AIDS-related Kaposi’s sarcoma (AIDS-KS) occurs in persons who are coinfected with HIV-1 and human herpesvirus 8 (HHV-8 or KSHV). In areas of the world where access to ART and chemotherapy is limited, and where rates of HIV and KSHV coinfection are higher, AIDS-KS is a more significant contributor to morbidity and mortality in HIV-1 infected persons.

Given that ART alone often improves or stabilizes AIDS-KS disease, it is possible that combining ART with chemotherapy might provide improved clinical responses.

A5263/AMC 066 is a prospective, randomized, active-controlled clinical trial. Randomization will be stratified by CD4+ lymphocyte cell count and country. The main objective is to compare the clinical efficacy of two regimens, oral Etoposide plus ART and Bleomycin and Vincristine (BV) plus ART, to pegylated liposomal doxorubicin (PLD) plus ART for initial treatment of advanced stage AIDS-KS

DESIGN:            This is a prospective, randomized, active-controlled clinical trial.

Step 1: Participants will be randomized 1:1:1 to oral etoposide (ET) plus antiretroviral therapy (ART), bleomycin and vincristine (BV) plus ART, or doxorubicin HCL liposome injection (Doxil^®, PLD) plus ART.

Step 2: Participants who originally have a Kaposi’s sarcoma (KS) response (complete or partial [CR or PR]) to Step 1 chemotherapy, but then progress at a time point of at least 12 weeks or longer after the last dose of Step 1 chemotherapy, but prior to week 72, may be provided a second course of up to 6 cycles of the same chemotherapy utilized in Step 1. This option is available for study participants who have a confirmed initial KS response and subsequent Independent Endpoint Review Committee (IERC)-confirmed KS progression and who, in the opinion of the investigator and with concurrence of the protocol Clinical Management Committee (CMC) (see Section 7.1 for definition of IERC-confirmed KS progression), could potentially benefit from another course of the same chemotherapy. Participants who have received ET in Step 1 will initiate treatment in Step 2 at the dose last tolerated in Step 1.

Step 3: Participants will be randomized (1:1) to one of the two chemotherapy arms not utilized in Step 1.  If IERC-confirmed KS progression or chemotherapy-related toxicity occurs in Step 1 or Step 2, participants will be offered alternative study treatment in Step 3. Participants must enter Step 3 within the 72 weeks following Step 1 randomization. Participants will move to Step 3 when (1) there is IERC-confirmed KS progression at any time during Step 1 chemotherapy; or (2) there is IERC-confirmed KS progression less than 12 weeks after the last chemotherapy dose in Step 1 in participants who have had complete or partial response; or (3) there is IERC-confirmed KS progression following Step 1 chemotherapy, without any prior response; or (4) there is IERC-confirmed KS progression in Step 2; or (5) there is dose-limiting toxicity after receiving less than 4 cycles of chemotherapy in Step 1 or Step 2, in the absence of a CR or PR. Participants otherwise eligible for Step 2 who, in the opinion of the investigator and the CMC, are unlikely to benefit from another course of the same chemotherapy received in Step 1 will also be eligible for randomization in Step 3.  If there is IERC-confirmed KS progression in Step 3, participants may enter Step 4 or be offered alternative care available locally outside of the study, whichever the investigator deems most appropriate. If an investigator offers locally-available alternative care, the participants will be followed according to their original Step 3 schedule.

Step 4: Following CMC and IERC-confirmed KS progression on Step 3, or if there is dose-limiting toxicity after receiving less than 4 cycles of chemotherapy in Step 3, in the absence of a CR or PR, participants will be assigned to the remaining study-provided chemotherapy not given in Step 1, Step 2, or Step 3. Participants must enter Step 4 within the 72 weeks following Step 1 randomization.  If there is IERC-confirmed KS progression in Step 4, participants may be offered alternative care available locally, outside of the study. If an investigator offers locally-available alternative care, the participants will be followed according to their original Step 4 schedule.

DURATION:       All participants will be followed for 5 years after randomization or assignment to the last step they enter. Therefore, participants could be followed for 5 to 7 years.

SAMPLE SIZE:  706 participants ≥ 18 years of age

POPULATION: HIV-infected men and women with the following characteristics:

• Biopsy diagnostic of KS
• Naïve to ART (as defined in Section 4.2.7), chemotherapy, and radiation therapy
• KS stage T1, (See section 4.1.3) 
• Persons with chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, must have completed at least 14 consecutive days of appropriate anti-infective treatment prior to study entry and be clinically stable

STRATIFICATION:

• CD4+ lymphocyte cell count < 100 or ≥ 100 cells/mm³
• By country

REGIMEN

Step 1:

Arm 1A: Coformulated efavirenz, tenofovir, and emtricitabine (EFV/FTC/TDF) plus ET 50 mg twice a day (with escalation on subsequent cycles up to a maximum of 100 mg twice a day, depending on toxicity) for 7 consecutive days of every 3-week cycle.  Treatment with ET will continue for a maximum of 6 cycles at the highest dose achieved, or until toxicity requiring discontinuation of study chemotherapy, or until the site investigator and A5263/AMC 066 CMC have determined that alternative therapy is required, whichever occurs first.

Arm 1B: Coformulated EFV/FTC/TDF plus bleomycin 15 units/m² IV (intravenous) plus vincristine 2mg IV every 3 weeks.  Treatment with BV may continue for a maximum of 6 cycles, or until toxicity requiring discontinuation of study chemotherapy, or until the site investigator and the A5263/AMC 066 CMC have determined that alternative therapy is required, whichever occurs first.

Arm 1C: Coformulated EFV/FTC/TDF plus pegylated liposomal doxorubicin (PLD) 20 mg/m² IV every 3 weeks.  Treatment with PLD will continue for a maximum of 6 cycles, or until toxicity requiring discontinuation of study

chemotherapy, or until the site investigator and the A5263/AMC 066 CMC have determined that alternative therapy is required, whichever occurs first.

Step 2: Coformulated EFV/FTC/TDF plus a second course of up to 6 cycles of the same chemotherapy utilized in Step 1

Step 3: Coformulated EFV/FTC/TDF plus a randomly assigned alternative study-provided chemotherapy regimen

Step 4: Coformulated EFV/FTC/TDF plus the remaining study-provided chemotherapy regimen