# Presentation: 154720

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

**DOXIL****®****(doxorubicin HCl liposome injection)**
** ****Treatment of ****Advanced, Metastatic Ovarian Cancer**

## Individuals Available for Questions

**Sponsor Representatives**
**Martine George, MD **
**Steven Hamburger, PhD **
**Surya Mohanty, PhD **
**April Teitelbaum, MD **
**Margaret Tonda, PharmD **
**Alex Zukiwski, MD **

## Ovarian Cancer Indication

**DOXIL****®**** (doxorubicin HCl liposomal injection) ****is indicated for:**
**“****The treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory disease is defined as disease that has progressed while on treatment, or within 6 months of completing treatment.”**

## Phase IV Status Update

**Original Phase IV commitment trial (30-49)**
**Completed**
**Planned final survival analysis underway**

**Second Phase IV commitment trial (SWOG: SO200)**
**Enrollment ongoing**

## Challenges Surrounding the Phase IV Commitment Trials

**The time to reach survival endpoint in original Phase IV commitment trial **

**Multiple parties involved in finalization and implementation of the second Phase IV commitment trial**
**Competition for accrual **
**DOXIL****®**** can be prescribed to patients with ovarian ****cancer outside of a clinical study **

## November 1998
Orphan drug designation
December 1998
sNDA submitted ovarian cancer indication

**Orphan drug designation**
**December 1998**
**sNDA submitted ovarian cancer indication**

- Ovarian Cancer Timeline

**Orphan ****Drug****Designation**

**sNDA****Submitted**

**Dec**

**Nov**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## June 1999: ODAC Meeting and Accelerated Approval 
sNDA contained data from:
3 Phase II non-comparative studies in relapsed or refractory ovarian cancer (primary endpoint response rate)
n = 176 patients 
Ongoing Phase III DOXIL® vs. topotecan trial (Study 30-49)  
Data from interim analysis 

**sNDA contained data from:**
**3 Phase II non-comparative studies in relapsed or refractory ovarian cancer (primary endpoint response rate)**
**n = 176 patients**** **
**Ongoing Phase III DOXIL****®**** vs. topotecan trial (Study 30-49)  **
**Data from interim analysis **

- Ovarian Cancer Timeline

**ODAC**

**Jun**

**Accelerated****Approval **

**Orphan ****Drug****Designation**

**sNDA****Submitted**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

**Phase IV commitment: Completion of Study 30-49 **

## May 1997
First patient enrolled 
March 1999
Last patient enrolled

**First patient enrolled **
**March 1999**
**Last patient enrolled**

**Phase IV Commitment Study 30-49 **

- Ovarian Cancer Timeline

**Mar**

**First****Patient****Enrolled**

**Last****Patient****Enrolled**

**Dec**

**May**

**sNDA****Submitted**

**Jun**

**Accelerated****Approval **

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## Phase III Randomized Study of DOXIL® vs. Topotecan in Ovarian Cancer 

***	******Objective:******	*****Compare efficacy and safety**
***	******Population:*****	****Patients with relapsed ovarian cancer following ****	****	****	****failure with platinum-based chemotherapy (n = 474)**
***	******Stratification:******	*****Platinum-sensitivity and bulk of disease**
***	******Treatments:*****	****DOXIL 50 mg/m****2**** q 4 wk**
**	****	****Topotecan 1.5 mg/m****2**** x 5 d q 3 wk**
***	******Outcomes:*****	****Primary ****–**** TTP**
**	****	****Secondary ****–**** ORR, response duration, ****	****	****survival, safety**
**	*****Original Design:*****	****Non-inferiority **

***Study 30-49 ***

## June 2000: Meeting with the FDA after End of Planned Treatment Analysis 
was provided for Study 30-49 
Analysis did not demonstrate superiority in TTP 
Significant survival advantage of DOXIL® compared to topotecan in the platinum-sensitive group
~50% of patients were alive

**was provided for Study 30-49 **
**Analysis did not demonstrate superiority in TTP **
**Significant survival advantage of DOXIL****®**** compared to topotecan in the platinum-sensitive group**
**~50% of patients were alive**

