Oncologic Drugs Advisory Committee on mtp for Osteosarcoma idm pharma, Inc



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Oncologic Drugs Advisory Committee on MTP for Osteosarcoma


Bonnie Mills, PhD

  • Vice President, Clinical Operations

  • IDM Pharma



MTP Sponsors

  • Ciba-Geigy 1988-1996

  • Non-clinical and Phase 1/2 studies

  • NCI 1993-1997

  • Cooperative Group Phase 3 trial

  • Jenner Biotherapies 1996-2003

  • IDM 2003-present

  • Completed Phase 3 primary final analysis 2004

  • Submitted NDA 2006



Phase 3 Trial

  • Large, well conducted, multi-center study in osteosarcoma (NCI/COG)

  • Clinically meaningful effect

    • DFS (primary): p = 0.0245, HR = 0.76, 95% CI (0.58, 0.98)
    • Survival: p = 0.0183, HR = 0.68, 95% CI (0.49, 0.95)
  • Subset analyses support internal consistency

  • Confirmatory study “practically or ethically impossible”



Agenda



Resources and References

  • Clinical

    • Curt Scribner, MD
    • Cheryl Graham, MD
  • Statistics

    • Mark Munsell
    • Neby Bekele, PhD


Unmet Need

  • Ian Lewis, MB ChB, FRCP, FRCPCH

  • Pediatric Oncologist, Leeds, UK

  • Chief Investigator: European Osteosarcoma Intergroup Randomized Trial 80931

  • NCI External Program Reviewer



Osteosarcoma

  • Sites of disease

    • Metaphyses of long bones particularly distal femur, proximal tibia and proximal humerus
  • Clinically evident metastases at diagnosis

    • Lung alone 20%
    • Bones/combined 5%


Single Agent Activity in Osteosarcoma



UK Osteosarcoma Survival 1960-2000



EOI 80931 Randomized Trial Doxorubicin/ Cisplatin: Standard vs Intensified



Osteosarcoma Survival by Time Epoch (SEER Ages 0 – 29)



Product Characteristics

  • Bonnie Mills, PhD



Muramyl Tripeptide-Phosphatidyl Ethanolamine (MTP-PE)



Liposomal MTP-PE



Administration of MTP



MTP Induces Infiltration of Inflammatory Macrophages into Lung Metastases



Efficacy



Osteosarcoma Survival: SEER Data



Phase 2 Results in Relapsed Osteosarcoma with Lung Metastases



Landmark Phase 3 Trial

  • NCI-sponsored, Cooperative Group study

    • Designed and conducted independently of corporate sponsor
  • Largest study completed in osteosarcoma

    • 178 sites – 1/3 of eligible incident cases in US
  • Newly diagnosed (within 30 days; age <31)

    • 678 non-metastatic resectable disease
    • 115 with more advanced disease


Phase 3 Study Design



Phase 3 Study Endpoints

  • DFS

    • Putative surrogate for OS
    • Prospectively defined primary endpoint
    • “To determine whether MTP can improve DFS…”
    • “To compare the results of a prospective, randomized trial of two chemotherapeutic regimens…” (A vs. B)
  • Survival

    • “To improve the survival of patients with osteogenic sarcoma”


Data Sources



Baseline Demographics and Disease Characteristics



Primary Analysis: DFS



Primary Analysis: DFS (Kaplan-Meier)





Primary Analysis: Survival



Primary Analysis: Survival (Kaplan-Meier)





Data Sources



Follow Up 2003 and 2006



Confirmatory Analysis 2006: Survival



Confirmatory 2006 Analysis: Survival (Kaplan-Meier)



Safety



Grade 3 or 4 Adverse Events Reported by ≥3% of Patients: Phase 3 ITT



Patient Discontinuation (Maintenance)



Osteosarcoma: Overall Survival (SEER Ages 0 - 29)



Osteosarcoma: Overall Survival SEER and COG 2006 Data (All Patients)





MTP factor: DFS, 2003 ITT

  • MTP factor: DFS, 2003 ITT

    • MTP versus no MTP (228 events):
      • p = 0.0245 (against 0.04)
      • Hazard ratio = 0.76, 95% CI (0.58, 0.98)
      • Meets statistical criterion
  • Chemotherapy factor: DFS, 2003 ITT

  • Primary analysis issues:

    • Timing of primary final analysis
    • DFS Interaction
    • Consequences of randomization timing


Goal

  • Goal

    • Conform to original statistical goals
    • Assess impact of deferred final primary analysis
  • Method

    • Used simulation
    • Interim analyses included in simulation
  • Finding: Refer primary analysis p-value, 0.0245, to 0.034 instead of 0.04

  • Conclusion: Deferred final analysis OK



Interaction test significance level = 0.1

  • Interaction test significance level = 0.1

  • MTP x Chemo Interaction test: p = 0.06

  • MTP HRs

    • A+ vs A-: HR = 0.96
    • B+ vs B-: HR = 0.63
  • Qualitative MTP interaction test: no evidence (Gail & Simon, Biometrics 41:361-72, 1985)

  • Quantitative interaction

    • Does not invalidate marginal MTP inference
    • Overall MTP HR = 0.74 (average effect)






Four-arm model (p = 0.0525, 3 df)

  • Four-arm model (p = 0.0525, 3 df)

    • Six possible 2-way comparisons
      • Only significant comparison is B versus B+MTP
      • All others differences consistent with chance
  • Interaction not present in survival analyses









2003 ITT (primary result)

  • 2003 ITT (primary result)

    • DFS
      • p = 0.0245 HR = 0.76, 95% CI (0.58, 0.98)
      • Robust against issues: alpha, interaction, drop-outs
    • Survival
      • p = 0.0183
      • HR = 0.68 95% CI (0.49, 0.95)
  • 2006 ITT (confirmatory result)

    • Survival
      • p = 0.035
      • HR = 0.72 95% CI (0.53, 0.97)




Side effects reflect activity of MTP

  • Side effects reflect activity of MTP

  • Flu-like symptoms; treated with acetaminophen

  • No increase in chemo toxicity

  • Optimal biologic dose < Maximum tolerated dose

  • Compliance rather than safety concerns









Summary

  • Over 20 years of data with MTP in young people

  • Phase 3 trial designed to determine efficacy

  • Phase 3 study is largest US trial in osteosarcoma

  • No new agents for osteosarcoma since MTX approved

  • Survival data translate into 50 more cures per year





Overall Survival (patients with active disease at last contact considered dead at last contact): 2006 ITT



Overall Survival (patients with active disease at last contact considered dead at last contact): 2003 ITT



FDA Modified 2003 COG Dataset

  • Modifications based on FDA review of 2003 CRFs

    • 7/14 ineligible patients excluded from ITT
    • New censor dates (2003 data)
      • Most (>30) ‘synchrony’ modifications
      • 4 last follow up not in CRF – from another COG database
      • 3 lost to follow up, last report excluded
    • Event changes/additions (2003 data)
      • death not on correct CRF
      • 1 relapse not reported but surgery for mets reported
      • 1 anecdotal relapse (mentioned in a letter but no date)
      • 1 surgery for benign lesions counted as relapse
      • 2 failures to respond to induction counted as relapse
      • rejected one estimated relapse date by COG
  • Inclusion of data from one site’s response to IDM’s 2005 audit

    • 28 patients including 5 new events


Ototoxicity: Cisplatin and MTP



Follow-up to 5 years: 2006 ITT





Treatment: Neoadjuvant Chemotherapy Response




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