Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Three Chemo Regimens as an Adjunct to ART for Treatment of Advanced AIDS-KS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01435018
Recruitment Status : Completed
First Posted : September 15, 2011
Results First Posted : April 8, 2019
Last Update Posted : October 20, 2021
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
National Cancer Institute (NCI)
National Institute of Dental and Craniofacial Research (NIDCR)
AIDS Malignancy Consortium
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Brief 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).

Condition or disease Intervention/treatment Phase
HIV-1 Infection Drug: Etoposide (ET) Drug: Bleomycin and Vincristine (BV) Drug: Paclitaxel (PTX) Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Phase 3

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 334 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Comparison of Three Regimens of Chemotherapy With Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings
Actual Study Start Date : October 1, 2013
Actual Primary Completion Date : March 13, 2018
Actual Study Completion Date : August 29, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: ET+ART
Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
Drug: Etoposide (ET)

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.


Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

The following ART regimens were used:

  1. EFV/FTC/TDF (Atripla) 200 mg/300 mg/600 mg orally once daily at bedtime or
  2. FTC/TDF 200 mg/300 mg (Truvada) orally once daily at bedtime plus EFV (Stocrin) 600 mg orally once daily at bedtime or
  3. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus nevirapine (NVP) 200 mg orally twice daily or
  4. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus PI/r at standard dosing or
  5. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus integrase inhibitor at standard dosing

Experimental: BV+ART
Bleomycin and Vincristine (BV) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
Drug: Bleomycin and Vincristine (BV)

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.


Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

The following ART regimens were used:

  1. EFV/FTC/TDF (Atripla) 200 mg/300 mg/600 mg orally once daily at bedtime or
  2. FTC/TDF 200 mg/300 mg (Truvada) orally once daily at bedtime plus EFV (Stocrin) 600 mg orally once daily at bedtime or
  3. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus nevirapine (NVP) 200 mg orally twice daily or
  4. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus PI/r at standard dosing or
  5. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus integrase inhibitor at standard dosing

Active Comparator: PTX+ART
Paclitaxel (PTX) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
Drug: Paclitaxel (PTX)
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.

Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

The following ART regimens were used:

  1. EFV/FTC/TDF (Atripla) 200 mg/300 mg/600 mg orally once daily at bedtime or
  2. FTC/TDF 200 mg/300 mg (Truvada) orally once daily at bedtime plus EFV (Stocrin) 600 mg orally once daily at bedtime or
  3. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus nevirapine (NVP) 200 mg orally twice daily or
  4. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus PI/r at standard dosing or
  5. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus integrase inhibitor at standard dosing




Primary Outcome Measures :
  1. Cumulative Rate of Progression-Free Survival by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    Progression-free survival (PFS) by week 48 is defined as a lack of the following events: (a) Independent Endpoint Review Committee (IERC)-confirmed KS progression, (b) death, (c) entry into an additional step, or (d) loss to follow-up, prior to week 48. PFS rate was estimated by the Kaplan-Meier survival probability at week 48. Time to event was computed as the number of weeks from study entry to the first among these events. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48. Overall KS outcome status (complete response, partial response, stable, disease progression) was based on comparing follow-up to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).

  2. Cumulative Rate of Progression-Free Survival by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    Progression-free survival (PFS) by week 48 is defined as a lack of the following events: (a) Independent Endpoint Review Committee (IERC)-confirmed KS progression, (b) death, (c) entry into an additional step, or (d) loss to follow-up, prior to week 48. PFS rate was estimated by the Kaplan-Meier survival probability at week 48. Time to event was computed as the number of weeks from study entry to the first among these events. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48. Overall KS outcome status (complete response, partial response, stable, disease progression) was based on comparing follow-up to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).


Secondary Outcome Measures :
  1. Cumulative Rate of Death by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of death by week 48. Time to death was computed as the number of weeks from study entry to date of death. For participants who did have the event, time to death was censored at the week of last contact with the participant. Time to death above 48 were censored at week 48.

  2. Cumulative Rate of Death by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of death by week 48. Time to death was computed as the number of weeks from study entry to the death date. For participants who did have the event, time to death was censored at the week of last contact with the participant. Time to death above 48 were censored at week 48.

  3. Cumulative Rate of IERC-confirmed KS Progression by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of IERC-confirmed KS progression by week 48. IERC-confirmed KS progression was defined as KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).

  4. Cumulative Rate of IERC-confirmed KS Progression by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of IERC-confirmed KS progression by week 48. IERC-confirmed KS progression was defined as KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).

  5. Cumulative Rate of AIDS-defining Event by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of AIDS-defining events by week 48. AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Time to event was computed as the number of weeks from study entry to the first AIDS-defining event. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48.

