# Presentation: 662805

## ODAC Discussion on Accelerated Approval 8 November 2005

**DOXIL****®****(doxorubicin HCl liposome injection)**
**Treatment of **** AIDS-related Kaposi’s Sarcoma**
**Johnson & Johnson Pharmaceutical Research & Development, L.L.C. **

## Individuals Available for Questions

**Johnson & Johnson Pharmaceutical Research & Development**
**Wayne Rackoff, MD**
**Alex Zukiwski, MD**
**Paul Manley**
**Consultant **
**Susan Krown, MD, 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-related KS Indication**

** ****Ovarian cancer indication converted to regular approval in January 2005**

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Study 30-38**

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

**DaunoXome****®****  approved **

## Study 30-38 Design

**Objective**
**Evaluate clinical benefit based on patients’ self assessment**
**Response: improvement in 1 of 5 symptom categories**
**Lymphedema**
**Pulmonary KS**
**Gastrointestinal KS**
**Disfiguring KS lesions**
**KS-associated pain**
**Not designed to test for differences between groups**

## Study 30-38 Design

**Key eligibility criteria**
**AIDS-related KS of a severity requiring systemic chemotherapy **
**Five or more measurable mucocutaneous lesions**
**Secondary end point**
**Tumor response (ACTG criteria)**
**Treatment: blinded, randomized 3:1**
**DOXIL 20 mg/m****2 ****Q 2 weeks x 6 (n = 60)**
**DaunoXome 40 mg/m****2 ****Q 2 weeks x 6 (n = 19)**

## 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%) |
| Median Time to Response | 30 days | 27 days |

**35 of 39 patients with tumor response also had clinical benefit**

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**sNDA submitted**

**Study 30-38**

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

**DaunoXome approved **

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Action letter****received**

**sNDA submitted**

**Study 30-38**

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

**DaunoXome approved **

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Action letter****received**

**sNDA submitted**

**Study 30-38**

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

**DaunoXome approved **

**FDA meetings**

**Request to waive commitment**

## Study 30-38Reanalysis Tumor Response Rate

|  | DOXIL | DaunoXome  |
| --- | --- | --- |
| Not confounded patients * | 50%
(11/22) | 50%
(5/10) |
| All patients | 55%
(33/60) | 32%
(6/19) |

*** No change in anti-retroviral therapy within 60 days before study treatment start and no change on study, unless that change occurred after the start of response**

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Action letter****received**

**sNDA submitted**

**Study 30-38**

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

**sNDA resubmitted with new analysis of Study 30-38**

**DaunoXome approved **

**FDA meetings**

**Request to waive commitment**

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Action letter****received**

**sNDA submitted**

**Study 30-38**

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

**sNDA resubmitted with new analysis of Study 30-38**

**DaunoXome approved **

**FDA meetings**

**Randomized Spanish study published**

**Request to waive commitment**

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Action letter****received**

**sNDA submitted**

**Study 30-38**

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

**sNDA resubmitted with new analysis of Study 30-38**

**DaunoXome approved **

**FDA meetings**

**Randomized Spanish study published**

**Meeting with Spanish study group**

**Request to waive commitment**

## DOXIL AIDS-related KS

**NDA submitted**

**1994****	****1995****	****1996****	****1997****	****1998****	****1999****	****2000****	****2001****	****2002****	****2003****	****2004****	****2005****	****2006****	**

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

**Accelerated approval for AIDS-related KS**

**Action letter****received**

**sNDA submitted**

**Study 30-38**

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

**sNDA resubmitted with new analysis of Study 30-38**

**Withdrawal of sNDA**

**DaunoXome approved **

**FDA meetings**

**Randomized Spanish study published**

**Meetings with Spanish study group**

**Request to waive commitment**

## Recently Published Data:DOXIL + HAART in AIDS-related Kaposi’s Sarcoma

**Recently Published Data:****DOXIL + HAART in AIDS-related ****Kaposi’s Sarcoma**

**Martín-Carbonero et al., AIDS 12: 1737, 2004**

## Recently Published Data:DOXIL + HAART in AIDS-related Kaposi’s Sarcoma

|  | HAART
N = 15 | DOXIL + HAART
N = 13  |
| --- | --- | --- |
| Response Rate (48 wks)
(95% CI) | 20%
(4.3, 48.1) | 76%*
(46.2, 95) |

**Recently Published Data:****DOXIL + HAART in AIDS-related ****Kaposi’s Sarcoma**

****P *****= 0.003**

**Martín-Carbonero et al., AIDS 12: 1737, 2004**

## Recently Published Data:DOXIL + HAART in AIDS-related Kaposi’s Sarcoma

**10 of 15 patients required rescue treatment with DOXIL**
**Reasons for cross-over**
**9 of 10 had progression**
**1 had no response to HAART alone after 9 months**
**8 of 10 had CR after cross-over treatment with DOXIL**

## Recently Published Data:Tumor Remission and CD4 Recovery with DOXIL + HAART for AIDS-related KS

**Cases HIV-1-infected with advanced KS (n = 54)**
**Treatment with DOXIL + HAART**
**Matched controls (n = 54) without KS**
**Recovery of CD4 counts not impaired by combination therapy **
**Response rate (complete + partial) = 81.5%, all within 8 weeks**
**Maintained at 1 year**

**Lichterfeld et al., Infection 33: 140-7, 2005**

## Treatment of AIDS-related KS

- Tumor confined to skin, lymph nodes, oral cavity, and non-symptomatic visceral disease

**Symptomatic visceral disease, rapidly progressive cutaneous lesions with extensive ulcerations, oedema and pain**

- Treat with HAART*

- Complete remission

- Partial remission or stable disease

**Progressive disease**

**Liposomal anthracycline + HAART**

- Complete remission

- Partial remission or stable disease

- Progressive disease

- Continue HAART

- Continue HAART; consider local therapy

- Continue HAART

- Continue HAART; consider second-line chemotherapy

- Paclitaxel+ HAART

- Progressive disease

- ____________________________________________________________________________________
- * Monthly evaluation of KS clinical response, CD4+ cell count and HIV-RNA levels are obtained.
- ° HAART regimen should be changed in the case of immuno-virological failure.

**Treatment of AIDS-related KS**

**Aversa et al., Critical Rev in Oncology/Hematology 53:253-65, 2005**

## New Anti-retrovirals in Development

| Nucleoside and Nucleotide Reverse Transcriptase Inhibitors  | Non-nucleoside Reverse Transcriptase Inhibitors | Protease Inhibitors | Entry inhibitors |
| --- | --- | --- | --- |
| SPD 754 (DOTC)
Amdoxovir
D-d4FC
Racivir (± FTC) 
SN1212

 | TMC125
GW678248 (prodrug=GW695634)
TMC278
BILR 355 BS
CSIC
DAPY/DATA
UC781 | GW0385
TMC114                    

 | Aplaviroc
Maraviroc
BMS-488043
TNX-355
NB-2, NB-64

 |

## Issues with an AdditionalRegistration Study for AIDS-related KS

**Delay of systemic chemotherapy for patients who require it is not acceptable**
**New anti-retrovirals: confounding issue remains**

## Conclusion

**Due diligence by conducting and reporting Study 30-38**
**Agreed upon with the FDA**
**AIDS-related KS patients still progress on HAART or present with aggressive, advanced disease**
**Benefit of the availability of the current indication**
**Body of evidence supports clinical benefit**