapy

9. History of another neoplastic disease (except basal cell carcinoma of the skin

or uterine cervix carcinoma in situ adequately treated), unless in remission

for 5 years

10. Patient unable to comply with the study protocol owing to psychological,

social or geographical reasons

11. Pregnant and lactating women


________________________________________________________________________________________________




12. Patients with history of hypersensitivity to either IMPs or excipients

13. Men and women of childbearing potential who are not using an effective

method of contraception

14. Participation in another clinical trial or treatment with any investigational

product within 4 weeks prior to inclusion in this study.

15. Subjects who have current active hepatic or biliary disease (with exception

of patients with Gilbert's syndrome, asymptomatic gallstones, liver

metastases or stable chronic liver disease per investigator assessment)

16. Patient with unresolved hypokalaemia, hypomagnesemia or hypocalcaemia

Patients replacement Patients not evaluable for efficacy (Section 16.2) will be replaced

Planned study timelines FPI Cohort A: August 2012

LPI Cohort A (27 pts): May 2015

Expected FPI Cohort A (6pts expansion): July 2015

Expected LPI Cohort A (6pts expansion): September 2015

Expected LPO Cohort A: August 2016

Expected FPI Cohort B: September 2015

Expected LPI Cohort B: December 2016

Expected LPO Cohort B: December 2017


________________________________________________________________________________________________




2 SCHEDULE OF EVENTS

COHORT A

Assessment/Event

Pre

study 1

Cycle Q3wks

Treatment day

End of

Treatment

Visit 2

F-up

visit3

D -14 to 0 D1

(D22) D8 D15

4 wks

from last

treatment

Q8 wks

Signed informed consent x

Demographic data x

Baseline condition x

Medical History/Diagnosis /Prior TX x

Physical examination 4 x x x x x

Vital signs x x x x x

ECOG PS x x x x x

Hematology 5 x x x

Chemistry 6 x x x

Tumor markers7 x x

Pregnancy test x

ECG8 x Only if clinically indicated

LVEF9 x Q3 months x

Plasma Sample for Companion study 10 x x Q2 weeks x x

Serum Sample for HER2 ECD determination14 x Q8 weeks x x

Tumor assessment11 x Q8 weeks x x

Concomitant medication Throughout the study

Adverse Events Monitoring Throughout the study

Lapatinib administration12 Daily continously

Trastuzumab administration 13 x x x

See numbered Footnotes for further details on Schedule of Events.

1. Within 2 weeks of starting therapy, except X-rays and scans (4 weeks). Laboratory assessments performed within 72 hrs of study treatment will be considered good also for D1.

2. End of Treatment visit to be performed approximately 4 weeks after last treatment cycle

3. Follow-up visit for patients without documented PD at the time of treatment withdrawal: to be performed every 8 weeks until PD or another anti-cancer therapy is initiated, whichever comes first. Evaluations to be performed

according to clinical practise

4. Physical examination including body skin exam according to Appendix 5


________________________________________________________________________________________________




5. Hematology: hemoglobin, hematocrit, platelet count, total white blood cell count (WBC) and differential (neutrophil count, lymphocyte, monocyte, eosinophil, and basophil counts), red blood cell count (RBC). To be

performed within 72 hours from the day reported on the schedule of assessment

6. Chemistry: sodium, potassium, chloride, bicarbonate, creatinine, calcium, albumin, total bilirubin, total protein, glucose, alkaline phosphatase, AST, ALT urea or BUN. To be performed within 72 hours from the day reported

on the schedule of assessment

7. Tumor Markers: CEA, CA19.9. to be performed on Day 1 of each 3 weeks cycle

8. 12 lead electrocardiogram (ECG)

9. After the basal assessment echocardiograpic monitoring of the potential cardio toxicity will be done every three months or if clinically indicated according to Section 11.7.5.1 and 11.7.5.2. At EOT visit echocardiograpic

monitoring has to repeated if previous echocardiogram was performed > 3 months before

10. Companion study Cohort A as specified in section 13.6. Samples to be taken at different time points according to the following indication: patients will be sampled at baseline, every two weeks (i.e wks 2, wks 4, wks 6, etc),

and at disease progression

11. A CT scan or MRI should be performed within 4 weeks prior to the first dose and every 8 weeks during treatment until PD; however in order to fulfil RECIST, the FIRST occurrence of response MUST be reconfirmed

after 4 + 1 week later. Patients without documented PD at the time of treatment withdrawal should continue to

have disease assessments done every 8 weeks until PD or another anti-cancer therapy is initiated, whichever

comes first

12. Lapatinib administration for patients enrolled in Cohort A: 1000 mg (4 tablets)

13. Trastuzumab administration for patients enrolled in Cohort A: trastuzumab 2 mg/kg iv weekly. A 4 mg/kg trastuzumab loading dose is required on day 1.

