BPCA Experience with Oncology Drugs

Victor M. Santana, MD

June 27, 2007

Outline of Presentation

• Review the 11 oncology drugs granted exclusivity

• For each drug: the regulatory history of WR, populations studied, brief study results, and label changes

• Summary• Concluding Comments

Busulfan Carboplatin Clofarabine Fludarabine Gemcitabine Imatinib Irinotecan Oxaliplatin Temozolamide Topotecan Vinorelbine

Busulfan-Busulfex(Orphan Medical)

• Regulatory history: – 1st approved in 2/4/1999 for use in combination with

cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for CML

– WR issued: 3/27/2000– Exclusivity Granted: 3/12/2002

• Population of Interest: Preparative regimen for allogeneic hematopoietic stem cell transplantation in children

• Types of Studies: A single, phase II, multi-center, open label &

pharmacokinetic study• Number of centers: 10 US• Age groups: 5mo - 16yr • Total # patients: 24

Busulfan-Busulfex

Label changes: Pediatric information on dosing,pharmacokinetics and safety.

• The population pharmacokinetic estimates of busulfan for clearance and volume of distribution were determined in an open-label, uncontrolled PK study in 24 pediatric patients 5 months to 16 years who received busulfan as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (n=15) or non-malignant diseases (n=9).

• BUSULFEX dosing was targeted to achieve an area under the

plasma concentration curve (AUC) of 900-1350 μM•min with an initial dose of 0.8 mg/kg or 1.0 mg/kg (based on ABW) if the patient was >4 or ≤4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1.

Busulfan-Busulfex

• Suggested dosing regimen:

Patient’s Actual Body Weight Busulfex dosage≤ 12 kgs 1.1 mg/kg> 12 kgs 0.8 mg/kg

Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target BUSULFEX exposure (AUC) between 900 to 1350 μM•min with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX is recommended.

Carboplatin–Paraplatin(Bristol-Myers-Squibb)

• Regulatory history:

– 1st approved in 1989 for advanced ovarian carcinoma– WR issued: 4/11/2001; amended 11/13/2002 extension of due date for

submission of reports/data– Exclusivity Granted: 4/30/2004

• Population of Interest: Refractory or relapsed pediatric malignancies• Types of Studies:

Phase I study to establish the MTD and recommended dose of carboplatin when given with irinotecan [carboplatin q 3 weeks with irinotecan daily (x5) x 2 q 3 weeks]

Number of centers - 8

Phase II randomized, 2-arm, non-comparative, open-label study to evaluate the response rate of carboplatin (AUC 4 mg/ml/min) administered in combination with irinotecan (12 mg/m2/day x 10 days) and of irinotecan administered as a single agent (20 mg/m2/day x 10 days)

Number of centers - 56• Age groups: 1-<21 yrs • Total # patients: Phase I = 28; Phase II = 151

Phase II Study: Activity

• Responses seen across all treatment arms but unable to quantify the contribution of carboplatin.

• PK data was inconclusive: only 33% of carboplatin AUCs were within 30% of the target AUC of 4 mg/ml/min.

• Label changes: No action

Drug Regimen Carbo/Irinotecan Irinotecan Carbo/Irinotecan Irinotecan

CNS tumor CNS tumor Non-CNS tumor Non-CNS tumor

Response Rate: CR+PR

[95% CI]

14% (4/28)

[4-33]

11% (3/28)

[2-28]

6% (3/47)

[1-18]

13% (6/48)

[5-25]

Response by Tumor Type

GBM -1 PR

Astrocytoma -1 PR

BSG -1 PR

PNB -1 CR

MB -3 PRs DSRCT -1 PR

Undiff. Epi. -1 PR

STS -1 PR

NB - 1 CR,1 PR

RMS - 1 CR,1PR

PNET -1 PR

HEP - 1 PR

GBM, glioblastoma; BSG, brain stem glioma; PNB, pinealoblastoma; MB, medulloblastoma; DSRCT, desmoplastic small round cell tumor; STS, soft tissue sarcoma: NB, neuroblastoma; RMS, rhabdomyosarcoma; PNET, primitive neuroectodermal tumor; HEP, hepatoblastoma

Clofarabine-Clolar(Genzyme)

• Regulatory history: – Approved in 2004 for treatment of children with relapsed or refractory

ALL after at least 2 prior regimens– WR issued: 3/7/2003; amended 10/04/2003 to include only studies in

hematological malignancies and to define primary endpoint as complete response (durable remission) for Phase II studies

– Exclusivity Granted: 7/14/2004• Population of Interest: Relapsed or refractory ALL after at least two

prior regimens • Types of Studies:

– Phase I study to determine the MTD and toxicity profile• Number of Centers – 1 (conducted at MDACC)

– Phase II open-label, single-arm efficacy study in patients with ALL• Number of Centers – 18

– Phase II open-label study in patients with AML• Number of Centers – 23

• Age groups: 0-22yr• Total # patients: Phase I = 25; Phase II = 84

Clofarabine-Clolar

• Results: – ALL: CR+CRp 10 of 49 (20.4%)– AML: CR+CRp = 1 of 35 (2.9%)

• Label: Complete first label for product. Labeling for patients 1 to 21 years old. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. Information on dose, PK parameters, and AE profile.

Fludarabine phosphate–Fludara(Berlex)

• Regulatory history: – 1st approved in 1991 for B-cell CLL– WR issued: 11/13/2001– Exclusivity Granted: 4/3/2003

• Population of Interest: Refractory or relapsed acute leukemia

• Types of Studies:– Dose finding PK study (CCG 097)

• CCG centers– Clinical and pharmacodynamic study (CCG 0895)

• CCG centers

• Age groups: 1-21; 1-18yr • Total # patients: 62

FludarabineResults • CCG097

– single agent as bolus/CI in 9 AML, 36 ALL and 17 ST patients– ST DLT is myelosupression at 7 mg/m2 bolus and 20 mg/m2 x 5 days CI– leukemia DLT not reached – differences in mean clearance: 0.61 L/hr/m2 vs 8.7 and 4.1 L/hr/m2

respectively in 2 adult studies; however, T1/2 and Vd similar to adults– Responses: 1 CR/3PR in ALL; 0 in AML and solid tumors

• CCG 0895– combination of Fludara + ara-C in 13 ALL + 18 AML relapsed patients– max tolerated plasma concentration was 10 µM fludarabine for 48 h

followed by 72 h of 15 µM ara-C – CR+PR in 9 of 18 evaluable AML patients (50%); CR+PR in 3 of 9

evaluable ALL patients (33%) but very brief durations of response

Label changes: Fludarabine was evaluated in 62 pediatric patientsand the data were insufficient to establish efficacy in any childhoodmalignancy.

Gemcitabine-Gemzar(Eli Lilly)

• Regulatory history: – 1st approved in 1996 for treatment of locally advanced or

metastatic pancreatic adenocarcinoma – WR issued: 1/9/2001; amendments 12/13/2002 and 10/1/2003 to

change the timeframe for submission of study reports/data – Exclusivity Granted:1/27/2005

• Population of Interest: Refractory ALL or AML and non-Hodgkin’s lymphoma

• Types of Studies:– A dose finding, PK study (CCG0955)

• Number of centers – 21– Efficacy trial in refractory ALL and AML or relapsed tumor(s) – a

COG study• Number of centers – 13

• Age groups: 1mo-21yr • Total # patients: Phase I = 14; Phase II = 32

Gemcitabine-Gemzar• Phase I – conducted by CCG as study 095514

– children with relapsed acute leukemia– MTD 10 mg/m2/minute CI for 360 min for 3 weeks (1 week rest)

• Phase II – same dose/schedule defined as MTD in Phase I– 20 ALL + 10 AML (evaluable patients)– endpoint CR rate: 1 CR in ALL i.e. 1 of 30 response rate– hematological toxicity, skin rash, ↑ transaminases, N/V

• Label changes: Effectiveness in pediatric patients has not been demonstrated.A Phase 1 trial in pediatric patients with refractory leukemia demonstrated a maximum tolerated dose; however, no meaningful clinical activity observed in a Phase 2 trial of gemcitabine in 22 patients with relapsed acute lymphoblastic leukemia and 10 patients with acute myelogenous leukemia. Toxicities observed were similar to those reported in adults.

Imatinib mesylate-Gleevec(Novartis)

• Regulatory history: – 1st approved in 2001 for adults with Ph+ CML– WR issued: 9/12/2000; amendment 5/28/2003 and 6/1/2005 to change

the timeframe for submission of study reports/data and 10/26/2004 to expand study population to newly diagnosed Ph+ CML in children

– Exclusivity Granted: 9/27/2006• Population of Interest: Pediatric patients with Philadelphia positive (Ph+)

leukemia• Types of Studies:

– Two Phase I, dose-finding studies to determine the safety, tolerability, PK and PD profiles and to evaluate for anti-leukemic effects (recurrent after stem cell transplant or resistant to alpha INF)

