# Presentation: 757632

## 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

- 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

- 	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 Investigation*_***s***_*”*

## 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 

- 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%

## 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

- 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

**Background ****High-grade Osteosarcoma **

## 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 

- 	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  

- Prospective
- Multi-center
- Randomized Study
- 2 pediatric cooperative groups
- CCG (Children’s Cancer Group)
- POG (Pediatric Oncology Group)
- 164 sites participated

## 2 Cohorts Studied
Non-metastatic and resectable high-grade osteosarcoma
CCG and POG participated
Metastatic or non-resectable high-grade osteosarcoma
CCG only

- Non-metastatic and resectable high-grade osteosarcoma
- CCG and POG participated
- Metastatic or non-resectable high-grade osteosarcoma
- CCG only

**INT 0133 Trial  **

## INT 0133 Schema

## INT 0133 Trial Regimen A Standard  MTP-PE     or 

## INT 0133 Trial Regimen B Experimental (+Ifosfamide) MTP-PE     or

## 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

## MTP-PE randomization at study entry 

MTP-PE treatment in maintenance 

10% of randomized patients did not enter maintenance

- MTP-PE treatment in maintenance
- 10% of randomized patients did not enter maintenance

**Trial Design Issues ****Timing of Randomization**

## Powered to evaluate DFS 
Non-metastatic and resectable cohort 
Assuming no interactions between regimens planned pooled analysis

- Non-metastatic and resectable cohort
- Assuming no interactions between regimens planned pooled analysis

**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    

-      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 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.”

- “ 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 ****Factorial Design**

## Trial Design Issues - Factorial Design Interaction between Chemotherapy and MTP-PE Arms

## Trial Design Issues 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

- 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

- 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 

- 	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)

## 	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

- 	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

**Review of Eligibility **

## Conduct of the Trial Interim Analyses

- CCG/POG performed 3 interim analyses.
- Statistical ramifications of these interim analyses discussed by Dr Lu

## Conduct of the Trial 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 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

- 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 

- 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

| “IDM Dataset 2003” | “FDA Dataset” |
| --- | --- |
| Source – Submitted by IDM with Application | Source - Review of Primary Data in CRFs |
| 678 All Patients Enrolled Non-Met/Resect Cohort | 671 Patients 
FDA Considered Eligible |
| DFS Events – 228/678 (225/671) | DFS Events – 230/671  |
| Deaths – 148/678
(145/671) | Deaths – 152/671 |
| Length of DFS Follow-up - 66 Discrepancies |  |
| Length Overall Survival Follow-up - 68 Discrepancies |  |

## 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

- 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 Length of Follow-up**

## Dataset 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

## Disposition 2

|  | Off Before Maintenance n = 68 | Entered Maintenance 
n = 603 |  |
| --- | --- | --- | --- |
|  |  | MTP-PE - | MTP-PE + |
| Received No Therapy | 7 |  |  |
| Death  | 2 | 1 | 2 |
| Major Deviation  of Therapy /Other  | 17 | 8 | 11 |
| Unacceptable Toxicity | 3 | 5 | 3 |
| Progressive Disease | 19 | 16 | 17 |
| Parent or Patient | 16 | 14 | 46 |
| Physician | 4 | 4 | 7 |
| Deemed Ineligible |  | 2 | 1 |
| Lost to Follow-up |  |  | 2 |
| Completed Therapy  |  | 250 | 214 |

## 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%  

- 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%

**Dose-Exposure MTP-PE**

## Efficacy

- 	Efficacy evaluation will be presented by Dr Lu.

##  Assessment of Adequacy of the Safety Pool  

- 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  

- 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

- 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) 

| Adverse Event 
≥ 2% | MTP-PE     Arm              336 entered maintenance | MTP-PE     Arm1
345 entered maintenance
332 received at least 1 dose  |
| --- | --- | --- |
| Stomatitis | 96 (29%) | 100 (30%) |
| Infection | 59 (18%) | 60 (18%) |
| Deafness | 24 (7%) | 42 (13%) |
| Vomiting | 29 (9%) | 34 (10%) |
| Rash Generalized | 15 (4%) | 14 (4%) |
| Cerebellar Ataxia | 8 (2%) | 13 (4%) |
| Depression | 7 (2%) | 10 (3%) |
| Ileus | 8 (2%) | 8 (2%) |
| 1Excludes adverse events reported in courses of maintenance therapy MTP not given |  |  |

## Per Patient Grade 3 or 4 Abnormal Lab Investigations in Maintenance (Excluding Hematology)

| Abnormal Lab
≥ 2% | MTP-PE     Arm              
336 entered maintenance | MTP-PE     Arm1
345 entered maintenance
332 received at least 1 dose |
| --- | --- | --- |
| Liver 
(AST/ALT/ Bili) | 125 (37%) | 104 (31%) |
| Glucose | 21 (6%) | 14 (4%) |
| Potassium | 23 (7%) | 14 (4%) |
| Magnesium | 3 (1%) | 7 (2%) |
| Renal
(Cr/BUN/Cr Clx) | 13 (4%) | 7 (2%) |
| 1Excludes adverse events reported in courses of maintenance therapy MTP not given |  |  |

## INT 0133 Deaths 

- 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

- 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 –

## 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

- 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

**Removed from Maintenance Prior to Completing MTP-PE  Arms 2**

## Conclusion 

- 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.

## Conclusion 

- 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.

## Conclusion 

- 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