14. Companion study Cohort A as specified in section 13.6. Samples to be taken at different time points according to the following indication: patients will be sampled at baseline, every eight weeks (i.e wks 8, wks 16, wks 24,

etc), and at disease progression.


________________________________________________________________________________________________




COHORT B

Assessment/Event

Pre

study 1

Cycle Q3wks

Treatment day

End of

Treatment

Visit 2

F-up

visit3

D -14 to 0 D1

(D22) D8 D15

4 wks

from last

treatment

Q8 wks

Signed informed consent x

Demographic data x

Baseline condition x

Medical History/Diagnosis /Prior TX x

Physical examination4 x x x

Vital signs x x x

ECOG PS x x x

Hematology 5 x x x

Chemistry 6 x x x

Tumor markers7 x x

Pregnancy test x

ECG8 x Only if clinically indicated

LVEF9 x Q3 months x

Plasma Sample for Companion study Cohort B10 x x x x

Serum Sample for HER2 ECD determination14 x Q8 weeks x x

Tumor assessment11 x Q8 weeks x x

Concomitant medication Throughout the study

Adverse Events Monitoring Throughout the study

Trastuzumab administration Cohort B 12 x

Pertuzumab administration13 x

See numbered Footnotes for further details on Schedule of Events.

1. Within 2 weeks of starting therapy, except X-rays and scans (4 weeks). Laboratory assessments performed within 72 hrs of study treatment will be considered good also for D1.

2. End of Treatment visit to be performed approximately 4 weeks after last treatment cycle

3. Follow-up visit for patients without documented PD at the time of treatment withdrawal: to be performed every 8 weeks until PD or another anti-cancer therapy is initiated, whichever comes first. Evaluations to be performed

according to clinical practise

4. Physical examination including body skin exam according to Appendix 5

5. Hematology: hemoglobin, hematocrit, platelet count, total white blood cell count (WBC) and differential (neutrophil count, lymphocyte, monocyte, eosinophil, and basophil counts), red blood cell count (RBC). To be

performed within 72 hours from the day reported on the schedule of assessment


________________________________________________________________________________________________




6. Chemistry: sodium, potassium, chloride, bicarbonate, creatinine, calcium, albumin, total bilirubin, total protein, glucose, alkaline phosphatase, AST, ALT urea or BUN. To be performed within 72 hours from the day reported

on the schedule of assessment

7. Tumor Markers: CEA, CA19.9. to be performed on Day 1 of each 3 weeks cycle

8. 12 lead electrocardiogram (ECG)

9. After the basal assessment echocardiograpic monitoring of the potential cardio toxicity will be done every three months or if clinically indicated according to Section 11.7.5.1 and 11.7.5.2. At EOT visit echocardiograpic

monitoring has to repeated if previous echocardiogram was performed > 3 months before

10. Companion study Cohort B as specified in section 13.6. Samples to be taken at different time points according to the following indication: Patients will be sampled at baseline, on Day 1 of each 3 weeks cycle, and at disease

progression

11. A CT scan or MRI should be performed within 4 weeks prior to the first dose and every 8 weeks during treatment until PD; however in order to fulfil RECIST, the FIRST occurrence of response MUST be reconfirmed after 4 + 1

week later. Patients without documented PD at the time of treatment withdrawal should continue to have disease

assessments done every 8 weeks until PD or another anti-cancer therapy is initiated, whichever comes first

12. Trastuzumab administration for patients enrolled in Cohort B: trastuzumab 8 mg/kg iv loading dose on day 1 of the first treatment cycle, followed by 6 mg/kg iv of each subsequent 3 weeks cycle

13. Pertuzumab administration for patients enrolled in Cohort B: pertuzumab 840 mg/kg iv loading dose on day 1of the first treatment cycle, followed by 420 mg/kg iv on day 1 of each subsequent 3 week cycle.

14. Companion study Cohort B as specified in section 13.6. Samples to be taken at different time points according to the following indication: patients will be sampled at baseline, every eight weeks (i.e wks 8, wks 16, wks 24, etc),

and at disease progression.


