Three Chemo Regimens as an Adjunct to ART for Treatment of Advanced AIDS-KS
Condition: HIV-1 Infection
Intervention: Etoposide (ET); Bleomycin and Vincristine (BV); Paclitaxel (PTX); Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
Intervention description: Beginning on day one of the chemotherapy cycle, ET was given orally in a dose of 50 mg twice daily for 7 consecutive days for the first cycle. If there was no Grade >= 2 toxicity attributable to ET after the first cycle, the dose was escalated to 150 mg daily for 7 days in divided doses of 100 mg/50 mg for the second cycle. After the second cycle, if there was no Grade >= 2 toxicity attributable to ET, the dose was escalated to 100 mg twice daily for 7 days for the third and subsequent cycles.
Treatment with ET was continued for six cycles at the maximum dose achieved or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the protocol CMC, had determined that alternative therapy is required, whichever occurs first.; BV was administered on day one of each chemotherapy cycle.
Vincristine sulfate was administered at a dose of 2 mg (fixed dose) in a volume of 2 mL over 1 minute into the sidearm of a rapidly flowing intravenous infusion every 3 weeks. The vincristine infusion was followed by bleomycin as detailed below.
Bleomycin sulfate was administered at a dose of 15 units/m^2 over 10 minutes every 3 weeks.
Treatment with BV was continued for six cycles, or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the protocol CMC, had determined that alternative therapy is required, whichever occurs first.; Paclitaxel was administered by IV infusion in 200 mL, 250 mL, or 500 mL of 5% dextrose or 0.9%Sodium Chloride for injection at a dose of 100 mg/m^2 body surface area (BSA) every 3 weeks.; The following ART regimens were used:
EFV/FTC/TDF (Atripla) 200 mg/300 mg/600 mg orally once daily at bedtime or
FTC/TDF 200 mg/300 mg (Truvada) orally once daily at bedtime plus EFV (Stocrin) 600 mg orally once daily at bedtime or
FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus nevirapine (NVP) 200 mg orally twice daily or
FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus PI/r at standard dosing or
FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus integrase inhibitor at standard dosing
Intervention MeSH terms: Tenofovir; Emtricitabine; Efavirenz; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Paclitaxel; Etoposide; Vincristine; Bleomycin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 334.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study was done to compare the safety and efficacy of three combination treatments for
      Kaposi's Sarcoma (KS) and AIDS:

        1. Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate
           (EFV/FTC/TDF) (ET+ART),

        2. Bleomycin and Vincristine (BV) plus co-formulated EFV/FTC/TDF (BV+ART),

        3. Paclitaxel (PTX) plus co-formulated EFV/FTC/TDF (PTX+ART).
    

Eligibility criteria:

        Inclusion Criteria for Step 1:

          1. HIV-1 infection

          2. Biopsy diagnostic of KS at any time prior to study entry.

          3. Current KS stage T1 using ACTG criteria.

          4. A minimum of five indicator KS cutaneous marker lesions (or if fewer than five marker
             lesions are available, the total surface area of the marker lesion(s) must be >=700
             mm^2) plus an additional two lesions greater or equal to 4x4 mm that are accessible
             for punch biopsy.

          5. CD4+ lymphocyte cell count obtained within 28 days prior to study entry at a
             DAIDS-approved laboratory.

          6. Certain laboratory values, as defined in the protocol, obtained within 14 days prior
             to study entry.

          7. Female study volunteers of reproductive potential must have a negative serum or urine
             pregnancy test with a sensitivity of 15-25 mIU/mL performed within 48 hours before
             initiating the protocol-specified medications.

          8. All participants must agree not to participate in a conception process (active attempt
             to become pregnant or to impregnate, donate sperm, in vitro fertilization).

          9. If participating in sexual activity that could lead to pregnancy, participant must
             agree that two reliable forms of contraceptives will be used simultaneously while
             receiving protocol-specified medications, and for 12 weeks after stopping the
             medications. Study volunteers who are not of reproductive potential (women who have
             been post-menopausal for at least 24 consecutive months or have undergone hysterectomy
             and/or bilateral oophorectomy or men who have documented azoospermia) are eligible
             without requiring the use of contraceptives.