**Phase IV Commitment Study 30-49 **

- Ovarian Cancer Timeline

**End of****Planned****Treatment****Meeting**

**Jun**

**First****Patient****Enrolled**

**Accelerated****Approval **

**sNDA****Submitted**

**Last****Patient****Enrolled**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## End of Planned Treatment:Time to Progression

***Study 30-49 ***

|  | DOXIL® | Topotecan | P |
| --- | --- | --- | --- |
| All Patients  | 18.4
n = 239 | 18.3
n = 235 | 0.632 |
| Platinum-Sensitive | 29.9
n = 109 | 26.7
n = 111 | 0.387 |
| Platinum-Refractory | 9.1
n = 130 | 14.3
n = 124 | 0.941 |

**Median (wks)**

## End of Planned Treatment:Survival

***Study 30-49 ***

**Median (wks)**

|  | DOXIL® | Topotecan | P |
| --- | --- | --- | --- |
| All Patients | 58.7
n = 239 | 56.7
n = 235 | 0.964 |
| Platinum-Sensitive | 110.7
n = 109 | 84.7
n = 111 | 0.027 |
| Platinum-Refractory | 34.6
n = 130 | 41.4
n = 124 | 0.126 |

## Percent of Patients by Severity of Adverse Events

***Study 30-49 ***

## June 2000: Outcome of FDA Meeting for End of Planned Treatment Analysis
FDA agreed to a final survival analysis to be performed when a percentage of the 474 randomized and treated patients died or were lost to follow-up 
90% events chosen to provide adequate power for survival analysis
Protocol amended accordingly
A second protocol to prove clinical benefit was required 

**FDA agreed to a final survival analysis to be performed when a percentage of the 474 randomized and treated patients died or were lost to follow-up **
**90% events chosen to provide adequate power for survival analysis**
**Protocol amended accordingly**
**A second protocol to prove clinical benefit was required **

**Phase IV Commitment Study 30-49 **

- Ovarian Cancer Timeline

**End of****Planned****Treatment****Meeting**

**Jun**

**First****Patient****Enrolled**

**Accelerated****Approval **

**sNDA****Submitted**

**Last****Patient****Enrolled**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## July 2000 
ALZA submitted a second Phase IV draft protocol 
DOXIL® and carboplatin vs. carboplatin in platinum-sensitive patients with recurrent epithelial ovarian carcinoma after failure of initial, platinum-based chemotherapy 

**ALZA submitted a second Phase IV draft protocol **
**DOXIL****®**** and carboplatin vs. carboplatin in platinum-sensitive patients with recurrent epithelial ovarian carcinoma after failure ****of initial, platinum-based chemotherapy **

**Phase IV Commitment Study 30-49 **

- Ovarian Cancer Timeline

**Second Phase IV Commitment Study**

**Second****Phase IV Protocol****Submitted**

**Jul**

**End of Planned****Treatment****Meeting**

**First****Patient****Enrolled**

**Accelerated****Approval **

**sNDA****Submitted**

**Last****Patient****Enrolled**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## September – December 2000 
Dialogue between ALZA and FDA regarding protocol design of the second Phase IV Commitment Trial

- Ovarian Cancer Timeline

**September – December 2000 **
**Dialogue between ALZA and FDA regarding protocol design of the second Phase IV Commitment Trial**

**Second Phase IV Commitment Study**

**Dialogue Between****ALZA & FDA**

**Sept-Dec**

**Second****Phase IV Protocol****Submitted**

**First****Patient****Enrolled**

**Accelerated****Approval **

**sNDA****Submitted**

**Last****Patient****Enrolled**

**Orphan ****Drug****Designation**

**End of Planned****Treatment****Meeting**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## January – November 2001
Discussions between SWOG and ALZA to conduct this study 
December 2001
ALZA submits SWOG protocol SO200 to FDA

**Discussions between SWOG and ALZA to conduct this study **
**December 2001**
**ALZA submits SWOG protocol SO200 to FDA**