________________________________________________________________________________________________




3 ABBREVIATIONS AND DEFINITIONS OF TERMS

AE Adverse Event

ALT Alanine Aminotransferase

ANC Absolute Neutrophil Count

AP Alkaline Phopsphatase

ARDS Acute Respiratory Distress Syndrome

AST Aspartate Aminotransferase

BSA Body Surface Area

BUN Blood Urea Nitrogen

CA Competent Authority

CHF Congestive Heart Failure

CR Complete Response

CTM Clinical Trial Monitor

CRC Colorectal Carcinoma

CRF (eCRF) Case Report Form (Electronic Case Report Form

CT Computerized Tomography

CTCAE Common Terminology Criteria For Adverse Events

CYP3A4 Human Cytochrome P450 34A

EC Ethics Committee

ECG Electrocardiography, Electrocardiogram

ECHO Echocardiogram

ECOG Eastern Cooperative Oncology Group

EE Efficacy Evaluable

FPPE Formalin Fixed Paraffin Embedded

GCP Good Clinical Practices

ICF Informed Consent Form

ICH International Conference On Harmonisation

IEC Independent Ethics Committe

IMP Investigational Medical Product

IRB Institutional Review Board

i.v. Intravenous

LDH Lactate Dehydrogenase


________________________________________________________________________________________________




LVEF Left Ventricular Ejection Fraction

MedDRA Medical Dictionary For Regulatory Activities

MRI Magnetic Resonance Imaging

NOAEL No observed adverse effect level

NYHA New York Heart Association

PD Progressive disease

PFS Progression Free Survival

PG Pharmacogenomics

PI Principal investigator

PLTs Platelets / thrombocytes

p.o. Per os / oral

PR Partial response

PS Performance status

PT Preferred Term

QA Quality assurance

RBC Red Blood Cell

RD Recommended Dose

RECIST Response evaluation criteria in solid tumors

SAE Serious adverse event

SD Stable disease

SE Safety evaluable

SISH Silver Immunohistochemistry

SOC System Organ Class

SOP Standard Operating Procedure

UNL Upper Normal Limit

WBC White Blood Count / White Blood Cells

WHO World Health Organization

wks weeks

WT Wild Type


________________________________________________________________________________________________




4 BACKGROUND INFORMATION

Metastatic colorectal carcinoma (mCRC) is the second or third most common cancer in both men and

women in developed countries and remains a nearly universally fatal disease; despite the treatment advances

made in the last decade, the 5-year survival for patients with mCRC remains indeed only 10%1. First line

chemotherapy for this disease is typically a 5-FU/oxaliplatin/folate containing regimen bevacizumab, with

irinotecan-containing regimens such as FOLFIRI used second line, but long-standing responses following

either of these regimens are rare, and the survival of patients failing both these regimens is usually measured

in months. The development monoclonal antibodies directed against the epidermal growth factor receptor

(EGFR), such as panitumumab and cetuximab, has provided additional therapeutic options for patients

progressing through chemotherapy and may increase the efficacy of chemotherapy when given in

combination2. Although initial response rates of about 10% were seen with these agents in patients with

chemorefractory mCRC, it was subsequently discovered that higher response rates in the range of 13%-17%

were achievable in tumours without mutations in codon 12 or 13 of the KRAS gene, whereas only 0%-1.2%

of the KRAS mutant tumours responded to therapy3. Nevertheless, even in KRAS wild-type CRCs, about

40% of the previously untreated and about 60%-70% of the previously treated do not respond to anti-EGFR

treatmentand additional detection of NRAS, BRAF and PIK3CA exon 20 mutations and loss of PTEN

protein4 or better discrimination among KRAS mutations by excluding G13D carriers

5 may further enhance

selection of patients, but elucidation of other mechanism(s) by which tumor cell resistance is acquired in this

setting and identification of druggable molecular targets to overcome resistance are an unmet need in mCRC,

since there are no other available therapeutic options for patients progressing through chemotherapy.

In a recent article by our group, we exploited direct transfer xenografts of mCRC surgical specimens in mice

(xenopatients) to discover novel determinants of therapeutic response and new druggable driver

oncoproteins6. This approach, combining the flexibility of preclinical analysis with the informative value of

population-based studies, led to the identification of HER2 amplification as an additional molecular marker

of resistance to EGFR-targeted therapy with cetuximab in xenopatients harbouring tumors for which other

known molecular alterations conferring resistance were excluded (i.e. KRAS, NRAS, BRAF and PIK3CA

mutations). In this defined subset, HER2 amplification was detected in 4 of 11 cases (36%), suggesting a

greater frequency of HER2 amplification in cetuximab-resistant cases and its progressive enrichment along

with refinement of genetic selection. Indeed, data from literature show that HER2 amplification occurs in a

small percentage (2%3%) of genetically unselected colorectal cancers7, 8, 9

, but its incidence increases in

KRAS wild-type colorectal cancer patients that displayed de novo resistance to anti-EGFR therapies (13.6%)

and possibly rises to a summit in KRAS/NRAS/BRAF/PIK3CA WT tumors resistant to EGFR-targeted

therapies6.

