Patricia dinndorf medical officer office of oncology drug products 5 9 07
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NDA 022-092 Mifamurtide (MTP-PE) Immuno-Designed Molecules, Inc (IDM) Treatment of High-grade Osteosarcoma in Combination with Chemotherapy. Patricia Dinndorf Medical Officer Office of Oncology Drug Products 5/9/07. Overview of the Presentation.

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Patricia dinndorf medical officer office of oncology drug products 5 9 07

NDA 022-092 Mifamurtide (MTP-PE) Immuno-Designed Molecules, Inc (IDM)Treatment of High-grade Osteosarcoma in Combination with Chemotherapy

Patricia Dinndorf

Medical Officer

Office of Oncology Drug Products

5/9/07


Overview of the presentation
Overview of the Presentation

  • Regulatory Considerations for an Adequate and Well-Controlled Trial

  • Background on MTP-PE and Osteosarcoma

  • Description of Trial

  • Conduct of the Trial and Quality of Data

  • Efficacy Analysis (Dr Laura Lu)

  • Safety Profile

  • Conclusions


Statutory requirements for fda approval of new drug
Statutory Requirements for FDA Approval of New Drug

For a new drug to be approved, the 1962 amendments to the FD&C Act require the manufacturer to provide

“Substantial Evidence of Effectiveness”

From

“Adequate and Well-controlled Clinical Investigations”


Background of mtp pe
Background of MTP-PE

MTP-PE

  • Biological response modifier developed by Ciba-Geigy in 1980s

  • Fully synthetic lipophilic derivative of Mycobacterium cell walls used in Freund’s complete adjuvant

  • Encapsulated in multi-lameller liposomes

  • Delivered to macrophages stimulates tumoricidal activity

  • Clinical development for osteosarcoma based on activity in animal models


Background high grade osteosarcoma
Background High-grade Osteosarcoma

Statistics

  • Uncommon tumor but most common tumor of the bone in children and adolescents

  • 5th most common malignancy among adolescents aged 15 to 19, M>F

  • 400 new cases per year in US

  • 20% have detectable pulmonary metastasis at the presentation

  • 5-year EFS in non-metastatic reported between 50 to 75%


Background high grade osteosarcoma1
Background High-grade Osteosarcoma

Standard of Care

  • Neoadjuvant chemotherapy -

    Cisplatin, Doxorubicin, HD Methotrexate

  • Surgery – The goal of surgery is a complete resection of disease

  • Adjuvant chemotherapy –

    Cisplatin, Doxorubicin, HD Methotrexate

    or alternative based on histological response


Regulatory history
Regulatory History

Sponsor: 1988-1996 - Ciba-Geigy

1996-2003 - Jenner Technologies

2003 - IDM

1993-1997 -- INT 0133 Trial enrolled subjects

Oct 2006 -- NDA 22-092 submitted


Applicant s proposed indication
Applicant’s Proposed Indication

MTP-PE is indicated for the treatment of newly diagnosed resectable high grade osteosarcoma following surgical resection in combination with multi-agent chemotherapy.


Int 0133 trial
INT 0133 Trial

  • Prospective

  • Multi-center

  • Randomized Study

  • 2 pediatric cooperative groups

    • CCG (Children’s Cancer Group)

    • POG (Pediatric Oncology Group)

  • 164 sites participated


Int 0133 trial1
INT 0133 Trial

2 Cohorts Studied

  • Non-metastatic and resectable high-grade osteosarcoma

    • CCG and POG participated

  • Metastatic or non-resectable high-grade osteosarcoma

    • CCG only



Int 0133 trial regimen a standard mtp pe or
INT 0133 Trial Regimen A Standard MTP-PE or


Int 0133 trial regimen b experimental ifosfamide mtp pe or
INT 0133 Trial Regimen B Experimental (+Ifosfamide) MTP-PE or


Mtp pe administration
MTP-PE Administration

  • Initial dose - 2 mg/m2

  • Escalated until biologic response

    • 2 mg/m2 + 1 mg

    • 2 mg/m2 + 2 mg

  • Biologic response

    • Fever

    • Chills

    • Elevated C-reactive protein

  • Twice a week x 12 weeks

  • Weekly x 24 weeks

  • 48 total doses


Trial design issues timing of randomization
Trial Design Issues Timing of Randomization

  • MTP-PE randomization at study entry

  • MTP-PE treatment in maintenance

  • 10% of randomized patients did not enter maintenance


Trial design issues factorial design
Trial Design Issues Factorial Design

  • Powered to evaluate DFS

  • Non-metastatic and resectable cohort

  • Assuming no interactions between regimens planned pooled analysis


Trial design issues factorial design1
Trial Design Issues Factorial Design

If there were no interactions, the investigators planned to use a factorial analysis of the pooled treatment arms.

