ABSTRACT THAB0108LB Superiority of paclitaxel compared to either bleomycin/vincristine or etoposide as initial chemotherapy for advanced AIDS-KS in resource-limited settings: A multinational randomized trial of the ACTG and the AIDS Malignancy Consortium July 26, 2018

A5263/AMC-066 Chairs Margaret Borok (University of Zimbabwe) A Randomized Comparison of Three Chemotherapy Regimens as an Adjunct to Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings A5263/AMC-066 Chairs Margaret Borok (University of Zimbabwe) Susan Krown (AIDS Malignancy Consortium)

Background & Rationale AIDS/KS contributes to morbidity and mortality in resource-limited settings (RLS) where HIV and KSHV co-infection is common AIDS/KS presents from mild to advanced disease ART is essential treatment for all stages of AIDS/KS Systemic chemotherapy indicated for advanced-stage (T1) AIDS/KS No evidence-based SOC in RLS to guide optimal use of chemotherapy with ART A well-designed clinical study is needed

Factors influencing selection of chemotherapy include: Anti-tumor activity (response rate, duration) Effects on QoL (relief of KS-associated signs and symptoms, drug-related toxicities, adherence) Potential drug-drug interactions Ease of administration (oral vs intravenous) Cost (may vary over time and in different settings)

Potential Benefits and Risks of Different Regimens Drug Regimen Benefits Risks Etoposide (ET) Oral administration Activity against KS in pre-ART era Neutropenia Secondary leukemia/ myelodysplasia Bleomycin + Vincristine (BV) Standard regimen in RLS - familiarity with use Minimal/mild hematologic toxicity Inexpensive and widely available Pulmonary toxicity (B) Cutaneous toxicity (B) Peripheral neuropathy (V) Vesicant (V) Infusion reactions (B) Paclitaxel (PTX) U.S. FDA-approved for this indication Standard regimen in high-resource settings (usually 2nd line) Peripheral neuropathy Premedication to prevent hypersensitivity reactions Special filters for administration All available as generics. All are included in 2017 WHO Model List of Essential Medicines. All have potential DDIs with ART

Study Overview Prospective, randomized, active-controlled, three-arm clinical trial Compare three regimens of chemotherapy + ART for treatment of advanced AIDS-KS in resource-limited setting Oral etoposide (ET) + ART Bleomycin and Vincristine (BV) + ART Paclitaxel (PTX) + ART Noninferiority: demonstrating clinical efficacy rate in the investigational arms is within 15% of the efficacy rate in the PTX+ART arm. Original sample size of 706 gave 88% power to demonstrate NI assuming true PFS rate in each arm is 65%.

Eligibility Adults (≥18) with confirmed HIV infection Limited(28 →42 days) or no prior ART Biopsy diagnostic of KS reviewed by study-approved pathologist No prior KS treatment Advanced KS stage (T1), i.e. any of the following: symptomatic tumor-associated edema tumor ulceration extensive oral KS gastrointestinal KS KS in any other non-nodal visceral organ (e.g., lung) Measurable cutaneous lesions Adequate hematologic, hepatic, renal, pulmonary function; KPS ≥60

Statistical Considerations Primary Endpoint Progression Free Survival (PFS) through week 48 Defined as: lack of KS progression, death, entry to another step, or loss to follow-up Primary Analysis Construct 95% CI for difference in PFS rates between treatment arms Examine if CI excludes 15% NI margin Interim Analyses Treatment arms compared at all DSMB reviews CI size based on available statistical information (e.g., 33% statistical information = 99.98% CI) Predicted Interval Plots used to assess power at the end of the study given current trends