  6. Cumulative Rate of AIDS-defining Event by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of AIDS-defining events by week 48. AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Time to event was computed as the number of weeks from study entry to the first AIDS-defining event. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48.

  7. Cumulative Rate of HIV-1 RNA Virologic Failure by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    Virologic failure is defined as two successive measurements of plasma HIV-1 RNA >=1000 copies/mL at week 12 to week 24 or RNA >=400 copies/mL at week 24 or later.

  8. Cumulative Rate of HIV-1 RNA Virologic Failure by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    Virologic failure is defined as two successive measurements of plasma HIV-1 RNA >=1000 copies/mL at week 12 to week 24 or RNA >=400 copies/mL at week 24 or later.

  9. Number of Participants With Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 12 ]
    KS-IRIS is defined as any IERC-confirmed KS-progression that occurs within 12 weeks of ART-initiation that is associated with an increase in CD4 cell count of at least 50 cells/mm^3 above the study entry value and/or a decrease in the HIV-1 RNA level by at least 0.5 log below the study entry value prior to or at the time of documented KS progression.

  10. Number of Participants With Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 12 ]
    KS-IRIS is defined as any IERC-confirmed KS-progression that occurs within 12 weeks of ART-initiation that is associated with an increase in CD4 cell count of at least 50 cells/mm^3 above the study entry value and/or a decrease in the HIV-1 RNA level by at least 0.5 log below the study entry value prior to or at the time of documented KS progression.

  11. Cumulative Rate of KS Progression, Death, or AIDS Defining Event by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of KS progression, death, or AIDS defining event by week 48

  12. Cumulative Rate of KS Progression, Death, or AIDS Defining Event by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of KS progression, death, or AIDS defining event by week 48

  13. Cumulative Rate of KS Progression, Death, AIDS Defining Event, or Virologic Failure by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, or virologic failure by week 48

  14. Cumulative Rate of KS Progression, Death, AIDS Defining Event, or Virologic Failure by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, or virologic failure by week 48

  15. Cumulative Rate of KS Progression, Death, AIDS Defining Event, Virologic Failure, or KS-IRIS by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, virologic failure, or KS-IRIS.

  16. Cumulative Rate of KS Progression, Death, AIDS Defining Event, Virologic Failure, or KS-IRIS by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, virologic failure, or KS-IRIS.

  17. Cumulative Rate of Change in KS Treatment by Week 48 for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of change in KS treatment by week 48. Change in KS treatment was defined as stopping Step 1 randomized chemotherapy and initiating a different chemotherapy.

  18. Cumulative Rate of Change in KS Treatment by Week 48 for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 48 ]
    The Kaplan-Meier estimate of the cumulative rate of change in KS treatment by week 48. Change in KS treatment was defined as stopping Step 1 randomized chemotherapy and initiating a different chemotherapy.

  19. Cumulative Rate of Death for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 240 ]
    The Kaplan-Meier estimate of the cumulative rate of death. Time to death was computed as the number of weeks between study entry and date of death. For participants who did not have the event, time to death was censored at the week of last contact with the participant or at the participant's off study week, whichever is later.

  20. Cumulative Rate of Death for BV+ART vs PTX+ART [ Time Frame: From study entry to week 240 ]
    The Kaplan-Meier estimate of the cumulative rate of death. Time to death was computed as the number of weeks between study entry and date of death. For participants who did not have the event, time to death was censored at the week of last contact with the participant or at the participant's off study week, whichever is later.

  21. Time to IERC-confirmed KS Progression or Death for ET+ART vs. PTX+ART [ Time Frame: From study entry to week 240 ]
    Time to IERC-confirmed KS progression or death was computed as the number of weeks between study entry and the earlier between date of IERC-confirmed KS progression or date of death. For participants who did not have the event, event time was censored at the week of last contact with the participant or the participant's off study week, whichever is later. The 25-th percentile and hazard ratio are presented.

  22. Time to IERC-confirmed KS Progression or Death for BV+ART vs. PTX+ART [ Time Frame: From study entry to week 240 ]
    Time to IERC-confirmed KS progression or death was computed as the number of weeks between study entry and the earlier between date of IERC-confirmed KS progression or date of death. For participants who did not have the event, event time was censored at the week of last contact with the participant or at the participant's off study week, whichever is later.The 25-th percentile and hazard ratio are presented.

  23. Number of Participants With Objective Response for ET+ART vs. PTX+ART [ Time Frame: From study entry up to week 144 ]
    The number of participants with objective response (complete response or partial response) as best overall KS response in Step 1. Overall KS response status (complete response, partial response, stable, disease progression) was based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).