• COG centers – A single Phase II study to evaluate the response rate and determine

the disease-free survival in newly diagnosed patients• COG centers

• Age groups: 2 - 20 yrs • Total # patients: Phase I =17; Phase II = 51

Imatinib mesylate-Gleevec• Phase I –

– open label single arm (0103) in relapse pts. after SCT or αINF, n=14– additional Phase I study 03001, n=3– rapidly absorbed after oral dosing with Cmax 2-4 hrs.– comparable AUCs are achieved at similar doses as used in adults– 340 mg/m2 in children comparable to fixed dose of 600 mg in adults

• Phase II – – multi-center, open-label, single arm study (2108) in 51 pediatric patients with

newly diagnosed, untreated chronic phase CML – dose: 340 mg/m2/day– CHR 78% after 8 weeks of therapy– CCyR 65%; PCyr 16%– median time to response 6.74 months

• Label changes: Gleevec is indicated as a single agent for the treatment of pediatric patients with newly diagnosed Ph+ CML in chronic phase. Also indicated for patients whose disease has recurred after stem cell transplant or who are resistant to INF-therapy. There are no controlled trials in pediatrics demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Dose as single agent for newly diagnosed patients is 340 mg/m2/day and for recurrent patients after stem cell transplant or resistant to INF-alpha therapy is 260 mg/m2/day. There is no experience in dosing children < 2 years.

Irinotecan-Camptosar(Pfizer)

• Regulatory history: – 1st approved in 1996 for metastatic colorectal cancer – WR issued: 1/22/2001; amendment 8/5/03 to change

the data source for anticonvulsant drug interaction (from study H6957→ to P9871)

– Exclusivity Granted: 3/10/2004

• Population of Interest: Refractory solid tumors• Types of Studies:

– 4 Phase I studies– 2 Phase II studies

Irinotecan: Summary of Phase I StudiesPhase I studies ScheduleSchedule No. of No. of

centerscentersAge groups;Age groups;

No. patientsNo. patients

ResultsResults

Phase 1 MTD study (H6957)

Weekly x 4, q 6 weeks

1 TCCC 4-17yr;

Clinical 16;

PK 14

MTD of 125 mg/m2 ; ? too high

Phase 1 PK/PD and dose finding study

[daily x 5] x 2, q 3 weeks

1 St Jude 1-<21 yr;

Clinical 22;

PK 23

MTD: 20 mg/m2/day

55% experienced DLT at starting dose

Phase 1 MTD study (POG 9571)

Daily x 5, q 3 weeks

19 US/CAN - COG

1 -20yr;

Clinical 33; PK 18

MTD:

stratum 1 = 39 mg/m2

stratum 2 = 50 mg/m2

stratum 3 (age <6yrs) = 30 mg/m2

Phase I study, refractory solid pts. concomitantly receiving anticonvulsants (P9871)

Daily x 5, q 3 weeks

54 US/CAN - COG

5-19 yr;

Clinical 9;PK 9

Study closed early due to slow accrual

Irinotecan: Phase II Studies

Phase II studies ScheduleSchedule No. of No. of centerscenters

Age groups;Age groups;

No. patientsNo. patients

ResultsResults

Multi-center, open-label, uncontrolled, single-arm, trial in refractory pts. < 2 prior Rx (9761)

50 mg/m2 qd x 5, q 3 weeks

80 US/CAN 1mo-22yr; n=170

16% Response rate in relapsed RMS (3 of 19)

Open label, single arm study, newly diagnosed stage 4 group, IV metastatic RMS (D9802)

20 mg/m2 qdx5, wks 0&1, 3&4

20 US 9mo-19yr;

n=21

42% response rate (9 of 21) but high rate of early PDs and deaths when used as single agent. However, subsequent evaluation of combination of IRN + VCR resulted in a high response rate of 70% with low PD rate 8%.

Irinotecan-CamptosarLabel changes:• Effectiveness in pediatric patients has not been established.• Adverse event profile from a Phase 2 trial with 170 children with

refractory solid tumors comparable to that seen in adults; Grade 3-4 neutropenia experienced by 54 (31.8%) patients, neutropenia complicated by fever in 15 (8.8%) patients, Grade 3-4 diarrhea observed in 35 (20.6%) patients.

• Accrual for phase 2 study with 21 children with previously untreated rhabdomyosarcoma halted due to high rate (23.6%) of progressive disease and early deaths (14%). Adverse event profile seen in the 21 children different than that observed in adults; most significant Grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%)(across all courses of therapy and irrespective of causal relationship).

• PK parameters comparable to adults. Minimal accumulation of irinotecan and SN-38 (active metabolite) observed in children on daily dosing.