Regimen A std vs Regimen B +Ifos

MTP-PE or MTP-PE or

Regimen A&B vs Regimen A&B

MTP-PE MTP-PE


Trial design issues factorial design2
Trial Design Issues Factorial Design

The investigators discussed the risk of employing this study design in the background section of INT 0133.

“ We hope that interactions between MTP-PE and the alternative chemotherapy arms will be similar. In this case it will be possible to analyze the proposed study by a factorial design. If the interactions are different, it will be necessary to consider the study as if it were a four-arm analysis.”



Trial design issues pre specified endpoints
Trial Design Issues Chemotherapy and Pre-specified Endpoints

  • Primary and secondary trial endpoints not clearly specified

  • No clear hierarchical assignment of endpoints specified

  • DFS analyzed as primary endpoint

  • Overall survival data was collected


Inclusion criteria
Inclusion Criteria Chemotherapy and

  • Patients with newly diagnosed (≤ 1 month) malignant high-grade osteosarcoma of bone

  • ≤ 30 years

  • Normal organ function - renal, liver, cardiac

  • IRB approved protocol with signed consent


Exclusion criteria
Exclusion Criteria Chemotherapy and

  • Low grade osteosarcoma, parosteal or periosteal sarcoma

  • Radiation-induced sarcoma

  • Pre-malignant bony lesion (Paget’s disease)

  • Previous chemotherapy or radiotherapy

  • Metastatic or non-resectable – POG patients ineligible


Review of eligibility
Review of Eligibility Chemotherapy and

COG Report of Trial INT 0133 JCO 2005

  • 14 of 678 patients ineligible

    • 6 patients > 1 month from diagnosis

    • 4 patients with ineligible pathology

      • lymphoma

      • mesenchymal chondrosarcoma

      • chondrosarcoma

      • chondroblastic osteosarcoma

    • 2 patients without appropriate IRB approval

    • 1 patient with an abnormal cardiac evaluation

    • 1 patient with metastatic disease at diagnosis

      (J Clin Oncol 23: 2004-11, 2005)


Review of eligibility1
Review of Eligibility Chemotherapy and

IDM

All 678 patients entered in the non-metastatic and resectable cohort as the analysis population

FDA

7 patients excluded from the analysis population. These were:

  • 4 patients with ineligible pathology

  • 1 patient determined to have metastatic disease at study entry

  • 2 patients determined not to have IRB approved consent


Conduct of the trial interim analyses
Conduct of the Trial Chemotherapy and Interim Analyses

  • CCG/POG performed 3 interim analyses.

  • Statistical ramifications of these interim analyses discussed by Dr Lu


Conduct of the trial endpoint determination
Conduct of the Trial Chemotherapy and Endpoint Determination

  • Determination of DFS events

    • By treating institution

    • Physical exam and CXR

    • No central or blinded review

  • CRFs did not capture if evaluations done by

    • Protocol-specified schedule

    • Protocol-specified modality


Conduct of the trial endpoint determination1
Conduct of the Trial Chemotherapy and Endpoint Determination

  • Relapse form captured

    • Date relapse identified

    • Sites of disease

  • Relapse form did not capture

    • Method relapse documented


Conduct of the trial unavailability of mtp pe filters
Conduct of the Trial Chemotherapy and Unavailability of MTP-PE Filters

  • Filters required to administer MTP-PE not available between 6/15/95 to 1/15/96

  • 98 patients (45 on MTP-PE arms) entered maintenance during this period

    • 7 received no MTP-PE

    • 13 received < 90% of doses

    • 25 received ≥ 90% of doses

  • Trial modified to increase accrual from 585 to 645 patients


Dataset data quality
Dataset – Data Quality Chemotherapy and

  • Datasets submitted by IDM, designated “IDM Dataset 2003,” constructed by COG for the 2005 JCO publication

  • FDA reviewed CRFs containing the primary data from of 677 of 678 patients

  • Results compared to “IDM Dataset 2003”

  • “FDA Dataset” constructed

  • “FDA Dataset” includes the 671 patients FDA considered eligible


Comparison of datasets
Comparison of Datasets Chemotherapy and


Dataset inadequate length of follow up
Dataset Chemotherapy and Inadequate Length of Follow-up

  • Follow-up inadequate in significant proportion of patients

  • Median time to relapse - 1.4 years.

  • 95% relapses occurred by 4 years

  • Excluding patients who died, 30% of patients (155 of 519) were followed less than 4 years


Dataset inadequate follow up for survival
Dataset Chemotherapy and Inadequate Follow-up for Survival

  • 26 patients with active disease either osteosarcoma or AML at the time of last patient contact.

    • 16 Regimen A&B MTP-PE +

    • 10 Regimen A&B MTP-PE –

  • The majority (if not all) of these patients probably died.


