Timing of the Initiation ofTiming of the Initiation of
Pediatric Clinical OncologyPediatric Clinical Oncology
StudiesStudi...
Historical Timing for Initiation ofHistorical Timing for Initiation of
Pediatric Phase I Clinical TrialsPediatric Phase I ...
Historical Timing for Initiation ofHistorical Timing for Initiation of
Pediatric Phase I Clinical TrialsPediatric Phase I ...
ZD1ZD1839
STI571STI571
ET-743ET-743
OO66
BGBG
ArsenicArsenic
FlavopiridolFlavopiridol
CI-980CI-980
BryostatinBryostatin
Do...
Drug Development Time LineDrug Development Time Line
ExampleExample
PublicationPublication
Phase I TrialPhase I Trial
Resu...
Pediatric Drug DevelopmentPediatric Drug Development
IrinotecanIrinotecan
Phase IPhase I
StudiesStudies
Phase IIPhase II
S...
Topotecan:Topotecan: Phase I to Phase IIIPhase I to Phase III
Study PhaseStudy Phase Date InitiatedDate Initiated
Phase I ...
What is the optimal timing forWhat is the optimal timing for
the initiation of pediatricthe initiation of pediatric
phase ...
Considerations in the Initiation ofConsiderations in the Initiation of
Pediatric Phase I Clinical TrialsPediatric Phase I ...
Considerations in the Initiation ofConsiderations in the Initiation of
Pediatric Phase I Clinical TrialsPediatric Phase I ...
Optimal Timing for Initiation ofOptimal Timing for Initiation of
Novel AgentsNovel Agents
• Early initiation is criticalEa...
What is early initiation forWhat is early initiation for
novel agents?novel agents?
• Evidence of biologic activity in adu...
Considerations for InitiatingConsiderations for Initiating
Trials for New AnalogsTrials for New Analogs
• Equivalent or su...
ConclusionsConclusions
• Timing for initiation of clinical trials of newTiming for initiation of clinical trials of new
ag...
ConclusionsConclusions
• Pediatric studies for novel agents should bePediatric studies for novel agents should be
initiate...
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Timing of the Initiation of Pediatric Clinical Oncology Studies

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Timing of the Initiation of Pediatric Clinical Oncology Studies