Lapatinib

Lapatinib is a reversible TKI that potently inhibits both ErbBl and ErbB2 tyrosine kinase activity. There are

several theoretical advantages of an inhilbitor of both ErbBl and ErbB2 compared to inhibitors of either one

of these tyrosine kinases alone. While small molecule Inhibitors of ErbBl will inhibit ErbBl homodimers,

they may not be as effective at inhibiting heterodimers containing ErbB I and ErbB2. For example, treatment

with gefitinib, a TKI of ErbBl, plus the antibody trastuzumab induces a greater apoptotic effect than either

inhibitor alone in ErbB2-overexpressing human breast cancer cell lines SKBR-3 and BT-17410

. Additionally,

lapatinib exhibits greater growth inhibition of TGF -activated colon cancer cells than antagonists targeting


________________________________________________________________________________________________




only ErbB1 or ErbB2 receptors11

. These data suggest that a dual ErbB1 and ErbB2 inhibitor may provide

improved therapeutic benefit as compared with Inhibitors that target either receptor alone12

.

A phase II study, EGF20008, of single agent lapatinib In subjects with advanced or metastatic breast cancer

who had progressed while receiving anthracyclines, taxanes, capecitabine and trastuzumab-containing

regimens demonstrated an Investigator determined response rate of 4.3% in 140 subjects whose tumors

overexpress the ErbB2 protein by immunohistochemistry (IHC) or demonstrate ErbB2 gene amplification by

fluorescence in situ hybridization (FISH). Furthermore, the investigator determined clinical benefit rate

(defined as partial response, complete response or stable disease > 6 months) was noted at 5.7%. These data

indicate that in a heavily pre-treated population where there exists an unmet medical need, single agent

lapatinib elicits a response.

Trastuzumab

Trastuzumab is a humanized monoclonal antibody directed at the HER2 receptor and is indicated for the

treatment of patients with HER2-positive breast cancer both in the adjuvant and metastatic setting. The

addition of trastuzurnab to standard chemotherapy increases time to progressive disease or the length of

progression free survival (PFS), and improves survival when given with chemotherapy to women with

HER2-positive breast cancer13, 14

.

Clinical benefits are greatest in patients with HER2 gene amplification and or tumors strongly

overexpressing HER2, graded 3+ by immunohistochemistry (IHC: see Herceptin Package Insert,

November 2006). Trastuzumab is well tolerated both as a single agent and in combination with standard

chemotherapy 15, 14

. The most significant adverse event (AE) observed in patients who received trastuzumab

was cardiac dysfunction, reflected by asymptomatic decreases in left ventricular ejection fraction (LVEF)

and, less frequently, by clinically symptomatic congestive heart failure (CHF). Risk factors for cardiac

failure in the setting of trastuzumab treatment include co-administration with anthracycline-based

chemotherapy, increasing age, declining LVEF during treatment to below the lower limit of normal, and the

use of anti-hypertensive medications16

.

Pertuzumab

Pertuzumab is a fully humanized monoclonal antibody based on the human immunoglobulin (I)Gl (k)

framework sequences and consisting of two heavy chains (449 residues) and two light chains (214 residues).

Similar to trastuzumab, pertuzumab is directed against the extracellular domain of HER2: however, it differs

from trastuzumab in the epitope-binding regions of the light chain (12 ammo acid differences) and heavy

chain (29 amino acid differences). As a result, pertuzumab binds to an epitope within what is known as sub-

domain 2 of HER2, while the epitope for trastuzumab is localized to sub-domain 417,18

.

Pertuzumab acts by blocking the dimerization of HER2 with other HER family members, including HER1

{epidermal growth factor receptor [EGFR]), HER3, and HER4. As a result, pertuzumab inhibits ligand-

initiated intra cellular signaling through two major signal pathways. MAP-kinase and PI3-kinase. Inhibition

of these signaling pathways can result in growth arrest and apoptosis, respectively19

. Data from a clinical trial

of lapatinib support the hypothesis that HER2 plays an active role in tumor biology, with progression of

MBC occurring even after treatment with trastuzumab20

. The results obtained suggest that a broader

blockade of HER2 through interruption of heterodimerization may provide clinical benefit.

Due to the different binding sites of pertuzumab and trastuzumab. ligand-activated downstream signaling is

blocked by pertuzumab, but not by trastuzumab. Due to their complementary modes of action, there is a

potential role for the combination of pertuzumab and trastuzumab m HER2-overexpressing diseases.


________________________________________________________________________________________________




5 STUDY RATIONALE

A proof-of-concept, multi-arm study in HER2-amplified xenopatients revealed that combinations of the dual

small molecule EGFR/HER2 inhibitor lapatinib and HER-dimerization inhibitor moAb pertuzumab induced

overt, long-lasting tumor regressions, while monotherapy with lapatinib led to disease stabilization6 and

either monotherapy with trastuzumab or pertuzumab was ineffective (Bertotti et al.6 and Trusolino, personal

communication). The combination of pertuzumab and trastuzumab has also a strong rationale for treatment

of HER2-amplified tumors, since recent clinical observations have demonstrated that combining these two

moAbs together yields synergistic results in HER2 positive breast cancers that progressed during prior

trastuzumab therapy19

, suggesting a cooperative mechanism of inhibition. Currently, this combination is also

being explored in our xenopatients platform (Trusolino, personal communication).