Disposition 1

Entered Trial Chemotherapy and

678

Eligible

671

Randomized

Reg A -

171

Reg A +

165

Reg B –

166

Reg B +

169

Maintenance

603

Reg A –

153

Reg A +

145

Reg B –

148

Reg B +

157

Completed Chemotherapy

464

Reg A –

130

15%

Reg A +

108

25%

Reg B –

120

19%

Reg B +

106

32%

Disposition 1


Disposition 2
Disposition 2 Chemotherapy and


Dose exposure mtp pe
Dose-Exposure MTP-PE Chemotherapy and

  • 303 of 334 MTP-PE entered maintenance

    • Regimen A+ n=145

    • Regimen B+ n=158

  • 12% of MTP-PE - none

    • 32 who did not enter maintenance

    • 7 patients who entered maintenance

  • Only 62% of MTP-PE - received ≥ 90%


Efficacy
Efficacy Chemotherapy and

Efficacy evaluation will be presented by Dr Lu.


Assessment of adequacy of the safety pool
Assessment of Adequacy of the Safety Pool Chemotherapy and

  • Safety data - 248 patients from phase I/II trials

  • Randomized safety pool INT 0133 study

    • non-metastatic and resectable (n=678 entered)

    • metastatic or non-resectable (n=115 entered)

  • 793 patients total

    • 681 who entered maintenance

    • 336 randomized MTP-PE

    • 345 randomized MTP-PE

    • 332 MTP-PE received MTP-PE


Int 0133 adverse event collection methodology
INT 0133 Adverse Event Chemotherapy and Collection Methodology

  • Adverse Event Data was collected on “End of Phase” Roadmaps

  • Grade 3 and 4 toxicities defined by CCG Toxicity Scale

  • No data was collected on timing of toxicity in relationship to the protocol-specified therapy.

  • No attribution was assigned.


Common adverse events
Common Adverse Events Chemotherapy and

  • Majority patients in Phase I/II studies at least 1 treatment-related adverse event

  • Related to the biological activity of MTP-PE.

  • The adverse events reported by ≥50% of patients

    • chills 89%

    • pyrexia 85%

    • fatigue 53%

    • nausea 57%

    • tachycardia 50%

    • headache 50%.

  • Most of these were mild or moderate.


Per patient grade 3 or 4 adverse events in maintenance excluding laboratory investigations
Per Patient Grade 3 or 4 Adverse Events in Maintenance Chemotherapy and (Excluding Laboratory Investigations)



Int 0133 deaths
INT 0133 Deaths Maintenance

  • 5 deaths documented as reason for discontinuing therapy prior to completion of therapy

    • Induction - 2 cases

      • MTP-PE – 2 Operative Complication

        Toxicity

      • MTP-PE + 0

    • Maintenance – 3 cases

      • MTP-PE - 1 Infection

      • MTP-PE + 2 Infection

        Infection


Removed from maintenance prior to completing mtp pe arms 1
Removed from Maintenance Prior to Completing MTP-PE Arms 1 Maintenance

  • There was a disparity between the number of patients on MTP-PE – arms and MTP-PE + arms who were removed from protocol therapy prior to completing maintenance:

  • Parent/Patient Physician

    46 MTP-PE + 7 MTP-PE +

    14 MTP-PE – 4 MTP-PE –


Removed from maintenance prior to completing mtp pe arms 2
Removed from Maintenance Prior to Completing MTP-PE Arms 2 Maintenance

  • Among patients who were removed from therapy on MTP-PE arms by family or physician request, the following reasons were documented on CRFs.

    • Allergy 3 -Arrhythmia 1

    • Chills 2 -Erythema Multiforme 1

    • Fatigue Malaise 1 -Hand Foot Synd/Cellulitis 1

    • Infusion Reactions 1 -Nausea Vomiting 1

    • Pain 1 -Reactions intolerable 1

    • Refused 10 -Rigors 3

    • Side Effects 5 -Too burdensome 1

    • Severe recurrent

      Abdominal pain 1


Conclusion
Conclusion Maintenance

  • The IDM’s pooled DFS results for MTP-PE were driven by an experimental chemotherapy arm Regimen B that did worse than Regimen A , the control arm.

  • Because of interactions between treatment arms it is not appropriate to use a pooled analysis to evaluate DFS.

  • For DFS, comparisons of results of Regimen A+ and Regimen B + individually to Regimen

    A , the control arm, are not significant.


Conclusion1
Conclusion Maintenance

  • A pooled analysis of DFS using the “FDA Dataset,” the dataset constructed based on data documented in the CRFs submitted with the application, is not significant.

  • Follow-up data on patients has not been rigorously collected and is incomplete with insufficient follow-up for patients at risk for relapse and death.


Conclusion2
Conclusion Maintenance

  • INT 0133 protocol contained no pre-specified statistical analysis for overall survival.

  • DFS results, the primary endpoint, are not significant; there is no alpha left to be applied to the analysis of overall survival.

  • Follow-up for survival was inadequate to perform a meaningful analysis.


The end
The End Maintenance


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