Upload
may-crawford
View
218
Download
2
Tags:
Embed Size (px)
Citation preview
1November 2005 ODAC: DOXIL®, AIDS-related KS
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.
2November 2005 ODAC: DOXIL®, AIDS-related KS
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
3November 2005 ODAC: DOXIL®, AIDS-related KS
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.”
AIDS-related KS Indication
Ovarian cancer indication converted to regular approval in January 2005
4November 2005 ODAC: DOXIL®, AIDS-related KS
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
5November 2005 ODAC: DOXIL®, AIDS-related KS
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
6November 2005 ODAC: DOXIL®, AIDS-related KS
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/m2 Q 2 weeks x 6 (n = 60)
– DaunoXome 40 mg/m2 Q 2 weeks x 6 (n = 19)
7November 2005 ODAC: DOXIL®, AIDS-related KS
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
8November 2005 ODAC: DOXIL®, AIDS-related KS
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
9November 2005 ODAC: DOXIL®, AIDS-related KS
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
10November 2005 ODAC: DOXIL®, AIDS-related KS
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
11November 2005 ODAC: DOXIL®, AIDS-related KS
Study 30-38Reanalysis Tumor Response Rate
DOXIL DaunoXome
Not confounded patients *
50%
(11/22)
50%
(5/10)
All patients55%
(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
12November 2005 ODAC: DOXIL®, AIDS-related KS
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
13November 2005 ODAC: DOXIL®, AIDS-related KS
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
14November 2005 ODAC: DOXIL®, AIDS-related KS
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
15November 2005 ODAC: DOXIL®, AIDS-related KS
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
16November 2005 ODAC: DOXIL®, AIDS-related KS
Highly Active Antiretroviral Therapy (HAART)
(N = 15)Moderate-severe AIDS-related KS
HAART naïve or failing HAART
DOXIL + HAART (N = 13)
DOXIL 20 mg/m2 every 3-weeks
Recently Published Data:DOXIL + HAART in AIDS-related
Kaposi’s Sarcoma
Martín-Carbonero et al., AIDS 12: 1737, 2004
17November 2005 ODAC: DOXIL®, AIDS-related KS
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
18November 2005 ODAC: DOXIL®, AIDS-related KS
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
19November 2005 ODAC: DOXIL®, AIDS-related KS
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
20November 2005 ODAC: DOXIL®, AIDS-related KS
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
21November 2005 ODAC: DOXIL®, AIDS-related KS
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
22November 2005 ODAC: DOXIL®, AIDS-related KS
Issues with an AdditionalRegistration Study for AIDS-related KS
Delay of systemic chemotherapy for patients who require it is not acceptable
New anti-retrovirals: confounding issue remains
23November 2005 ODAC: DOXIL®, AIDS-related KS
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