         10. Ability to swallow oral medications and adequate venous access.

         11. Karnofsky performance status >= 60 within 28 days prior to entry.

         12. Ability and willingness of participant or legal guardian/representative to provide
             informed consent.

        Exclusion Criteria for Step 1:

          1. Current chronic, acute, or recurrent serious infections for which the participant has
             not completed at least 14 days of therapy prior to study entry and/or is not
             clinically stable.

          2. Serious illness requiring systemic treatment and/or hospitalization within 14 days
             prior to entry.

          3. Current or history of known pulmonary fibrosis, chronic obstructive pulmonary disease
             (COPD), emphysema, bronchiectasis, or diffuse or significant local radiographic
             interstitial infiltrates on chest x-ray (CXR) or computed axial tomography (CT) scan.

          4. Oxygen saturation less than 90% and/or exercise desaturation greater than 4% within 14
             days prior to study enrollment.

          5. Grade >=3 peripheral neuropathy (PN) at entry.

          6. Breastfeeding.

          7. Receipt of ART for more than 42 days immediately prior to entry.

          8. Prior or current systemic or locally administered chemotherapy.

          9. Prior or current radiation therapy.

         10. Prior or current immunotherapy, e.g., interferon alfa.

         11. Corticosteroid use at doses above those given as replacement therapy for adrenal
             insufficiency within the last 30 days prior to study entry.

         12. Any immunomodulator, HIV vaccine, live attenuated vaccines, or other investigational
             therapy or investigational vaccine within 30 days prior to study entry.

         13. Known allergy/sensitivity or any hypersensitivity to components of study drugs or
             their formulation.

         14. Active drug or alcohol use or dependence that would interfere with adherence to study
             requirements.

         15. Current or anticipated receipt of any of the prohibited medications listed in section
             5.5.2 of the protocol.

         16. In the opinion of the investigator, any psychological or social condition, or
             addictive disorder that would preclude compliance with the protocol.

        Inclusion Criteria for Step 2:

          1. IERC-confirmed complete response (CR) or partial response (PR) to the chemotherapy
             regimen used in Step 1.

          2. IERC-confirmed KS progression at least 12 weeks after the last dose of Step 1
             chemotherapy.

          3. Fewer than 72 weeks after Step 1 entry

          4. Certain laboratory values, as defined in the protocol, obtained within 14 days prior
             to Step 2 entry.

          5. For females of reproductive potential or females not of reproductive potential who do
             not have required documentation, negative serum or urine pregnancy test with a
             sensitivity of 15-25 mIU/mL within 7 days prior to Step 2 entry.

          6. Karnofsky performance status >=50 within 28 days prior to Step 2

          7. All participants must agree not to participate in a conception process (active attempt
             to become pregnant or to impregnate, donate sperm, in vitro fertilization).

        Exclusion Criteria Step 2:

          1. Current chronic, acute, or recurrent infections that are serious, in the opinion of
             the site investigator, for which the participant has not completed at least 14 days of
             therapy prior to Step 2 entry and/or is not clinically stable.

          2. Severe toxicity to the chemotherapy regimen used in Step 1 requiring discontinuation
             of study chemotherapy.

          3. Serious illness, other than progressive KS, requiring systemic treatment and/or
             hospitalization within 14 days prior to Step 2 entry.

          4. For volunteers who received bleomycin in Step 1

               -  Development of of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and
                  diffuse or significant local radiographic interstitial infiltrates on CXR or CT
                  scan that in the opinion of the site investigator would exclude bleomycin use.

               -  Oxygen saturation less than 90% or exercise desaturation greater than 4% within
                  the last 30 days prior to Step 2 entry.

          5. For volunteers who received Vincristine or Paclitaxel in Step 1, Grade >=3 PN at Step
             2 entry.

          6. Breastfeeding.

          7. Other concurrent chemotherapy, immunotherapy, or radiotherapy.

          8. Systemic corticosteroid use at doses above those given as replacement therapy for
             adrenal insufficiency within 30 days of Step 2 entry.