Based on these findings, the combinations of trastuzumab and lapatinib or pertuzumab and trastuzumab

appear to have a sounded rationale for the treatment of those mCRC harbouring amplification of the HER2

oncogene. This hypothesis-driven trial will test whether these two distinct anti-HER2 therapy combinations

would produce a response rate 30% in chemorefractory mCRC patients, for whom further effective

treatment remains an unmet clinical need. Safe doses for both trastuzumab combinations have been already

established in the clinic: association of trastuzumab and lapatinib has been evaluated in breast cancer

(trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly and lapatinib 1000 mg qd)21

and is being

currently evaluated in other clinical settings. Combination of pertuzumab and trastuzumab has also been

tested in breast cancer patients (pertuzumab 840 mg/loading dose, followed by 420 mg q3wks, plus

trastuzumab 4 mg/kg loading dose, then 2 mg/kg weekly or 8 mg/kg loading dose, then 6 mg/kg q3wks)19

.

6 STUDY OBJECTIVES

6.1 Primary Objective

Define the antitumor activity of the anti-HER2 combinations of lapatinib + trastuzumab and pertuzumab +

trastuzumab given to two separate, sequential cohorts of patients with chemo-refractory advanced disease

and HER2 amplified tumours.

6.2 Secondary Objective(s)

- Define the safety profile of the two combinations

- Define the PFS of the combinations lapatinib + trastuzumab and pertuzumab + trastuzumab given to two separate, sequential cohorts of patients with chemo-refractory advanced disease and HER2 amplified

tumours.

6.3 Exploratory Objective(s)

To determine whether selected tumor biomarkers evaluated in tumor specimens, including but not limited to molecular alterations of effectors downstream of HER-family receptors (such as mutations of

KRAS, BRAF and PIK3CA) or related tyrosine kinase receptors, have association with

response/resistance to experimental treatment

To determine whether selected tumor biomarkers as evaluated from circulating tumor DNA, including but not limited to molecular alterations of effectors downstream of HER-family receptors (such as


________________________________________________________________________________________________




mutations of KRAS, BRAF and PIK3CA) or related tyrosine kinase receptors, evolve during tumor

progression

7 STUDY ENDPOINTS

7.1 Primary Endpoint

Objective response rate according to RECIST criteria

7.2 Secondary Endpoint(s)

Description of the frequency and severity of Adverse Events based on the NCI CTCAE V4.0

PFS

7.3 Exploratory Endpoint(s)

Correlation between selected tumor biomarkers (including but not limited to molecular alterations of effectors downstream of HER-family receptors - such as mutations of KRAS, BRAF and PIK3CA, or

related tyrosine kinase receptors), and tumor response/resistance to experimental treatment

Comparison of tumor biomarkers status in blood samples collected before start of treatment, with that collected during treatment and after progression

8 STUDY DESIGN

This is a phase II, open label, two-sequential cohorts, multicenter study.

Patients with advanced colon rectal cancer (CRC) harbouring an amplified HER2 tumor (SISH), progressed

while on treatment or within 6 months from last therapy, are eligible to participate in the study and will be

treated with the anti HER2 monoclonal antibody trastuzumab, used in combination with either the small

molecule tyrosine kinase inhibitor lapatinib (Cohort A) or the monoclonal antibody pertuzumab (Cohort B).

Approximately 27 patients are foreseen to be enrolled sequentially in each cohort.

Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent

or death.

Main objective of the study is the evaluation of the response rate, followed by the progression free survival

and the safety profile of the 2 combinations. As exploratory objectives the study foresees to evaluate the

correlation between selected biomarkers from tumor specimens and tumor response, and to evaluate whether

those tumor biomarkers (circulating tumor DNA) evolve during tumor progression.

Patient enrolled in cohort A will receive lapatinib 1000 mg daily per os and trastuzumab 4 mg/kg iv loading

dose on D1, followed by 2 mg/kg iv weekly. Patients enrolled in Cohort B will receive pertuzumab 840

mg/kg iv loading dose on the first day of cycle 1, followed by 420 mg/kg iv on D1 of each subsequent 3

weekly cycle and trastuzumab 8 mg/kg iv loading dose, followed by 6 mg/kg iv on Day 1 of each subsequent

3 weeks cycle.

9 STUDY POPULATION

9.1 Subject Selection


________________________________________________________________________________________________




9.1.1 Subject Inclusion Criteria

Subjects must meet all the following inclusion criteria to be eligible for enrolment into the study:

1. Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery

2. Pathology mandatory requirements:

a. the original tumour specimen must be KRAS WT and SISH/FISH positive or IHC 3+ positive in more than 50% cells.

