Pegfilgrastim (Neulasta?)

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Pegfilgrastim (Neulasta?)

• Oncologic Drugs Advisory Committee
• Pediatric Subcommittee
• October 20, 2005
• Amgen 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 Ewings sarcoma enrolled into study

Incidence
Per 1,000,000 pediatric population SEER Cancer
Statistics Review, 1975-2002, National Cancer
Institute.
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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
Multi-center, randomized (61), open-label, using
VAdriaC/IE
Daily ANC and PK samples
Doses Vincristine 2 mg/m2 Adriamycin 75 mg/m2
Cyclophosphamide 1200 mg/m2 Ifosphamide 1800
mg/m2 Etoposide 100 mg/m2
ClinicalTrials.gov identifier NCT00035620
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Age Groups Defined in Study Protocol
Dose selection for each age group is done
independently
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Dose Selection Algorithm Requires Two Successive
Cohorts Showing ANC Recovery
All numbers refer to the 6 patients treated with
pegfilgrastim
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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
Cohort 1
Cohort 2
0 to 5 years 3 enrolled 4 more needed
0 to 5 years ENROLLMENT ANDTREATMENT COMPLETED
6 to 11 years 3 enrolled 4 more needed
6 to 11 years ENROLLMENT ANDTREATMENT COMPLETED
12 to 21 years ENROLLMENT AND TREATMENT COMPLETED
12 to 21 years ENROLLMENT ANDTREATMENT COMPLETED
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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