          9. Receipt of Etoposide (ET) in Step 1.

        Inclusion Criteria Step 3:

          1. (a) IERC-confirmed KS progression at any time during Step 1 chemotherapy, or (b)
             IERC-confirmed KS progression fewer than 12 weeks after the last chemotherapy dose in
             Step 1 in participants who have had an IERC-confirmed CR or PR, or (c) IERC-confirmed
             KS progression following Step 1 chemotherapy, without any prior response, or (d)
             IERC-confirmed KS progression in Step 2, or (d) with concurrence of the CMC, there is
             dose-limiting toxicity after receiving fewer than four cycles of chemotherapy in Step
             1 or Step 2, in the absence of a CR or PR, or (e) volunteers otherwise eligible for
             Step 2 who, in the opinion of the investigator and with concurrence of the CMC, are
             unlikely to benefit from another course of the same chemotherapy received in Step 1.

          2. Fewer than 72 weeks after Step 1 entry.

          3. Certain laboratory values, as defined in the protocol, obtained within 14 days prior
             to Step 3 entry.

          4. For females of reproductive potential or females not of reproductive potential who do
             not have required documentation, negative serum or urine pregnancy test with a
             sensitivity of 15-25 mIU/mL within 7 days prior to Step 3 entry.

          5. Karnofsky performance status >=50 within 28 days prior to Step 3 entry.

          6. All participants must agree not to participate in a conception process (active attempt
             to become pregnant or to impregnate, donate sperm, in vitro fertilization).

        Exclusion Criteria Step 3:

          1. Current chronic, acute, or recurrent infections that are serious, in the opinion of
             the site investigator, for which the participant has not completed at least 14 days of
             therapy prior to Step 3 entry and/or is not clinically stable.

          2. Serious illness, other than progressive KS, requiring systemic treatment and/or
             hospitalization within 14 days prior to Step 3 entry.

          3. Eligible for Step 2 entry.

          4. For participants who did not receive bleomycin in Step 1 or Step 2:

               -  Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and diffuse
                  or significant local radiographic interstitial infiltrates on CXR or CT scan that
                  in the opinion of the site investigator would exclude bleomycin use.

               -  Oxygen saturation less than 90% or exercise desaturation greater than 4% within
                  the last 30 days prior to Step 3 entry.

          5. Grade >=3 PN at Step 3 entry.

          6. Breastfeeding

          7. Other concurrent chemotherapy, immunotherapy, or radiotherapy.

          8. Systemic corticosteroid use at doses above those given as replacement therapy for
             adrenal insufficiency within 30 days of Step 3 entry.

        Inclusion Criteria Step 4:

          1. (a) IERC-confirmed KS progression in Step 3, or (b) With concurrence of the CMC,
             dose-limiting toxicity after receiving fewer than four cycles of chemotherapy in Step
             3, in the absence of a CR or PR, or (c) Current receipt of ET in Step 3.

          2. Fewer than 72 weeks after Step 1 entry.

          3. Certain laboratory values, as defined in the protocol, obtained within 14 days prior
             to Step 4 entry.

          4. For females of reproductive potential or females not of reproductive potential who do
             not have required documentation, negative serum or urine pregnancy test with a
             sensitivity of 15-25 mIU/mL within 7 days prior to Step 4 entry.

          5. Karnofsky performance status >=50 within 28 days prior to Step 4 entry.

          6. All participants must agree not to participate in a conception process (active attempt
             to become pregnant or to impregnate, donate sperm, in vitro fertilization).

          7. Receipt of ET in Step 1, Step 2, or Step 3.

        Exclusion Criteria Step 4:

          1. Current chronic, acute, or recurrent infections that are serious, in the opinion of
             the site investigator, for which the participant has not completed at least 14 days of
             therapy prior to Step 4 entry and/or is not clinically stable.

          2. Serious illness, other than progressive KS, requiring systemic treatment and/or
             hospitalization within 14 days prior to Step 4 entry.

          3. For participants who did not receive bleomycin in Step 1, Step 2, or Step 3:

               -  Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and diffuse
                  or significant local radiographic interstitial infiltrates on CXR or CT scan that
                  in the opinion of the site investigator would exclude bleomycin use.

               -  Oxygen saturation less than 90% or exercise desaturation greater than 4% within
                  the last 30 days prior to Step 4 entry.

          4. Grade >=3 PN at Step 4 entry.

          5. Breastfeeding.

          6. Other concurrent chemotherapy, immunotherapy, or radiotherapy.

          7. Systemic corticosteroid use at doses above those given as replacement therapy for
             adrenal insufficiency within 30 days of Step 4 entry.