# Presentation: 290615

## Mylotarg®(gemtuzumab ozogamicin)

**Lee F. Allen, M.D., Ph.D.**
**Vice President, Medical Research- Oncology**
**Wyeth Pharmaceuticals**
**Oncologic Drugs Advisory Committee**
**8 November 2005**** **

## Agenda- Mylotarg

**Background- Indication**
**Subpart H Phase 4 Clinical Commitment**
**Commitment Related Activities****:**
**Preparatory activities:**
**Prerequisite Pilot Combination Studies**
**Protocol Development, Review, & Approval**
**Study- S0106**
**Study Design/Current Status**
**Study Progress Assessment**
**Study Challenges**
**Accrual Action Plan**
**Opportunities to Fulfill our Post-approval Commitment**
**Conclusions**
**Discussion/Feedback**

## Background- Mylotarg

**Orphan Drug Status ***(November 24,1999)*
**Indication: ***(May 17, 2000)*
**Mylotarg is indicated for the treatment of patients with CD33 positive Acute Myeloid Leukemia (AML) in first relapse who are  **_**>**_** 60 years of age and are not candidates for other cytotoxic chemotherapy. The safety and efficacy of Mylotarg in patients with poor performance status and organ dysfunction has not been established.**
**The effectiveness of Mylotarg is based on OR rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival, compared to any other treatment.**

## Subpart H Clinical Phase 4 Commitment

**	****A randomized controlled trial of Mylotarg, daunorubicin, and cytarabine versus daunorubicin and cytarabine as induction therapy in patients with *****de novo***** CD33-positive AML.**
**	****	****	****	***From: Mylotarg Approval Letter May 17, 2000*
*	**As a prerequisite to the planned post-approval commitment study, the sponsor will:*_**                 **_
**	****	****Perform appropriate Phase 1 trials to ensure that ****	****toxicities observed with the dose combination are ****	****acceptable **(*Pilot Combination Studies 205 and 206*)

## Mylotarg Approved

- 8/00

- 11/01

- 4/

- 3/0

**Mylotarg Approved**

**ODAC Meeting- March 2003**

**Addition of NCI Canada Sites**

**Conduct S0106**

**IRB Approvals**

**Contract Negotiations**

**Final S0106 Protocol**
**Submitted to FDA**

**NCI/CTEP Review & Approval**

**TASK**

*SPA submitted*
*to FDA*

**Conduct & Complete Pilot**
**Combo Studies 205 & 206**

**Develop and Reach**
**Agreement on S0106 Protocol**

## Mylotarg Pilot Combination Studies

_**Study 205**_
- **Patients ******** ****60 years of age**
- **Mylotarg and cytarabine**
- **N = 38**
- **Mylotarg MTD:****	****6 mg/m****2 ****(Day 1) ****	****4 mg/m****2 ****(Day 8)**

_**Study 206**_
- **Patients 18 to 60 years of age**
- **Mylotarg and daunorubicin + cytarabine**
- **N = 71**
- **Mylotarg MTD: 6 mg/m****2 ****(Day 4) **

|  | Study 205 | Study 206 |
| --- | --- | --- |
| CR | 9/21 (43%) | 41/ 53 (77%)  |
| OR (CR + CRp) | 10/21 (48%) | 42/ 53 (79%)  |
| Median PFS | 377 Days (12.6 mos) | 389 Days (13 mos) |
| Median OS | 408 Days (13.6 mos) | Not Achieved |