Note: for immunohistochemistry a positive staining (3+) is defined as an intense membrane

staining which can be circumpherential, basolateral, or lateral of the tumor cells.

b. the original paraffin block or a minimum of 15 polarized unstained slides from the original paraffin block must be made available to the Pathology Core within 15 days from registration.

3. Age 18

4. ECOG PS 0-1

5. Measurable disease as defined by RECIST 1.1 criteria.

6. Progression (PD) while on, or within 6 months from therapy with approved standard drugs

7. Unless otherwise contraindicated patients should have received and failed the following previous therapies for mCRC: fluoropirimidines, oxaliplatin, irinotecan, cetuximab or panitumumab

containing regimens. Bevacizumab is allowed

8. Adequate haematological function as defined by: ANC 1.5 x 109/L, platelet count 100 x 109/L,

haemoglobin 10 g/dL

9. Adequate renal function, as defined by: creatinine 1.5 x UNL

10. Adequate hepatobiliary function, as defined by the following baseline liver function tests:

o total serum bilirubin 1.5 upper normal limit (UNL)

o alanine aminotransferase (ALT), aspartate aminotransferase (AST) 2.5xUNL

o alkaline phosphatase (AP) 2.5xUNL; if total alkaline phosphatase (AP) > 2.5xUNL, alkaline

phosphatase liver fraction must be 2.5xUNL

11. Adequate contraception for all fertile patients

12. Negative pregnancy test

9.1.2 Subject Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study:

1. Radiotherapy 4 weeks prior to enrolment

2. Other chemotherapy or biological therapy treatment 4 weeks prior to enrolment

3. Symptomatic brain metastases

4. Active infection


________________________________________________________________________________________________




5. Gastro-intestinal abnormalities, inability to take oral medication, any condition affecting absorption

6. Impaired cardiac function including any of the following: uncontrolled hypertension (systolic >150 mmHg and/or diastolic > 100 mmHg) or clinically significant (ie active) cardiovascular disease:

cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study

medication; unstable angina; chronic heart failure (CHF) of New York Heart Association (NYHA)

Grade II or higher (See Appendix 4); or serious cardiac arrhythmia requiring medication, baseline

Left Ventricular Ejection Fraction (LVEF) 55% measured by echocardiography (ECHO)

7. Major surgery in the two weeks prior to entering the clinical trial

8. Concurrent treatment with any other anti-cancer therapy

9. History of another neoplastic disease (except basal cell carcinoma of the skin or uterine cervix carcinoma in situ adequately treated), unless in remission for 5 years

10. Patient unable to comply with the study protocol owing to psychological, social or geographical reasons

11. Pregnant and lactating women

12. Patients with history of hypersensitivity to either IP or excipients

13. Men and women of childbearing potential who are not using an effective method of contraception

14. Participation in another clinical trial or treatment with any investigational product within 4 weeks prior to inclusion in this study.

15. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator

assessment)

16. Patient with unresolved hypokalaemia, hypomagnesemia or hypocalcaemia

9.2 Screening failures

For all screened patients, a Subject Screening Log will be completed and in case of screening failure the

reason(s) for failure will be documented. CRFs have to be completed only for registered patients.

9.3 Replacements

Patients not evaluable for efficacy according to the definition described in section 16.2 will be replaced.

10 ENROLLMENT PROCEDURES

Before any screening procedure all patients must sign a written informed consent for the study. The

following logs must be maintained at each study site and kept in the Investigator File: a Subject Screening

and Enrolment Log, to document the identification of subjects who are screened and enrolled; a Subject

Identification Code List for all subjects registered to maintain the correlation with the patient's full

identification data (name, surname - confidential). Before registration in the study, all the pre-treatment

evaluations must be reported on the "Registration Form and faxed to FPO fax number +39 011-993.3318 or

e-mailed to [email protected]. Upon review of all inclusion/exclusion criteria, if the patient is eligible,
mailto:[email protected]


________________________________________________________________________________________________




a progressive Registration Number, is centrally assigned by FPO and provided to the Investigator by fax or

by E-mail on a Confirmation of Registration Form.

Any controversial eligibility assessment will be discussed with the Study Chair.

11 STUDY TREATMENT

11.1 Description of Investigational Product (s)

11.1.1 Lapatinib

Lapatinib Ditosylate Monohydrate Tablets, 250 mg, are oval, biconvex, orange, filmcoated tablets that are

debossed on one side with FG HLS. The tablets contain 410 mg of lapatinib ditosylate monohydrate,

equivalent to 250 mg lapatinib free base per tablet. Lapatinib may also be supplied as oval, biconvex, tan

tablets, with no markings. Refer to the Investigators Brochure (IB) for information regarding the physical

and chemical properties of the drug substance and list of excipients. Lapatininb is provided free of charge by

Glaxo Smith Kline.

