1. 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

2. 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)

3. 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

4. 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)

5. 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

6. 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%.

7. 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

9. 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

10. 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%

11. 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%

12. 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%

13. 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

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

15. 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.

16. 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 UM1CA UM1AI UM1AI068634
Special Thanks to: Tim Wilkin; GCAB; AMC CAB; CRS Leaders, The Participants!