## Conduct & Complete Pilot

- 8/00

- 11/01

- 4/

- 3/0

**Conduct & Complete Pilot**
**Combo Studies 205 & 206**

**Mylotarg Approved**

**Develop and Reach**
**Agreement on S0106 Protocol**

**ODAC Meeting- March 2003**

**Addition of NCI Canada Sites**

**Conduct S0106**

**IRB Approvals**

**Contract Negotiations**

**Final S0106 Protocol**
**Submitted to FDA**

**NCI/CTEP Review & Approval**

**TASK**

*SPA submitted*
*to FDA*

*First Subject*
*Enrolled*

*FDA Meeting*

## Protocol S0106

**	****A Phase 3 study of the addition of Mylotarg to standard induction therapy versus standard induction followed by consolidation and randomization to post-consolidation therapy with Mylotarg or no additional therapy**
**	****Study Design****-****  *****addresses two important clinical questions:***
- 	**INDUCTION** – Compare the use of Mylotarg in combination with standard induction therapy
*specifically addresses our subpart H commitment*
**	****POST-CONSOLIDATION** – Compare the use of Mylotarg in the post-consolidation phase versus no therapy
*elected to expand study size to address an additional area of unmet medical need*

## Protocol S0106: Schema

**Protocol S0106: Schema**

_**Induction**_

_**Consolidation**_

_**Post**__-__**Consolidation**_

**Complete Remission**

**Disease-Free Survival**

**Daunomycin**
**Ara-C**
**+ Mylotarg**

**Daunomycin**
**Ara-C**

**Mylotarg x 3 cycles     **

**No Therapy                **

## Protocol S0106 – Study Design/Current Status

**Target enrollment: 684 pts **
- expanded from initial estimate of 400 patients required           to address post-approval commitment
**Estimated Accrual rate: 160 subjects/year**
- projected accrual duration- 4.5 years
**Target Patient Follow-up: 3 years**
**Planned Interim Analyses:**
- 2 interim analyses during Induction Phase (durable CR)
- 3 interim analyses during Post-Consolidation Phase (DFS)
**Current Status: October 2005**
- 234 centers with IRB approval
- 57 patients enrolled

## Study Progress Assessment

- Mylotarg is a valuable drug to treat AML
- Safety profile of Mylotarg is acceptable
**Are there challenges with the study design?**
- Study Objective and Design:
- Answers important clinical questions
- Contains appropriate inclusion/exclusion criteria
- Enrollment:
- Orphan disease
- Slow study site start-up
- Recent participation of historically high enrolling sites

**Study Progress Assessment**

## Accrual Action Plan

**Continuing to add sites with historically high enrollment**

**Accrual Action Plan**

**Adding sites through NCI Canada (~ 50 subjects/year) **
**Providing additional site and data management support to SWOG**
**Helping raise investigator awareness/participation through:**
- Quarterly SWOG Newsletter for all leukemia studies
- Publication of pilot combination studies
**Monitoring enrollment and addressing issues on a monthly basis**
**Meetings with SWOG to review enrollment goals/study progress**
- Targeting Study Progress Re-assessment- 2Q 2006

## Study Progress Assessment and Action Plan Summary

**expect that there will be a marked increase in the rate of enrollment into this study**
**have not identified any insurmountable challenges to study completion**

**Study Progress Assessment and Action Plan Summary**

## Opportunities to Fulfill our Post-approval Commitment

**Completion and delivery of the S0106 study data (1Q12)**
**Use of durable complete response rate endpoint from one of the planned interim analyses of the Induction Phase (1Q07, 3Q08) **
**Proposal to amend the statistical analysis plan to add an additional analysis of durable complete response rate on all patients in the Induction Phase (1Q10)**

## Conclusions

**Accelerated approval has allowed Mylotarg to be made available as a treatment option to AML patients in first relapse who are **_**>**_**60 and have no other treatment options**

**Prerequisite pilot combination studies (205 and 206) have been completed**
**The post-approval commitment study, S0106, is ongoing and will provide answers to meaningful clinical questions**
**Wyeth and SWOG are:**
**partnering to implement several additional measures to enhance accrual in S0106**
**continuing to assess the progress of this study and respond to meet study challenges**

## Conclusions

**Wyeth is committed to meeting our Post-Approval Commitment and is diligently pursuing opportunities to fulfill it**