11.1.2 Trastuzumab

Trastuzumab (Herceptin) is supplied in 150 mg single-dose vials or 440 mg multidose vials containing white

to pale yellow lyophilized powder for concentrate for infusion. Reconstituted Trastuzumab concentrate

contains trastuzumab 21 mg/mL. The concentrate for infusion will be accompanied by a solvent vial (for use

with 440mg vial) and bacteriostatic water for injection containing 1.1% benzyl alcohol. Trastumuzumab has

to be stored at 2C8C. Refer to the Product Information Sheet for information regarding the physical and

chemical properties of trastuzumab as well as drug substance and list of excipients. Trastuzumab is provided

free of charge by Roche.NTIAUM2005/00071/04

1040

11.1.3 Pertuzumab

Pertuzumab is provided as a single-use formulation containing 30 mg/mL pertuzumab formulated in 20 mM

L-histidine (pH 6.0), 120 mM sucrose, and 0.02% polysorbate 20. Each 20-cc vial contains approximately

420 mg of pertuzumab (14.0 mL/vial). For further details, see the pertuzumab Investigator Brochure (IB).

Pertuzumab is provided free of charge by Roche. UM2005/00071/04

11.2 Drug preparation

11.2.1 Instructions for trastuzumab reconstitution

1) Using a sterile syringe, slowly inject 7.2 ml of sterile water for injections in the vial containing the

lyophilised trastuzumab, directing the stream into the lyophilised cake.

2) Swirl vial gently to aid reconstitution. DO NOT SHAKE!

Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for

approximately 5 minutes. The reconstituted trastuzumab results in a colourless to pale yellow transparent

solution and should be essentially free of visible particulates.


________________________________________________________________________________________________




Determine the volume of the solution required:

Cohort A: based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose of 2

mg trastuzumab/kg body weight:

Volume (ml) =Body weight (kg) x dose (4 mg/kg for loading or 2mg/kg for maintenance)

21 (mg/ml, concentration of reconstituted solution)

Cohort B: based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose of

6 mg trastuzumab/kg body weight:

Volume (ml) = Body weight (kg) x dose (8 mg/kg for loading or 6mg/kg for maintenance)

21 (mg/ml concentration of reconstituted solution)

The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag

containing 250 ml of 0.9 % sodium chloride solution. Do not use with glucose-containing solutions. The bag

should be gently inverted to max the solution in order to avoid foaming. Parenteral solutions should be

inspected visually for particulates and discoloration prior to administration. Once the infusion is prepared it

should be administered immediately. If diluted aseptically, it may be stored for 24 hours (do not store above

30C). No incompatibilities between trastuzumab and polyvinylchloride or polyethylene bags have been

observed.

11.2.2 Instructions for pertuzumab reconstitution

Because the pertuzumab formulation does not contain a preservative, the vial seal may only be punctured

once. Any remaining solution should be discarded.

The indicated volume of pertuzumab solution should be withdrawn from the vials and added to a 250-cc IV

bag of 0.9% sodium chloride injection. Gently invert the bag to mix the solution. DO NOT SHAKE

VIGOROUSLY. Visually inspect the solution for particulates and discoloration prior to administration. The

entire volume within the bag should be administered as a continuous IV infusion. The volume contained in

the administration tubing should be completely flushed using a 0.9% sodium chloride injection.

The solution of pertuzumab for infusion diluted in PVC or non-PVC polyolefin bags containing 0.9%

sodium chloride injection may be stored at 2C8C for up to 24 hours prior to use. Diluted pertuzumab has

been shown to be stable for up to 24 hours at room temperature. However, since diluted pertuzumab contains

no preservative, the aseptically diluted solution should be stored refrigerated (2C8C) for no more than 24

hours.

11.3 Treatment Dose and Schedule

Table 1 below provides study therapies with their respective dosage and the mode of administration:


________________________________________________________________________________________________




Table 1. Dose and Mode of administration

Drug Dosage Time administration

Cohort A

Lapatinib 1000 mg (4 Tablets) Daily

Approximately the same time of day, preferably either at

least 1 hour before or 1 hour after breakfast

Trastuzumab

Loading Dose

4 mg/Kg iv infusion

On Day 1 of first week.

Approximately 90 minutes infusion

Subsequent therapy 2 mg/kg iv infusion Weekly.


Cohort B

Pertuzumab

Loading Dose

840 mg/Kg iv infusion

On Day 1 of the first cycle.

Approximately 60 ( 10) minutes infusion

Subsequent therapy 420 mg/kg iv infusion On Day 1 of each 3 week cycle


Trastuzumab

Loading Dose

8 mg/Kg iv infusion

To administer after pertuzumab, on Day 1 of the 1st cycle


Subsequent therapy 6 mg/kg iv infusion To administer after pertuzumab, on Day 1 of each

subsequent 3 week cycle.

