Antiretroviral Therapy (ART) Alone or With Delayed Chemo Versus ART With Immediate Chemo for Limited AIDS-related Kaposi's Sarcoma
Condition: HIV-1 Infection; Kaposi's Sarcoma
MeSH terms: Sarcoma, Kaposi; Sarcoma
Intervention: efavirenz/emtricitabine/tenofovir disoproxil fumarate; etoposide
Intervention description: 600 mg efavirenz/200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally at night; 50 mg taken orally daily from days 1-7 of each 2-week cycle. For participants without PR or CR after two cycles of therapy and no toxicity greater than Grade 2, the dose of ET was escalated to 100 mg/day orally, days 1-7, every 2 weeks. A cycle could be delayed for a maximum of 14 days. ET could not be initiated prior to 7 days after the last dose in previous cycle. ET could be administered up to a maximum of eight cycles (2 cycles during dose titration and 6 cycles at maximum dose). Participants who could not tolerate escalation of the ET dose to 100 mg/day were treated for a maximum of six cycles.
Intervention MeSH terms: Tenofovir; Emtricitabine; Efavirenz; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Etoposide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 192.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      AIDS-related Kaposi's sarcoma (AIDS-KS) occurs in persons with HIV infection who are also
      infected with the Kaposi's sarcoma herpesvirus (KSHV). Several chemotherapy (anti-cancer)
      drugs work well in treating KS, but there is no treatment that cures KSHV infection. One
      chemotherapy drug called etoposide (VePesid®, ET) has caused KS 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 HIV from growing in the body. When this
      happens, the immune system, which fights infection and some cancers like KS, gets stronger.
      For some people, limited stage KS often improves or stays the same when they take ART.
      However, in some people KS continues to get worse when taking ART. These people may need
      chemotherapy at a later date.

      This study was done to find out if taking ART with immediate etoposide (ET) is better than
      taking ART alone or ART with delayed ET to treat limited stage KS. The study also tried to
      better understand KSHV and to see what kind of side effects are caused by ART and ET and how
      safe ART and ET are.
    

Eligibility criteria:

        Step 1: Inclusion Criteria

          1. HIV-1 infection.

          2. Biopsy diagnostic of KS at any time prior to study entry.

          3. Limited stage KS defined as stage T0 and some presentations of stage T1. Stage T0 was
             confined to skin and/or lymph nodes and/or minimal oral disease defined as non-nodular
             KS confined to the palate. The following presentations of stage T1 KS were also
             eligible at the discretion of the site investigator:

               -  Tumor-associated edema limited to the area(s) of KS without significant
                  functional impairment.

               -  Oral KS that consists of flat (non-nodular and non-ulcerating) lesions confined
                  to the soft palate, hard palate, gums, and buccal mucosa.

               -  Asymptomatic gastrointestinal KS (i.e., no unexplained abdominal pain or
                  gastrointestinal bleeding).

          4. A minimum of 5 cutaneous marker lesions

          5. Certain laboratory values obtained within 14 days prior to study entry.

          6. For female participants of reproductive potential, a negative serum or urine pregnancy
             test performed within 7 days prior to study entry.

          7. All participants must have agreed not to participate in a conception process (e.g.,
             active attempt to become pregnant or to impregnate, donate sperm, in vitro
             fertilization).

          8. Participants who are participating in sexual activity that could lead to pregnancy
             must have agreed to use a combination of TWO of the following methods- Condoms (male
             or female) with or without a spermicidal agent, diaphragm or cervical cap with
             spermicide, IUD, tubal ligation, and/or hormone-based contraception. For Etoposide,
             confirmation of lack of reproductive potential was required for all participants. More
             information on this criterion can be found in the study protocol.

          9. Ability to swallow oral medications.

         10. Karnofsky performance score >= 60 within 30 days prior to entry.

         11. Ability and willingness of participant or legal guardian/representative to provide
             informed consent.

         12. Peripheral blood CD4+ lymphocyte cell count obtained within 30 days prior to study
             entry at a DAIDS-approved laboratory.

         13. For treatment-experienced patients, the availability of an ART regimen that includes
             at least two ART drugs that in the opinion of the site investigator are expected to
             have activity based on historical genotypic testing (if available) and treatment
             history.

         14. For participants who were to receive ART other than EFV/TDF/FTC, the availability of
             those ART components.

        Step 2: Inclusion Criteria

          1. KS progression compared to study entry or best response with ART alone while on Step
             1, between weeks 8 and 80.

          2. Need for ET for treatment of KS progression, in the opinion of the site investigator,
             after confirmation of KS progression by the IERC.

          3. Willingness to receive ET for treatment of KS progression.

          4. For female participants of reproductive potential, a negative serum or urine pregnancy
             test performed within 7 days prior to initiating ET.

          5. Karnofsky Performance Score >= 50.

          6. Certain laboratory values obtained within 14 days prior to Step 2 entry.

          7. Ability to swallow oral medications.

          8. All participants must have agreed not to participate in a conception process (e.g.,
             active attempt to become pregnant or to impregnate, donate sperm, in vitro
             fertilization).

          9. Participants who are participating in sexual activity that could lead to pregnancy
             must have agreed to use a combination of TWO of the following methods- Condoms (male
             or female) with or without a spermicidal agent, diaphragm or cervical cap with
             spermicide, IUD, tubal ligation, hormone-based contraception. For Etoposide,
             confirmation of lack of reproductive potential was required for all participants. More
             information on this criterion can be found in the study protocol.

        Step 3: Inclusion Criteria

        1. Received at least one dose of ET (Arm B participants and Arm A participants who entered
        Step 2)

        Step 1: Exclusion Criteria

          1. Any manifestation of KS which, in the opinion of the site investigator, requires
             immediate chemotherapy.

          2. More than 14 days of ART after onset of KS within 6 months prior to study entry.

          3. Biopsy proven KS during previous ART.

          4. Breastfeeding.

          5. Allergy/sensitivity to any study drug or its formulations.

          6. Any prior systemic anti-neoplastic treatment for KS (including chemotherapy,
             biological therapy, immunotherapy or investigational therapy).

          7. Any prior local treatment of cutaneous marker lesions unless there was evidence of a
             clear-cut progression of the lesion.

          8. Receipt of any investigational therapy within 30 days prior to study entry.

          9. Current or anticipated receipt of any of the prohibited medications indicated in the
             study protocol.

         10. In the opinion of the site investigator, any psychological or social condition, or
             addictive disorder that would have precluded compliance with the protocol.

         11. Chronic, acute, or recurrent infections that were serious, in the opinion of the site
             investigator, for which the participant had not completed at least 14 days of therapy
             prior to study entry and/or was not clinically stable.

        Step 2: Exclusion Criteria

          1. Chronic, acute, or recurrent infections that were serious, in the opinion of the site
             investigator, for which the participant had not completed at least 14 days of therapy
             prior to initiating ET and/or was not clinically stable.

          2. Current or anticipated receipt of any of the prohibited medications indicated in the
             study protocol.

          3. Breastfeeding.

        There are no exclusion criteria for Step 3.