**Phase IV Commitment Study 30-49 **

- Ovarian Cancer Timeline

**Second Phase IV Commitment Study SO200**

**Discussions****between SWOG & ALZA**

**SWOG Protocol****Submitted to FDA**

**Dec**

**Jan-Nov**

**Dialogue Between****ALZA & FDA**

**Second****Phase IV Protocol****Submitted**

**First****Patient****Enrolled**

**Accelerated****Approval **

**sNDA****Submitted**

**Last****Patient****Enrolled**

**Orphan ****Drug****Designation**

**End of Planned****Treatment****Meeting**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## SWOG SO200 Ovarian Cancer

***	******Objectives:******	*****Compare between the two treatment groups:****	****	****• Primary endpoint: Overall survival ****	****	****• Secondary endpoints: PFS, confirmed CRs, TTF, toxicity**
**	*****Population:*****	****Patients with recurrent disease or disease ****	****	****	****progression with a progression-free and platinum-****	****	****	****free interval of 6 to 24 months after completion of ****	****	****first line platinum-based chemotherapy (n = 900)**
**	*****Study Design:*****	****Randomized, intergroup*, open-label study **
**	*****Treatments:******	*****Carboplatin AUC = 5 q 4 wks plus ****	****	****DOXIL****®**** 30 mg/m****2**** q 4 wks **
**	****	****Carboplatin AUC = 5 q 4 wks**

## Ovarian Cancer Timeline

**Phase IV Commitment Study 30-49 **

**August 2002**
**SWOG activates protocol**
**September 2002**
**First patient enrolled **

**Sept**

**1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Orphan Drug****Designation**

**Last****Patient****Enrolled**

**sNDA****Submitted**

**Accelerated****Approval **

**End of****Planned****Treatment****Meeting**

**Dialogue****Between****ALZA &****FDA**

**First****Patient Enrolled****SWOG**

**Protocol****Activated**

**SWOG Protocol****Submitted to FDA**

**Aug**

**Discussions****between SWOG & ALZA**

**Second Phase IV Commitment Study SO200**

**First****Patient****Enrolled**

**Second****Phase IV Protocol****Submitted**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## June 2000
FDA agreed to a final survival analysis from Study 30-49 performed when 90% of the 474 randomized and treated patients had died or were lost to follow-up
March 2003
Analysis of final survival results for Study 30-49 is ongoing 

**1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003**

**Orphan Drug****Designation**

**Phase IV Commitment Study 30-49 **

- Ovarian Cancer Timeline

**Last****Patient****Enrolled**

**sNDA****Submitted**

**Accelerated****Approval **

**End of****Planned****Treatment****Meeting**

**90%****Survival Analysis****(30-49)**

**Mar**

**Dialogue****Between****ALZA &****FDA**

**First****Patient Enrolled****SWOG**

**Protocol Activated**

**SWOG Protocol****Submitted to FDA**

**June 2000**
**FDA agreed to a final survival analysis from Study 30-49 performed when 90% of the 474 randomized and treated patients had died or were lost to follow-up**
**March 2003**
**Analysis of final survival results for Study 30-49 is ongoing **

**Jun**

**Discussions****between SWOG & ALZA**

**First****Patient****Enrolled**

**Second Phase IV Commitment Study SO200**

**Second****Phase IV Protocol****Submitted**

**March 2003 ODAC: DOXIL****®****, Ovarian Cancer**

## Issues Surrounding Phase IV Commitment Trials

**After the end of planned treatment analysis, the primary endpoint for Study 30-49 was modified to become overall survival **
**The time to reach the 90% event endpoint in Study 30-49 ****was > 3.5 years**
**Finalization and implementation of the second Phase IV SO200 commitment trial **
**Multiple parties involved (SWOG, other cooperative groups, ****NCI, FDA and Sponsor) **
**Transfer of clinical responsibilities**
**Competition for accrual **
**Ongoing clinical trials**
**DOXIL****®**** can be prescribed to patients with ovarian cancer ****outside of a clinical study**** **

## Summary

**Conversion from Accelerated Approval to Full Approval:**
**Original Phase IV commitment study (30-49)**
**Study started before NDA submission**
**Design agreed with FDA**
**Enrollment completed prior to approval**
**Planned final survival analysis underway**
**Second Phase IV commitment study (SWOG: SO200)**
**Study design acceptable to FDA**
**Currently enrolling patients **