Approximately 30 ( 10) minutes infusion

Notes on administration of Lapatinib

Lapatinib should not be taken with grapefruit or grapefruit juice. Ingestion of grapefruit or grapefruit juice is

not permitted during the study

If subject vomits after taking lapatinib therapy, the subject should be instructed not to retake the dose Subject

should take the next schedule dose. If vomiting persists , then the subject should contact the investigator.

Notes on administration of pertuzumab

1. Initial infusions of pertuzumab will be administered over 60 ( 10) minutes and patients observed for a further 60 minutes from the end of infusion for infusion-associated symptoms such as fever, chills etc.

Interruption or slowing of the infusion may reduce such symptoms. If the infusion is well tolerated,

subsequent infusions may be administered over 30 ( 10) minutes, with patients observed for a further

30 minutes.

2. Pertuzumab administration may be delayed to assess or treat AEs such as cardiac AEs, myelosuppression, or other events. No dose reduction will be allowed for pertuzumab.

3. To avoid or reduce the risk of infusion reactions a premedication must be administered before each pertuzumab infusion according to dosage and timing reported in the following table:


________________________________________________________________________________________________




Chlorphenamine Maleate Dexamethasone Ranitidine

Dose 10 mg 4 mg 50 mg

Route im iv iv

Timing 30 minutes before infusion After Chlorphenamine 15 minutes before infusion

Notes on administration of trastuzumab

1. Trastuzumab administration should be follow by an observational period in line with approved local Product Information.

2. Trastuzumab administration may be delayed to assess or treat AEs such as cardiac AEs, myelosuppression, or other events. No dose reduction will be allowed for trastuzumab.

3. To avoid or reduce the risk of infusion reactions a premedication must be administered before each trastuzumab infusion according to dosage and timing reported in the following table:

Chlorphenamine Maleate Dexamethasone Ranitidine

Dose 10 mg 4 mg 50 mg

Route im iv iv

Timing 30 minutes before infusion After Chlorphenamine 15 minutes before infusion

11.4 Duration of Treatment

Duration of treatment will depend on the response to therapy. Patients enrolled in both cohorts will receive

study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever

come first.

11.5 Drug Accountability

The Investigator and/or a pharmacist or other appropriate individual designated by the Investigator, should

maintain records of the amount of investigational drug delivered to the trial site, the inventory at the site, the

amount of drug administered to each subject and the unused drug to be destroyed locally. The pharmacist, or a delegated person at the site, will be responsible for handling study drug(s) preparation

of the appropriate doses to be administered, and completion of drug accountability forms.

Study drug(s) must be handled and administered strictly in accordance with the protocol and/or the specific

manual and will be stored in a limited access area or in a locked cabinet under appropriate storage

conditions. Study drug(s) should be administered under the supervision of the investigator or co-investigator,

only to subjects participating in the study in accordance with the approved protocol.

Unused study drug(s) must be available for verification by the sponsors site monitor during on site

monitoring visits.


________________________________________________________________________________________________




11.6 Safety Profile of Investigational Products

11.6.1 Lapatinib Warnings and Precautions

Cardiac dysfunction

Lapatinib has been associated with decreases in LVEF. Caution should be taken if lapatinib is to be

administered to patients with conditions that could impair left ventricular function. LVEF should be

evaluated in all patients prior to initiation of treatment with lapatinib to ensure that the patient has a baseline

LVEF that is within the institutions normal limits and > 55%. LVEF should continue to be evaluated during

treatment with lapatinib to ensure that LVEF does not decline to an unacceptable level (see Section 11.7.5

Continuation/discontinuation study treatment based on LVEF assessment)

A small, concentration dependent increase in QTc interval was observed in an uncontrolled, open-label dose

escalation study of lapatinib in advanced cancer patients. Caution should be taken if lapatinib is administered

to patients who have or may develop prolongation of QTc. These conditions include patients with

hypokalemia or hypomagnesemia, congenital long QT syndrome, patients taking anti-arrhythmic medicines

or other medicinal products that lead to QT prolongation. Hypokalemia, hypocalcaemia or hypomagnesemia

should be corrected prior to lapatinib administration.

Pulmonary dysfunction

Lapatinib has been associated with reports of Interstitial Lung Disease (ILD) and pneumonitis. Patients

should be monitored for pulmonary symptoms indicative of ILD/pneumonitis.

Hepatic impairment

Lapatinib is metabolised in the liver. Moderate and severe hepatic impairment have been associated,

respectively, with 56% and 85% increases in systemic exposure Hepatotoxicity (ALT or AST >3 times the

UNL and total bilirubin >1.5 times the UNL) has bee

istitutofondazione ricerca piemonte per l’ cura del cancro ... · with her2-positive metastatic...

Documents