Pharmacy and Poisons Board
Protocol No: ECCT/10/11/06 Date of Protocol: 04-08-2010
Study Title:

A5264/AMC 067 "A Randomized Evaluation of Antiretroviral Therapy Alone or with Delayed Chemotherapy versus Antiretroviral Therapy with Immediate Adjunctive Chemotherapy for Treatment of Li1mited Stage AIDS-KS in Resource-Limited Settings (REACT-KS)"
Study Objectives:

Primary Objective

 

To compare, in participants with limited stage KS, the week 48 KS tumor outcomes of low-dose concurrent administration of oral ET with ART to ART alone or ART with delayed ET with outcome at week 48 compared to entry categorized into one of three categories:

 

E1 (Failure) = KS progression at week 48 compared to baseline, initiation of a new chemotherapy agent other than ET by week 48, or no follow-up at  week 48 (including death and lost to follow-up by week 48 and missed visit at week 48);

 

E2 (Stable) = In follow-up at week 48, with neither KS progression nor response at week 48 and without initiation of a new chemotherapy other than ET by week 48,

 

E3 (Response) = In follow-up at week 48, with KS partial (PR) or complete response (CR) at week 48 compared to baseline and without initiation of a new chemotherapy agent other than ET by week 48.

 

1.3       Secondary Objectives

 

1.3.1    To evaluate the effects of randomized study treatment on the rate of KS clinical response. This will include comparison of the time to initial KS progression, time to initial KS response (PR and CR combined and separately), and KS progression and response rates at weeks 48 and 96.

 

  1. To evaluate the safety and tolerability of randomized study treatment.  This will include comparison of adverse events, dose-limiting toxicities, treatment/dose changes related to management of toxicities, and KS-IRIS events.

 

  1. To investigate the effects of randomized study treatment on quality of life.

 

  1. To compare the effects of randomized study treatment on plasma HIV-1 RNA levels and peripheral blood CD4+ T-cell counts including both magnitudes and rates of change.

 

  1. To evaluate the effects of concomitant ET on adherence to ART.

 

  1. To investigate the response to delayed ET after KS progression on ART alone.

 

  1. To determine baseline KS-associated herpesvirus (KSHV) viral load in saliva, plasma and peripheral blood mononuclear cells (PBMCs), compare the effects of randomized study treatment on KSHV viral load changes, and evaluate the relationship of KSHV viral load changes to KS clinical response.

 

  1. To evaluate the relationship between response of KS to randomized treatment, development of KS-IRIS, and the following markers:

 

1.3.8.1 Baseline immunohistochemical markers of viral and cellular gene expression in KS tumors

 

1.3.8.2 RNA levels for genes in tumor biopsies at baseline and during therapy

 

1.3.8.3 Cellular and humoral markers of immune function and immune activation.

 

  1. To investigate the relationship between salivary, plasma, and PBMC KSHV viral load.

 

  1. To encourage donation of excess biopsy materials to the AIDS and Cancer Specimen Resource (ACSR).

 

  1. To assess the risk of secondary leukemia and myelodysplasia after etoposide use.
Laymans Summary:

AIDS-related Kaposi’s sarcoma (AIDS-KS) occurs in persons who are coinfected with HIV-1 and KSHV.  AIDS-KS remains a significant cause of morbidity and mortality in HIV-1 infected persons in areas of the world where access to ART and chemotherapy is limited. 

 

Because AIDS-KS is a malignancy that results from HIV-1-related immunosuppression, optimal management of this disease may require immune reconstitution by treatment of HIV-1 infection with ART and treatment of KS disease.  KS disease stage is an important factor associated with prognosis of AIDS-KS.  Stage T0 disease (KS limited to the skin and lymph nodes with minimal oral disease) is associated with better clinical outcome compared to stage T1 disease (KS with tumor-associated edema or ulceration, extensive oral disease, and/or visceral disease). Advanced AIDS-KS is usually treated with combined ART and chemotherapy, but limited AIDS-KS often responds to ART alone.

 

A5264/AMC 067 is a phase III, open-label, prospective, randomized study stratified by CD4+ lymphocyte cell count and antiretroviral therapy (ART) history.  The study will compare the KS tumor outcomes of ART alone or with delayed Etoposide (ET) to ART with immediate ET, for initial treatment of limited stage AIDS-KS in chemotherapy and radiation treatment naïve HIV-1 infected participants who are currently not receiving ART
Abstract of Study:

DESIGN                      A phase III, open-label, prospective, randomized study stratified by CD4+ lymphocyte cell count and antiretroviral therapy (ART) history.  This study will compare ART alone or with delayed chemotherapy to ART with immediate adjunctive chemotherapy for initial treatment of limited stage AIDS-related Kaposi’s sarcoma (AIDS-KS) in chemotherapy and radiation treatment naïve HIV-1 infected participants who are currently not receiving ART.

 

DURATION                Participants never recieving etoposide (VePesid®, ET): 96 weeks

Participants receiving ET at any point: 240 weeks (96 weeks + 144 weeks of follow-up for safety)

 

SAMPLE SIZE            468 participants (234 in each Arm of Step 1)

 

POPULATION            Males and females ³ 18 years of age with the following characteristics:

  • Documentation of HIV-1 infection

  • Biopsy diagnostic of KS

  • Current limited stage KS (T0 and some T1 stage KS; see section 4.1.3 for details)

  • Systemic chemotherapy for KS and radiation treatment naïve

  • Currently not receiving ART

 

STRATIFICATION     Randomization will be stratified by screening peripheral blood CD4+ lymphocyte cell count (< 200 or  ³ 200 cells/mm³) and ART history (naïve or experienced). 

NOTE: Naïve is defined as no prior history of ART or <7 days cumulative therapy with any ART (except NVP or ZDV taken during pregnancy) at any time prior to study entry.  Experienced is defined as having had ART for ³ 7 cumulative days in the past (but must not have received ART within 6 months prior to study entry).

 

REGIMEN                  At study entry participants will be randomized 1:1 to one of the following arms in Step 1:

Step 1:                         Arm 1A:

Co-formulated efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)

                       

Arm 1B:          

Co-formulated EFV/FTC/TDF and ET

 

Step 2:                         Arm 2A:

At the discretion of the site investigator, after confirmation of disease progression by the IERC (Independent Endpoint Review Committee), participants who experience KS progression in Arm 1A will receive ET in addition to co-formulated EFV/FTC/TDF.

 

Step 3:                         Participants who received ET will remain on the study for 240 weeks (96 weeks + 144 weeks of follow-up for safety).