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Individuals Available for QuestionsIndividuals Available for Questions
Sponsor RepresentativesSponsor Representatives Martine George, MD Martine George, MD Steven Hamburger, PhDSteven Hamburger, PhD Surya Mohanty, PhD Surya Mohanty, PhD April Teitelbaum, MD April Teitelbaum, MD Margaret Tonda, PharmD Margaret Tonda, PharmD Alex Zukiwski, MDAlex Zukiwski, MD
ConsultantConsultant Susan Krown, MDSusan Krown, MD
Member and Attending PhysicianMember and Attending PhysicianDepartment of MedicineDepartment of MedicineMemorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer Center
““The treatment of AIDS-related Kaposi’s sarcoma The treatment of AIDS-related Kaposi’s sarcoma (AIDS-KS) in patients with disease that has progressed on (AIDS-KS) in patients with disease that has progressed on prior combination chemotherapy or in patients who are prior combination chemotherapy or in patients who are intolerant to such therapy.”intolerant to such therapy.”
Ongoing Challenges for Ongoing Challenges for AIDS-KS Studies AIDS-KS Studies
Incidence of AIDS-KS in the US Incidence of AIDS-KS in the US
Introduction of highly active anti-retroviral therapy (HAART) Introduction of highly active anti-retroviral therapy (HAART)
DOXILDOXIL®® is regarded as standard of care when systemic is regarded as standard of care when systemic chemotherapy is appropriatechemotherapy is appropriate
NDA studies
Sequus submits DOXILSequus submits DOXIL®® NDA based on 4 clinical studies NDA based on 4 clinical studies
Efficacy data on 383 patients Efficacy data on 383 patients
– FDA medical review focused on 77 patients retrospectively identified as FDA medical review focused on 77 patients retrospectively identified as having disease progression on prior systemic combination having disease progression on prior systemic combination chemotherapy or as being intolerant to such therapychemotherapy or as being intolerant to such therapy
Safety data on 753 patientsSafety data on 753 patients
Discussions at ODAC (Feb 14, 1995)Discussions at ODAC (Feb 14, 1995)
March 2003 ODAC: DOXILMarch 2003 ODAC: DOXIL®®, AIDS-KS, AIDS-KS
NDA studies
FDA agrees to Phase IV commitment Study 30-38FDA agrees to Phase IV commitment Study 30-38
Double-Blind, Randomized Evaluation of the Clinical Benefits Double-Blind, Randomized Evaluation of the Clinical Benefits of DOXILof DOXIL®® in Patients with AIDS-Related Kaposi’s Sarcoma in Patients with AIDS-Related Kaposi’s Sarcoma Treated with DOXIL or DaunoXomeTreated with DOXIL or DaunoXome®®
Study start dependent upon commercial availability of Study start dependent upon commercial availability of DaunoXome (approved for AIDS-KS: Apr 1996) DaunoXome (approved for AIDS-KS: Apr 1996)
AIDS-KS of a severity requiring systemic chemotherapy AIDS-KS of a severity requiring systemic chemotherapy with one or more of the following:with one or more of the following:
– Edema impairing functional activity Edema impairing functional activity (extremities, groin or face)(extremities, groin or face)
Photographs of patients also evaluated by Photographs of patients also evaluated by an independent reviewer blinded to patient an independent reviewer blinded to patient treatment treatment
Relationship between clinical benefit and tumor Relationship between clinical benefit and tumor responseresponse
Improvement in 1 of the 5 symptom categories lasting Improvement in 1 of the 5 symptom categories lasting for at least 4 wks in the absence of tumor progression for at least 4 wks in the absence of tumor progression or severe drug-induced toxicityor severe drug-induced toxicity
Patients assessed the 5 symptom categories using a Patients assessed the 5 symptom categories using a questionnaire questionnaire
Patients rated degree of symptom interference with Patients rated degree of symptom interference with daily activities daily activities
Assessment of Clinical BenefitAssessment of Clinical Benefit
Symptom CategorySymptom Category SymptomsSymptoms
LymphedemaLymphedema Difficulty wearing shoes or clothingDifficulty wearing shoes or clothingDifficulty moving due to swellingDifficulty moving due to swelling
Pulmonary KSPulmonary KS Shortness of breathShortness of breathCoughCough
Gastrointestinal KSGastrointestinal KS Difficulty swallowing or eatingDifficulty swallowing or eatingAble to eat only small amounts of foodAble to eat only small amounts of foodBloatingBloatingDiarrheaDiarrheaNausea and / or vomitingNausea and / or vomiting
Sep – Nov 2002Sep – Nov 2002 Convened an advisory board of US AIDS-KS experts Convened an advisory board of US AIDS-KS experts Submitted a new Phase IV commitment trial protocol outlineSubmitted a new Phase IV commitment trial protocol outline
AIDS-KS TimelineAIDS-KS Timeline
NDA studies
Highly active anti-retroviral therapy (Highly active anti-retroviral therapy (HAART) HAART)
Nov 2002 – PresentNov 2002 – Present Ongoing communication with FDA regarding a new protocol Ongoing communication with FDA regarding a new protocol
and development plan to confirm the clinical benefit of DOXILand development plan to confirm the clinical benefit of DOXIL®® in AIDS-KSin AIDS-KS
Feb 3, 2003 Feb 3, 2003 FDA meeting to discuss our proposed study design and alternativesFDA meeting to discuss our proposed study design and alternatives
AIDS-KS TimelineAIDS-KS Timeline
NDA studies
Highly active anti-retroviral therapy (Highly active anti-retroviral therapy (HAART) HAART)
AIDS-KS Protocol Design and AIDS-KS Protocol Design and Implementation IssuesImplementation Issues
Declining incidence of AIDS-KS in the USDeclining incidence of AIDS-KS in the US
In practice, DOXILIn practice, DOXIL®® is regarded as the first-line systemic is regarded as the first-line systemic chemotherapy of choice chemotherapy of choice
Patients who present with AIDS and KS who require Patients who present with AIDS and KS who require aggressive intervention are treated concomitantly with aggressive intervention are treated concomitantly with HAART and chemotherapyHAART and chemotherapy
– The effect of HAART alone on AIDS-KS regression is The effect of HAART alone on AIDS-KS regression is not well documented not well documented
– The contribution of each treatment component is The contribution of each treatment component is difficult to assess difficult to assess
The introduction of new anti-retroviral agents will further The introduction of new anti-retroviral agents will further confound interpretation of future study resultsconfound interpretation of future study results
AIDS-KS Protocol Design and AIDS-KS Protocol Design and Implementation IssuesImplementation Issues
Not all patients with AIDS-KS require systemic Not all patients with AIDS-KS require systemic chemotherapychemotherapy
It is not acceptable to delay cytotoxic chemotherapy It is not acceptable to delay cytotoxic chemotherapy when medically indicated and such a trial design may when medically indicated and such a trial design may not be executablenot be executable
It will be difficult to conduct a placebo-controlled or It will be difficult to conduct a placebo-controlled or active comparator-controlled trial in this patient active comparator-controlled trial in this patient populationpopulation
– Insufficient accrual in recently terminated ECOG, Insufficient accrual in recently terminated ECOG, SWOG, and AMC Study: TaxolSWOG, and AMC Study: Taxol®® vs. DOXIL vs. DOXIL®® in in AIDS-KS AIDS-KS