| Protocol No: | ECCT/11/09/01 | Date of Protocol: | 11-11-2011 |
| Study Title: | A Randomized Evaluation of Antiretroviral Therapy Alone or with Delayed Chemotherapy versus Antiretroviral Therapy with Immediate Adjunctive Chemotherapy for Treatment of Limited Stage AIDS-KS in Resource-Limited Settings (REACT-KS) |
| Study Objectives: | Primary Objective1. To compare, in participants with limited stage Kaposi’s sarcoma (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 study entry, initiation of a new KS treatment (chemotherapy agent other than ET or other treatment triggered by worsening KS) by week 48, or lost to follow-up at week 48 (including death and lost to follow-up by week 48 and missed visit at week 48); E2 (Stable) = Without KS progression nor KS partial response (PR), nor complete response (CR) at week 48 compared to study entry, and without initiation of a new KS treatment (chemotherapy agent other than ET or other treatment triggered by worsening KS) by week 48, E3 (Response) = With KS partial response (PR) or complete response (CR) at week 48 compared to study entry and without initiation of a new KS treatment (chemotherapy agent other than ET or radiation therapy triggered by worsening KS) by week 48.
Secondary Objectives1 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 and suspected KS IRIS (KS-associated immune reconstitution inflammatory syndrome), time to initial KS response (PR and CR combined and separately), and KS progression and response (compared to study entry) rates at weeks 48 and 96. 2 To evaluate the safety and tolerability of randomized study treatment. This will include comparison of adverse events, dose-limiting toxicities, and treatment/dose changes related to management of toxicities. 3 To investigate the effects of randomized study treatment on quality of life. 4 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. 5 To evaluate the effects of concomitant ET on adherence to ART. 6 To investigate the response to delayed ET after KS progression on ART alone. 7 To determine baseline KS-associated herpesvirus (KSHV) viral load in 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. 8 To evaluate the relationship between response of KS to randomized treatment, development of KS-IRIS, and the following markers: 8.1 Baseline immunohistochemical markers of viral and cellular gene expression in KS tumors 8.2 RNA levels for genes in tumor biopsies at baseline and during therapy 8.3 Cellular and humoral markers of immune function and immune activation. 9 To investigate the relationship between plasma, and PBMC KSHV viral load. 10 To encourage donation of excess biopsy materials to the AIDS and Cancer Specimen Resource (ACSR). 11 To assess the risk of secondary leukemia and myelodysplasia after etoposide use. 12 To compare the effects of randomized treatment on serum levels of inflammatory cytokines and/or molecules associated with angiogenesis. 13 To determine whether serum levels of cytokines and angiogenesis-associated molecules are associated with clinical response, immunological response (assessed by measuring CD4 T cell numbers), virological responses (assessed by measurement of HIV-1 and KSHV viral load), and the development of IRIS 14 To determine anti-KSHV specific T cell immune response in patients with AIDS-related KS before and after ART. 15 To follow the trajectory of the anti-KSHV T cell response at various time points after ART is started. 16 To correlate changes in the anti-KSHV T cell response with both HIV and KSHV viremia at specific time points. 17 To correlate the magnitude of the anti-KSHV T cell immune response with clinical outcome. 18 To explore changes in regulatory T cell frequency in patients developing KS-IRIS. 19 To evaluate CD8+ T cell exhaustion before and after ART treatment and during the development of KS-IRIS. 20 To determine the effects of randomized treatment on KS as a function of patterns of viral gene expression 21 To determine the effect of the treatment on KSHV viral gene expression in tumors we will be utilizing a RT-QPCR (Quantitive polymerase chain reaction) for KSHV |
