C-1 Pegfilgrastim (Neulasta ) Oncologic Drugs Advisory Committee Pediatric Subcommittee October 20, 2005 Amgen Inc

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Pegfilgrastim (Neulasta)

Oncologic Drugs Advisory CommitteePediatric Subcommittee

October 20, 2005Amgen Inc.

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Pegfilgrastim

Approved in January 2002 to decrease febrile neutropenia in patients with non‑myeloid malignancies receiving myelosuppressive therapy

To date, approximately 3,800 adult patients have been treated in clinical trials and approximately 517,000 patients have been treated worldwide since commercial introduction

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Primary Goals of Pediatric Development of Pegfilgrastim

To determine an appropriate dose of pegfilgrastim for use in the pediatric population

Introduce a pediatric dosage form to ensure coverage for all age and weight groups– Current dosage form

6mg syringe (10mg/ml) Fixed dose for patients 45kg

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Common Challenges of Pediatric Oncology Drug Development

Limited patient population Majority of pediatric patients enter clinical

studies Limited study centers Need for pharmacokinetic and

pharmacodynamic data– Intensive monitoring and blood sampling

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Pegfilgrastim-Specific Challenges in Pediatric Development

Availability of filgrastim

Competition with therapeutic agent trials

Study of tumor and associated chemotherapy regimen across pediatric age ranges

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Pediatric Study Tumor Type: Sarcoma

Challenge– Higher incidence in older ages

Predominantly Ewing’s sarcoma enrolled into study

*Per 1,000,000 pediatric population*Per 1,000,000 pediatric populationSEER Cancer Statistics Review, 1975-2002, National Cancer Institute.SEER Cancer Statistics Review, 1975-2002, National Cancer Institute.

0.2 0.7 2.3 4.3 4.8

15.011.1 13.7

23.730.6

0

10

20

30

40

Age < 1 Age 1-4 Age 5-9 Age 10-14 Age 15-19

Ewing's All Sarcoma

Inci

denc

e*In

cide

nce*

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Pediatric Study Summary Primary objective – To determine an appropriate pediatric dose

Clinical hypothesis– At the identified dose, pegfilgrastim will provide Absolute Neutrophil

Count (ANC) recovery and safety profile similar to filgrastim

Parameters to be measured– Duration of severe neutropenia– Rates of febrile neutropenia– Pharmacokinetic profile of pegfilgrastim– Incidence of adverse events

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Pediatric Sarcoma Study Schema

Cycle 1Cycle 1VV

AdAdCC

Cycle 1Cycle 1VV

AdAdCC

PegfilgrastimPegfilgrastim

FilgrastimFilgrastim

Day 1 to 21Day 1 to 21


Cycle 2Cycle 2IIEE

Cycle 2Cycle 2IIEE



Cycle 3Cycle 3VV

AdAdCC

Cycle 3Cycle 3VV

AdAdCC




Cycle 4Cycle 4IIEE

Cycle 4Cycle 4IIEE




Daily ANC and Daily ANC and PK samplesPK samples

Doses: Vincristine 2 mg/mDoses: Vincristine 2 mg/m22; Adriamycin 75 mg/m; Adriamycin 75 mg/m22; Cyclophosphamide 1200 mg/m; Cyclophosphamide 1200 mg/m22; ; Ifosphamide 1800 mg/mIfosphamide 1800 mg/m22; Etoposide 100 mg/m; Etoposide 100 mg/m22

Multi-center, randomized (6:1), open-label, using VAdriaC/IE Multi-center, randomized (6:1), open-label, using VAdriaC/IE

ClinicalTrials.gov identifier NCT00035620ClinicalTrials.gov identifier NCT00035620

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Age Groups Defined in Study Protocol

0 to 5 years0 to 5 years



Dose selection for each age group is done independentlyDose selection for each age group is done independently

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Dose Selection Algorithm Requires Two Successive Cohorts Showing ANC Recovery

ANC recovery ANC recovery in in 5 patients5 patients

Cohort 2Cohort 2Dose 1.5 x ADose 1.5 x A

Cohort 3Cohort 3Dose 1.5 x ADose 1.5 x A


Cohort 2Cohort 2Dose ADose A




Scenario AScenario A

ANC recovery ANC recovery in <5 patientsin <5 patients


Scenario BScenario B

All numbers refer to the 6 patients treated with All numbers refer to the 6 patients treated with pegfilgrastimpegfilgrastim

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Rationale for Selection of Pediatric Starting Dose of 100 g/kg

Pharmacokinetics and mechanism of action are expected to be similar in adults and pediatric patients– Neutrophil-mediated clearance

This dose is safe and effective in adults

Commonly-used filgrastim pediatric dose (5 g/kg/day) is same as adult dose

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Pediatric Study Status

0 to 5 years0 to 5 years3 enrolled3 enrolled

4 more needed4 more needed

6 to 11 years6 to 11 years3 enrolled3 enrolled

4 more needed4 more needed

12 to 21 years12 to 21 yearsENROLLMENT ANDENROLLMENT AND

TREATMENT COMPLETEDTREATMENT COMPLETED







Cohort 1Cohort 1 Cohort 2Cohort 2

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Challenges to Completing the Pediatric Study

Filgrastim available and commonly used Accrual issues– Low incidence of sarcoma in younger patients– Therapeutic protocols have higher priority than

supportive care– Daily monitoring / blood draws may keep

children in hospital or clinic

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Addressing Current Accrual Challenges

Maintained contact with pediatric community to advise on ways to improve enrollment

Competing therapeutic trials have recently completed accrual resulting in a small window of opportunity– Expand site numbers– Enroll more patients at existing sites

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Lessons Learned for the Future

Whenever possible, integrate into therapeutic protocols

Design more efficient studies by continued collaboration with pediatric community and regulatory authorities (e.g. targeted collection of data)

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Summary and Conclusions

Pediatric patients, like adult patients, are expected to benefit from the addition of pegfilgrastim as a supportive care option

Significant progress has been made in determining the appropriate dose for pegfilgrastim in pediatric patients

Amgen looks forward to continued collaboration with cooperative groups and FDA to expedite pediatric drug development

Documents

C-1 Pegfilgrastim (Neulasta ) Oncologic Drugs Advisory Committee Pediatric Subcommittee October 20, 2005 Amgen Inc