# Presentation: 662808

## ODAC Discussion on Accelerated ApprovalMarch 12-13, 2003

**DOXIL****®****(doxorubicin HCl liposome injection)**
**Treatment of **** AIDS-Related Kaposi’s Sarcoma**

## Individuals Available for Questions

**Sponsor Representatives**
**Martine George, MD **
**Steven Hamburger, PhD**
**Surya Mohanty, PhD   **
**April Teitelbaum, MD **
**Margaret Tonda, PharmD  **
**Alex Zukiwski, MD**
**Consultant**
**Susan Krown, MD**
**Member and Attending Physician**
**Department of Medicine**
**Memorial Sloan-Kettering Cancer Center**

## DOXIL® (doxorubicin HCl liposomal injection) is indicated for:
“The treatment of AIDS-related Kaposi’s sarcoma (AIDS-KS) in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy.”

**“****The treatment of AIDS-related Kaposi’s sarcoma ****(AIDS-KS) in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy.”**

- AIDS-KS Indication

## Status Update

**Original Phase IV commitment trial **

** ****New Phase IV commitment trial**
** ****Discussions ongoing**

**Completed**
**Non-approvable letter received from FDA**

## Ongoing Challenges for AIDS-KS Studies 

**Incidence of AIDS-KS in the US**

## Ongoing Challenges for AIDS-KS Studies 

## Ongoing Challenges for AIDS-KS Studies 

**Incidence of AIDS-KS in the US **

**Introduction of highly active anti-retroviral therapy (HAART) **

**DOXIL****®**** is regarded as standard of care when systemic chemotherapy is appropriate**

## Sequus submits DOXIL® NDA based on 4 clinical studies
Efficacy data on 383 patients 
FDA medical review focused on 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy or as being intolerant to such therapy
Safety data on 753 patients

**Sequus submits DOXIL****®**** NDA based on 4 clinical studies**
**Efficacy data on 383 patients **
**FDA medical review focused on 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy or as being intolerant to such therapy**
**Safety data on 753 patients**

**Sep**

- AIDS-KS Timeline

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Discussions at ODAC (Feb 14, 1995)**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## FDA agrees to Phase IV commitment Study 30-38
Double-Blind, Randomized Evaluation of the Clinical Benefits of DOXIL® in Patients with AIDS-Related Kaposi’s Sarcoma Treated with DOXIL or DaunoXome®
Study start dependent upon commercial availability of DaunoXome (approved for AIDS-KS: Apr 1996) 

**FDA agrees to Phase IV commitment Study 30-38**
***Double-Blind, Randomized Evaluation of the Clinical Benefits of DOXIL******®****** in Patients with AIDS-Related Kaposi’s Sarcoma Treated with DOXIL or DaunoXome******®***
**Study start dependent upon commercial availability of DaunoXome (approved for AIDS-KS: Apr 1996) **

**Jun**

- AIDS-KS Timeline

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**FDA agrees to 30-38 study design**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## Nov 1995
Accelerated approval for AIDS-KS
Based on objective response rate

**Nov 1995**
**Accelerated approval for AIDS-KS**
**Based on objective response rate**

**Nov**

- AIDS-KS Timeline

**NDA studies**

**Accelerated approval received**

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**FDA agrees to 30-38 study design**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## AIDS-KS Timeline

**Double-blind, randomized study **
**50 US sites contacted, 7 sites participated**
**60 patients – DOXIL****®**** 20 mg/m****2**** q 2 wk x 6 **
**19 patients – DaunoXome****®**** 40 mg/m****2**** q 2 wk x 6 **
**Patients with AIDS-KS, either previously-treated ****or chemo-naïve **
**Primary endpoint – clinical benefit**
**Not designed to test for differences between ****DOXIL and DaunoXome**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Nov**

**NDA submitted**

**FDA agrees to 30-38 study design**

**Phase IV Commitment Study 30-38  **

**Accelerated approval received**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## Patient Population

**Key Eligibility Criteria:**
**AIDS-KS of a severity requiring systemic chemotherapy with one or more of the following:**
**Edema impairing functional activity ****(extremities, groin or face)**
**Symptomatic evaluable pulmonary KS**
**Symptomatic evaluable gastrointestinal KS**
**Associated pain**
**Disfiguring lesions**
**Five or more measurable mucocutaneous lesions**

***Study 30-38 ***

## Efficacy Parameters

**Clinical benefit (primary endpoint)**
**Tumor response (ACTG criteria)**
**Photographs of patients also evaluated by ****an independent reviewer blinded to patient ****treatment **
**Relationship between clinical benefit and tumor response**

***Study 30-38 ***

## Primary Endpoint: Clinical Benefit

**Improvement in 1 of the 5 symptom categories lasting for at least 4 wks in the absence of tumor progression or severe drug-induced toxicity**
**Patients assessed the 5 symptom categories using a questionnaire **
**Patients rated degree of symptom interference with daily activities  **