| Laymans Summary: | Kaposi’s sarcoma is the most common cancer seen in HIV-infected patients. Limited stage Kaposi’s sarcoma means the Kaposi’s sarcoma is not very advanced. AIDS-related Kaposi’s sarcoma (AIDS-KS) occurs in persons with HIV infection, who are also infected with the Kaposi’s sarcoma herpes virus (KSHV). Several chemotherapy (anti-cancer) drugs work well in treating Kaposi’s sarcoma; but there is no treatment that cures KSHV infection. One chemotherapy drug called etoposide has caused Kaposi sarcoma tumors to get smaller in some people. Antiretroviral therapy (anti-HIV drugs or ART) is a group of medicines taken together to treat HIV infection. These medicines help to stop replication of HIV in the body. When this happens, the immune system, which fights infection and some cancers like Kaposi’s sarcoma, improves. For some people, limited stage Kaposi’s sarcoma often improves or stays the same when they take ART. However, in some people Kaposi’s sarcoma gets worse when taking ART. These people may need chemotherapy at a later date Taking ART has been shown to be helpful in treating KS as well as HIV infection. Taking additional anti-cancer medications may be beneficial as well. This study is being done to find out if taking ART with etoposide is better than taking ART alone or ART with delayed etoposide to treat limited stage KS. The study will also try to better understand KSHV, and to see what kind of side effects are caused by ART and etoposide, and how safe ART and etoposide are Each participant will be assigned (by chance) to one of two treatment groups; ART alone or ARTcombined with an anti-cancer drug called Etoposide. There will be a total of 468 participants in the study, 234 in each treatment group. The Kericho site will recruit 40-60 participants, both male and female of 18 years and above with documented HIV-1 infection and must have a biopsy diagnostic of Kaposi’s sarcoma. |
| Abstract of Study: | Acquired immunodeficiency syndrome-related Kaposi’s sarcoma (AIDS-KS) occurs in persons who are coinfected with human immunodeficiency virus type 1(HIV-1) and kaposi’s sarcoma-associated herpes virus (KSHV). Although the availability of potent antiretroviral therapy (ART) has coincided with a substantial decrease in AIDS-KS incidence in the developed world, 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 is associated with better clinical outcome compared to stage T1 disease. Advanced -KS is usually treated with combined ART and chemotherapy, but limited AIDS-KS often responds to ART alone. Current Kenya ministry of Health guidelines recommends use of highly active antiretroviral therapy (HAART) in the management of limited stage KS and use of chemotherapy for the treatment of advanced KS. The primary objective of the study is to compare in participants with limited stage KS, the week 48 KS tumor outcomes of low dose concurrent administration of oral etoposide with ART to ART alone or ART with delated etoposide with outcome at week 48 compared to entry categorized into; treatment failure where KS progresses despite treatment, Stable disease where there is no KS progression or response to therapy or response where there is response of KS to treatment. This is A phase III, open-label, prospective, randomized study stratified by CD4+ lymphocyte cell count and antiretroviral therapy (ART) history. The participants (male and female) must be 18 years and above with documented HIV-1 infection and must have a biopsy diagnostic of KS. They must not have used radiation and chemotherapy treatment for KS and, are currently not receiving ARTor are pregnant. At study entry participants will be randomized 1:1 to either arm 1A (Efavirenz/emtricitabine/tenofovir) or arm 1B where they will receive (EFV/FTC/TDF) and ET. Those on etoposide will receive an initial single dose of 50mg/day taken from day 1-7 of each 2-week cycle. For participants without partial response or complete response after two cycles of therapy with no toxicity of more than G2 the dose of etoposide will be escalated to 100mg/day orally, days 1-7, every 2 weeks. ET may be administerd up to a maximum of eight cycles. Participants in arm 1A who experience KS progression will enter step 2 and receive oral etoposide. The Kericho site will recruit 40-60 participants. Recruitment will primarily be done through Kericho District Hospital HIV clinic. The site accrual will be approximately 4 participants per month; hence estimated duration of accrual of 10-15months. Participants who will receive HAART only, will be followed up for 96 weeks while those who will receive oral etoposide with HAART will be followed up for 240 weeks. If the immediate use low dose etoposide given together with HAART shows better KS tumor outcome; this may lead to a decrease in the morbidity/mortality among patients infected with HIV-1andKaposissarcoma.
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