  1. 1. Timing of the Initiation ofTiming of the Initiation of Pediatric Clinical OncologyPediatric Clinical Oncology StudiesStudies
  2. 2. Historical Timing for Initiation ofHistorical Timing for Initiation of Pediatric Phase I Clinical TrialsPediatric Phase I Clinical Trials • Following assessment of initial safetyFollowing assessment of initial safety data and reasonable evidence ofdata and reasonable evidence of potential benefitpotential benefit After the completion and publication of adultAfter the completion and publication of adult phase I and/or phase II studiesphase I and/or phase II studies
  3. 3. Historical Timing for Initiation ofHistorical Timing for Initiation of Pediatric Phase I Clinical TrialsPediatric Phase I Clinical Trials • Following the completion of adult phase IIIFollowing the completion of adult phase III trialstrials • Following a successful NDAFollowing a successful NDA • At the first signs of “biologic activity” inAt the first signs of “biologic activity” in adultsadults • Initially in the pediatric populationInitially in the pediatric population - Monoclonal antibodies for neuroblastoma- Monoclonal antibodies for neuroblastoma - Cytotoxics for intrathecal administration- Cytotoxics for intrathecal administration
  4. 4. ZD1ZD1839 STI571STI571 ET-743ET-743 OO66 BGBG ArsenicArsenic FlavopiridolFlavopiridol CI-980CI-980 BryostatinBryostatin DocetaxelDocetaxel TopotecanTopotecan TemozolomideTemozolomide IrinotecanIrinotecan GemcitabineGemcitabine 2525 5050 7575 Time(months)Time(months) Mean - 25 mo Median - 15 mo Initiation of Phase I Pediatric Trial after Publication of Adult Phase I Trial Results
  5. 5. Drug Development Time LineDrug Development Time Line ExampleExample PublicationPublication Phase I TrialPhase I Trial Results JapanResults Japan 8/918/91 9/99/9 33 PublicationPublication Phase IPhase I TrialTrial Results USResults US Drug ApprovedDrug Approved for Adultsfor Adults 6/96/9 66 Pediatric Phase IPediatric Phase I Trials InitiatedTrials Initiated
  6. 6. Pediatric Drug DevelopmentPediatric Drug Development IrinotecanIrinotecan Phase IPhase I StudiesStudies Phase IIPhase II StudiesStudies AdultAdult ClinicalClinical StudiesStudies Phase IIIPhase III StudiesStudies CombinationCombination StudiesStudies 2 yr2 yr 3 - 5 yr3 - 5 yr 5 yr5 yr 12 yr12 yr 18+ yr18+ yr DrugapprovedforDrugapprovedfor adultsadults 19981998 20032003 2008200819961996
  7. 7. Topotecan:Topotecan: Phase I to Phase IIIPhase I to Phase III Study PhaseStudy Phase Date InitiatedDate Initiated Phase I StudyPhase I Study Sept, 1992Sept, 1992 Phase I Combination studyPhase I Combination study Oct, 1993Oct, 1993 Phase II StudyPhase II Study May, 1994May, 1994 Phase II Combination studyPhase II Combination study Oct, 1996Oct, 1996 Phase III StudyPhase III Study July, 1999July, 1999 Phase III study completes accrualPhase III study completes accrual July, 2004July, 2004
  8. 8. What is the optimal timing forWhat is the optimal timing for the initiation of pediatricthe initiation of pediatric phase I clinical trials ofphase I clinical trials of new anticancer agents?new anticancer agents?
  9. 9. Considerations in the Initiation ofConsiderations in the Initiation of Pediatric Phase I Clinical TrialsPediatric Phase I Clinical Trials • Type of agent and mechanism of actionType of agent and mechanism of action - novel agent vs. analog- novel agent vs. analog - non-specific cytotoxic vs. specific target- non-specific cytotoxic vs. specific target • Underlying disease being treatedUnderlying disease being treated - brainstem glioma vs. Hodgkin’s- brainstem glioma vs. Hodgkin’s • Safety profile of the agentSafety profile of the agent • Availability of pediatric formulationsAvailability of pediatric formulations
  10. 10. Considerations in the Initiation ofConsiderations in the Initiation of Pediatric Phase I Clinical TrialsPediatric Phase I Clinical Trials • Type of agent and mechanism of actionType of agent and mechanism of action - novel agent vs. analog- novel agent vs. analog - non-specific cytotoxic vs. specific target- non-specific cytotoxic vs. specific target • Underlying disease being treatedUnderlying disease being treated - brainstem glioma vs. Hodgkin’s- brainstem glioma vs. Hodgkin’s • Safety profile of the agentSafety profile of the agent • Availability of pediatric formulationsAvailability of pediatric formulations
  11. 11. Optimal Timing for Initiation ofOptimal Timing for Initiation of Novel AgentsNovel Agents • Early initiation is criticalEarly initiation is critical - Improve outcome for children with incurable CNS or- Improve outcome for children with incurable CNS or other high-risk pediatric tumorsother high-risk pediatric tumors - Develop alternative treatment strategies that may- Develop alternative treatment strategies that may eliminate (or postpone) the need for XRT ineliminate (or postpone) the need for XRT in children with developing nervous systemschildren with developing nervous systems
  12. 12. What is early initiation forWhat is early initiation for novel agents?novel agents? • Evidence of biologic activity in adultEvidence of biologic activity in adult phase I trialsphase I trials • Determination of the MTD and/orDetermination of the MTD and/or optimal biologic dose in adult trialsoptimal biologic dose in adult trials • Upon the completion of preclinicalUpon the completion of preclinical studies (studies (in vitroin vitro andand in vivoin vivo) if target is) if target is primarily pediatricprimarily pediatric
  13. 13. Considerations for InitiatingConsiderations for Initiating Trials for New AnalogsTrials for New Analogs • Equivalent or superior activity inEquivalent or superior activity in preclinical studies?preclinical studies? • Advantages to the toxicity profile?Advantages to the toxicity profile? • Advantages with regard to potential forAdvantages with regard to potential for drug interactions?drug interactions? • Advantages with regard to theAdvantages with regard to the formulation?formulation?
  14. 14. ConclusionsConclusions • Timing for initiation of clinical trials of newTiming for initiation of clinical trials of new agents is highly variable and in manyagents is highly variable and in many instances has not been optimalinstances has not been optimal • Ongoing communication between theOngoing communication between the pediatric cooperative groups, industry, thepediatric cooperative groups, industry, the FDA, and NCI is required to ensure theFDA, and NCI is required to ensure the earliest possible access to promising newearliest possible access to promising new agents with novel mechanisms of actionagents with novel mechanisms of action
  15. 15. ConclusionsConclusions • Pediatric studies for novel agents should bePediatric studies for novel agents should be initiated as soon as there is evidence ofinitiated as soon as there is evidence of biologic activity and an acceptable safetybiologic activity and an acceptable safety profile in early (phase I) adult clinical trialsprofile in early (phase I) adult clinical trials • Early access requires ongoing scrutiny andEarly access requires ongoing scrutiny and constant re-evaluation to ensure optimalconstant re-evaluation to ensure optimal prioritization, safety and potential for benefitprioritization, safety and potential for benefit for children with recurrent or refractoryfor children with recurrent or refractory cancercancer

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