Oxaliplatin–Eloxatin (Sanofi-Synthelabo)

• Regulatory history: – 1st approved in 2002 for refractory advanced colorectal cancer– WR issued: 12/9/2004; amendment 3/4/05 to extend

timeframe for submission of study results– Exclusivity Granted: 9/27/2006

• Population of Interest: Advanced or refractory solid tumors

• Types of Studies:– 2 Phase I studies: ARD5531 (8 centers in France) and

DFI7434 (1 US center)– 2 Phase 2 studies: ARD5021(10 US centers) and ARD5530

(COG centers) • Age groups: 7mo-21yr • Total # patients: Phase I: 69; Phase II: 90

Oxaliplatin–EloxatinTumor Types Schedule No. Pts. Results

Phase I

ARD5531 Relapsed solid tumors

2-hr infusion D1,8 & 15 q 4 weeks

28 DLT sensory neuropathy at 110 mg/m2; clearance similar to adults

DFI7434 Relapsed solid tumors

2-hr infusion D1 q 3 weeks

26 DLT sensory neuropathy at 160 mg/m2; clearance similar to adults

Phase II

ARD5021 Relapsed embryonal CNS tumors

130 mg/m2 q 3 weeks

43 1 PR

ARD5530 Relapsed solid tumors

130 mg/m2 q 3 weeks

48 0 responses

Oxaliplatin–Eloxatin

• Label changes:

The effectiveness of oxaliplatin in children has not been established. No significant activity observed in 2 Phase I and 2 Phase II trials in 159 patients, ages 7 months to 22 years with solid tumors. Information on clinical studies and summary of AEs.

Temozolomide-Temodar(Schering)

• Regulatory history: – 1st approved in 1999 for adults with refractory anaplastic astrocytoma – WR issued: 1/9/2001

• amendment 8/24/01 allowing a summary of previous phase I data submitted to the NDA, and defining the patient population for Phase II studies as recurrent CNS tumors; re-defining the age groups to 3-17 years

– Exclusivity Granted: 11/20/2002• Population of Interest: Pediatric patients with malignant brain tumors• Types of Studies:

– 2 Phase I PK and dose finding studies (Study 193-125 Dose Escalation and Extended)

• Number of centers– 1 Phase II study in children with recurrent CNS tumors (H97-017)

• Number of centers

• Age groups: 1-23 yr • Total # patients: Phase I = 90; Phase II = 122

Temozolomide-Temodar• Results:

– Cmax and AUCs higher in children (unknown if ↑ bioavailability or ↓clearance)

– proportionality between dose and AUC– no relationship between age and clearance– Activity: 5% CR+PR (1+5)

• Label changes:– Temozolomide effectiveness in children has not been

demonstrated.– New data from 2 open-label Phase 2 studies in pediatric patients

3-18 years of age. In one study there were 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocyoma. In a second study there were 122 patients enrolled with various types of tumors; 113 CNS tumors and 9 non-CNS tumors.

– The temozolamide toxicity profile in children is similar to adults.

Topotecan–Hycamtin (GlaxoSmithKline)

• Regulatory history: – 1st approved in 1996 for treatment of recurrent metastatic ovarian

cancer – WR issued: 5/16/2000; amended 12/27/2001 with extension to deadline

for submitting study reports/data– Exclusivity Granted: 11/20/2002

• Population of Interest: Pediatric patients with relapsed or refractory malignancies

• Types of Studies:– Phase I PK and dose finding PK/PD study in children with refractory solid tumors

• Number of Centers – 15 (US & Canada) POG– Phase I PK/PD Study in patients with leukemia (9275L)

• Number of Centers – 10 (9 US; 1Canada) POG– Phase II study in pediatric patients with solid tumors (Study 9361)

• Number of Centers – 74 (70 US; 4 Canada) POG

• Age groups: 2-< 16yr; 1mo-21yr • Total # patients: Phase I = 52; Phase II = 150

Topotecan–Hycamtin

• Results:– PK: parameters across age groups from 2-16 yrs.; CL 8.02

L/hr/m2, Vd-ss 32.64 L/m2 and T ½ of 4.19 hr.; all similar to adult reported values.

– Activity: overall RR 8% but 18% (7 of 38) in neuroblastoma.– Dosing: in solid tumors – 1.4 mg/m2 without G-CSF and 2.0 mg/m2

with G-CSF support. Adult recommended dose is 1.5 mg/m2.

• Label changes: No action. [Submitted data are inadequate to independently support an indication. Safety and efficacy not demonstrated in pediatric cancer patients.]