***Study 30-38 ***

## Assessment of Clinical Benefit

| Symptom Category	 | Symptoms |
| --- | --- |
| Lymphedema | Difficulty wearing shoes or clothingDifficulty moving due to swelling |
| Pulmonary KS	 | Shortness of breathCough |
| Gastrointestinal KS | Difficulty swallowing or eatingAble to eat only small amounts of foodBloatingDiarrheaNausea and / or vomiting |
| Disfiguring KS lesions	 | Unsightly skin lesions |
| KS-associated pain | Pain |

***Study 30-38 ***

## Efficacy Results

|  | DOXIL®(n = 60) | DaunoXome® (n = 19) |
| --- | --- | --- |
| Clinical Benefit (Primary Endpoint) | 48 (80%) | 12 (63%) |
| Objective Tumor Response | 33 (55%) | 6 (32%) |

***Study 30-38 ***

**Median time to objective tumor response ~ 30 days **

## Clinical Benefit by Symptom Category

***Study 30-38 ***

## Oct 2001
ALZA submits sNDA containing AIDS-KS Phase IV commitment data

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**sNDA submitted**

**Oct 2001**
**ALZA submits sNDA containing AIDS-KS Phase IV commitment data**

**Oct**

- AIDS-KS Timeline

**Accelerated approval received**

**NDA submitted**

**FDA agrees to 30-38 study design**

**Phase IV Commitment Study 30-38  **

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## Jul 2002
Regulatory conclusion
Changes in anti-retroviral therapy confounded efficacy assessment 

**Regulatory conclusion**
**Changes in anti-retroviral therapy confounded efficacy assessment **

**Jul**

- AIDS-KS Timeline

**NDA studies**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Action letter****received**

**sNDA submitted**

**Accelerated approval received**

**NDA submitted**

**FDA agrees to 30-38 study design**

**Phase IV Commitment Study 30-38  **

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## Regulatory conclusion
Changes in anti-retroviral therapy confounded efficacy assessment 

**Changes in anti-retroviral therapy confounded efficacy assessment **

- AIDS-KS Timeline

**NDA studies**

**Highly active anti-retroviral therapy (****HAART) **

**Anti-retroviral therapy**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Jul**

**sNDA submitted**

**Action letter****received**

**Phase IV Commitment Study 30-38  **

**Accelerated approval received**

**NDA submitted**

**FDA agrees to 30-38 study design**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## Sep – Nov 2002
Convened an advisory board of US AIDS-KS experts 
Submitted a new Phase IV commitment trial protocol outline

**Convened an advisory board of US AIDS-KS experts **
**Submitted a new Phase IV commitment trial protocol outline**

- AIDS-KS Timeline

**NDA studies**

**Highly active anti-retroviral therapy (****HAART) **

**Anti-retroviral therapy**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**New Phase IV****Study Design**

**sNDA submitted**

**Action letter****received**

**Phase IV Commitment Study 30-38  **

**Accelerated approval received**

**NDA submitted**

**FDA agrees to 30-38 study design**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## Nov 2002 – Present
Ongoing communication with FDA regarding a new protocol and development plan to confirm the clinical benefit of DOXIL® in AIDS-KS
Feb 3, 2003 
FDA meeting to discuss our proposed study design and alternatives

**Ongoing communication with FDA regarding a new protocol ****and development plan to confirm the clinical benefit of DOXIL****®**** ****in AIDS-KS**
**Feb 3, 2003 **
**FDA meeting to discuss our proposed study design and alternatives**

- AIDS-KS Timeline

**NDA studies**

**Highly active anti-retroviral therapy (****HAART) **

**Anti-retroviral therapy**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Feb**

**FDA meeting**

**sNDA submitted**

**Action ****letter****received**

**Phase IV Commitment Study 30-38  **

**Accelerated approval received**

**NDA submitted**

**FDA agrees to 30-38 study design**

**New Phase IV****Study Design**

**March 2003 ODAC: DOXIL****®****, AIDS-KS**

## AIDS-KS Protocol Design and Implementation Issues

**Declining incidence of AIDS-KS in the US**
**In practice, DOXIL****®**** is regarded as the first-line systemic chemotherapy of choice **
**Patients who present with AIDS and KS who require ****aggressive intervention are treated concomitantly with ****HAART and chemotherapy**
**The effect of HAART alone on AIDS-KS regression is ****not well documented **
**The contribution of each treatment component is ****difficult to assess **
**The introduction of new anti-retroviral agents will further ****confound interpretation of future study results**

## AIDS-KS Protocol Design and Implementation Issues

**Not all patients with AIDS-KS require systemic chemotherapy**
**It is not acceptable to delay cytotoxic chemotherapy when medically indicated and such a trial design may not be executable**

**It will be difficult to conduct a placebo-controlled or active comparator-controlled trial in this patient population**
**Insufficient accrual in recently terminated ECOG, SWOG, and AMC Study: Taxol****®**** vs. DOXIL****®**** in ****AIDS-KS **

## Conclusion

**We are committed to design and implement, with FDA agreement, a new Phase IV trial as quickly as possible to convert this accelerated approval to full approval**