Study Timeline DSMB #3 DSMB #6 First Accrual Protocol v1 ET arm closed Based on analysis of 257 participants (67% of planned total) randomized to the two remaining study arms, DSMB recommended stopping the study Included analyses predicting final results of the study if enrollment and follow-up continued as planned for different assumptions about future data, and further supported by Step 3 response Study Timeline DSMB #3 ET arm closed DSMB #6 Accrual closed First Accrual Protocol v1 Protocol v2 Oct-2010 Aug-2012 Mar-2016 Oct-2013 Mar-2018 Based on analysis of the first 118 participants, DSMB recommended closure of ET arm based on primary endpoint analysis Study revised as a 2-arm comparison with sample size of 386 with 80% power to demonstrate NI assuming true PFS rate in each arm is 65%

Baseline Characteristics   RANDOMIZED TREATMENT ARM ALL PARTICIPANTS N=316 ET + ART N=59 BV + ART N=125 PTX + ART N=132 Women 22% 23% Age 35 (31, 42) (30, 42) (31, 40) (31, 41) KPS ≥ 90 56% 60% 54% 57% Visceral KS 35% 27% 24% KS-associated Edema 95% 94% 89% 92% Oral KS 68% 63% CD4 count (cells/mm3) 194 (99, 318) 230 (134, 369) 232 (125, 348) 228 (120, 362) HIV VL < 400 c/mL 7% 21% 26% ART Regimen: EFV/FTC/TDF 96%

Progression-free survival by treatment group (numbers of participants as of the time of the last DSMB review prior to arm closure) -20% PFS difference CI for difference excludes zero difference Prediction showed low chance of showing NI and current result unlikely to change Ad-hoc summary showed better response with PTX as second-line therapy than BV 63% 43% PTX + ART BV + ART ET + ART -39.4% PFS difference More than -25% team threshold Consistent trend over time that ET worse than PTX CI for difference almost excludes zero difference Prediction showed low chance of showing NI 19%

Targeted Toxicities (Grade 3 or higher) on Step 1 Event Type Randomized Treatment Arm ET + ART N=59 BV + ART N=125 PTX + ART N=132 Neutropenia 12% 11% Anemia 2% 9% 5% Thrombocytopenia 1% Dyspnea Sensory Neuropathy Infections 18% 16% Death by week 48

CD4 Count Changes – HIV-RNA Suppression Median (IQR) (VL <50 copies/ml) BV + ART ET + ART PTX + ART

Conclusions PTX + ART established as a SOC for initial treatment of advanced AIDS-KS in RLS Increased PFS compared to oral ET+ART or BV+ART. Similar adverse event profiles of the 3 regimens. Similar profiles for CD4 count recovery and HIV-RNA suppression. Additional secondary analyses to include components of the primary endpoint, QoL, viral and cellular gene expression, cellular and humoral markers of immune function and activation, PK interaction substudy. Possible cost-effectiveness analysis to further inform drug policy. Need to improve cancer therapeutic infrastructure and accessibility of essential chemotherapeutic agents in RLS.

Acknowledgments Statisticians (SDAC) Carlee Moser Roy Matining Scott Evans Protocol Vice-Chairs Tom Campbell Patrick MacPhail Bill Wachsman FSTRF Data Manager Stephanie Caruso Protocol Specialists Lara Hosey Jennifer Rothenberg Sean McCarthy DAIDS Medical Officer Catherine Godfrey Director, AIDS Cancer Clinical Program, NCI/OHAM Mostafa Nokta Lead Site Investigators Agnes Moses (Lilongwe) Wadzanai Samaneka (Harare) Mulinda Nyirenda (Blantyre) Naftali Busakhala (Eldoret) Henriette Burger (Cape Town) Noluthando Mwelase (Johannesburg) Brenda Hoagland (Rio) Josphat Kosgei (Kericho) Jackson Orem (Kampala) Vincent Otieno (Kisumu) Rosie Mngqibisa (Durban) Pharmaceutical Support Bristol-Myers Squibb Gilead Merck Grant support UM1CA121947 UM1AI068636 UM1AI068634 Special Thanks to: Tim Wilkin; GCAB; AMC CAB; CRS Leaders, The Participants!