Vinorelbine-Navelbine(GlaxoSmithKline)

• Regulatory history: – 1st approved in 1994 for treatment of unresectable/advanced

non-small cell lung cancer– WR issued: 1/9/2001– Exclusivity Granted: 8/15/2002

• Population of Interest: Leukemia, lymphoma or refractory solid tumors including brain tumors

• Types of Studies:– Phase I PK and dose finding study (CCG0936)

• Number of centers – 13 US– Phase II study (A09705)

• Number of centers – 26 US

• Age groups: 2-17 yr; 1-25 yr.• Total # patients: Phase I = 29; Phase II = 46

Vinorelbine-Navelbine

• Results: – MTD is 33.75 mg/m2

– Activity: 22 pts. evaluable for response; 1 PR in RMS

• Label changes: New data from a single-arm study in 46 patients with recurrent solid malignant tumors, including rhabdomyosarcoma /undifferentiated sarcoma, neuroblastoma, and CNS tumors, at doses similar to those used in adults showed no meaningful clinical activity.

Summary: BPCA Experience with Oncology Drugs+

1392 pediatric cancer patients in 31 clinical trials

Time from issued WR to exclusivity determination

19 months* range, 12 - 48

# of amendments to WR 1* range, 0 - 3

# of studies contained in WR 3* range, 1 - 6

# of patients Phase I: 29**

Phase II: 46**

range, 3 - 63

range, 13 - 170

Data source for studies (# studies):

Cooperative/consortia group

Sponsor/individual institutions

21

10

+As of June 2007; *Median value; **mean value

Reasons for Amendments

• Extension to the deadline for submission of study reports and data

• Re-defining/clarifying primary endpoints

• Change in study population and age groups

• Clarifying protocols or studies generating the data

Types of Studies, n=31

0

1

2

3

4

PK, safety Activity PK, safety, activity

BU

S

CA

R

CL

O

FL

U

GE

M

IMT

OX

A

TM

Z

TP

T

VIN

IRI

BUS, busulfan; CAR, carboplatin; CLO, clofarabine; FLU, fludarabine; GEM, gemcitabine; IMT, imatinib; IRI, irinotecan; OXA, oxaliplatin; TMZ, temozolamide; TPT, topotecan; VIN, vinorelbine

Nu

mb

er

Comparative Clinical PharmacologyDrug Comment

Clofarabine Current label is pediatric specific (no adult data)

Busulfan ↑ CL; different dose in children required to achieve similar AUC to adults; dosing nomogram

Fludarabine Lower clearance in children

Temozolamide Cmax and AUC higher in children

Vinorelbine ↑ CL; terminal elimination half-life is ~ ½ the value in adults

Gemcitabine Similar half-life for short and long infusions; lower CL in females.

Imatinib Similar oral clearance and half-life compared to adult values; AUC at 260 mg/m2 = 400 mg in adults

Irinotecan Dose-normalized SN-38 AUC values comparable to adults

Oxaliplatin Similar CL and Cmax of ultrafilterable platinum at similar doses

Topotecan Similar CL, Vss and t½ to adults

Carboplatin No comparative data

Label

• New information resulted in label changes for 9 drugs including new dosing information, safety information and indications.

Label Changes Labeling Changes SummaryA - Expanded Age to Include Pediatric Age Groups Previously not Included, Including New

Indications for the Pediatric Population

D - Specific Pediatric Dosing Change/adjustment

S -New or Enhanced Pediatric Safety Information

X – Safety & Effectiveness Not Established in Pediatrics

NME – New molecular entity

BB-P – Boxed Warning containing Pediatric related information in labeling

PF – Pediatric formulation

EF – Extemporaneous formulation

PK - PK differences between pediatric and adults patients

A D S X BBP NME PF EF PK

Busulfan

Clofarabine

Fludarabine

Gemcitabine

Imatinib

Irinotecan

Oxaliplatin

Temozolamide

Vinorelbine

Types of information included in new label

Moving Forward• Voluntary process: constraints• Uniqueness of pediatric oncology practice: clinical

research as the cornerstone of therapy• Drafting the content of an oncology WR to address issues

of clinical importance– Stakeholders: sponsors, regulators, investigators, cooperative

groups, subject experts, patient community – Content of the PPSR in relation to the final WR – Timing of the WR relative to product development– Use of preclinical science to better inform the questions to be

answered by the WR studies– Types of studies and designs that may be the most informative– Formulations and dosages for unique groups (< 2 yrs. age) – Building flexibility in the process

• Defining success

Acknowledgements

Members of the review team(s)

Karen Weiss

Ramzi Dagher