  24. Number of Participants With Objective Response for BV+ART vs. PTX+ART [ Time Frame: From study entry up to week 144 ]
    The number of participants with objective response (complete response or partial response) as best overall KS response in Step 1. Overall KS response status (complete response, partial response, stable, disease progression) was based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).

  25. Duration of Objective Response for ET+ART vs. PTX+ART [ Time Frame: From study entry up to week 144 ]
    Duration of objective response is the number of weeks from first complete or partial response to the earliest among progression, death or off study week. The 25th percentile duration is presented.

  26. Duration of Objective Response for BV+ART vs. PTX+ART [ Time Frame: From study entry up to week 144 ]
    Duration of objective response is the number of weeks from first complete or partial response to the earliest among progression, death or off study week. The 25th percentile duration is presented.

  27. Number of Participants With Symptomatic Peripheral Neuropathy (SPN) [ Time Frame: Screening, Weeks 3, 6, 9, 12, 15, 18, 21. Assessment of SPN for ET+ART was only done at screening, weeks 9 and 21. ]
    SPN consists of three assessments: (1) pain, aching or burning in feet, legs, (2) "pins and needles" in feet, legs, and (3) numbness (lack of feeling) in feet, legs. SPN is graded on a severity scale from 0 (not present), 1 (mild) to 10 (severe). Presence of SPN is defined as having grade >=1 in at least one of the three assessments.

  28. Number of Participants With Peripheral Neuropathy (PN) [ Time Frame: Screening, Weeks 3, 6, 9, 12, 15, 18, 21. Assessment of PN for ET+ART was only done at screening, weeks 9 and 21. ]
    Presence of PN is defined as having all of the following results: presence of symptomatic PN, abnormal perception of vibrations, and absent or hypoactive deep tendon reflexes.

  29. Number of Participants With Treatment-related Toxicities and Adverse Events (AEs) [ Time Frame: From study entry to week 240 ]
    Adverse events classified by the site personnel as possibly, probably or definitely related to ART or chemotherapy.

  30. Changes in CD4+ Lymphocyte Cell Count for ET+ART vs. PTX+ART [ Time Frame: Baseline, weeks 12, 24, 48 ]
    Baseline CD4 lymphocyte cell count is the mean of screening and Step 1 entry CD4 values. Absolute change in CD4+ lymphocyte cell count was calculated as value at a given visit minus the baseline CD4 lymphocyte cell count.

  31. Changes in CD4+ Lymphocyte Cell Count for BV+ART vs. PTX+ART [ Time Frame: Baseline, weeks 12, 24, 48 ]
    Baseline CD4 lymphocyte cell count is the mean of screening and Step 1 entry CD4 values. Absolute change in CD4+ lymphocyte cell count was calculated as value at a given visit minus the baseline CD4 lymphocyte cell count.

  32. Self-reported Adherence to ART Therapy [ Time Frame: At Weeks 6, 12, 18, 30 and 48 ]
    ART adherence is based on participant's recall of the number of missed ART doses for the past month. Perfect adherence is defined as having zero missed ART doses.

  33. Presence of Oral KS [ Time Frame: From study entry to week 240 ]
    Funding for oral KS objectives including data and sample collection was withdrawn during the study conduct.

  34. Salivary KSHV [ Time Frame: Baseline, weeks 60, 120, 180, 240 ]
    Funding for oral KS objectives including data and sample collection was withdrawn during the study conduct.

  35. Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 2 [ Time Frame: From Step 2 study entry to Step 2 discontinuation, up to 144 weeks ]
    IERC-confirmed KS progression refers to KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Virologic failure is defined as two successive measurements of plasma HIV-1 RNA >=1000 copies/mL at week 12 to week 24 or RNA >=400 copies/mL at week 24 or later. Objective response refers to complete response or partial response as best overall KS response. Results are presented by Step 2 treatment arm.

  36. Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 3 [ Time Frame: From Step 3 study entry to Step 3 discontinuation, up to 144 weeks ]
    IERC-confirmed KS progression refers to KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Virologic failure is defined as two successive measurements of plasma HIV-1 RNA >=1000 copies/mL at week 12 to week 24 or RNA >=400 copies/mL at week 24 or later. Objective response refers to complete response or partial response as best overall KS response. Results are presented by Step 3 treatment arm.

  37. Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 4 [ Time Frame: From Step 4 study entry to Step 4 discontinuation, up to 96 weeks ]
    IERC-confirmed KS progression refers to KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Virologic failure is defined as two successive measurements of plasma HIV-1 RNA >=1000 copies/mL at week 12 to week 24 or RNA >=400 copies/mL at week 24 or later. Objective response refers to complete response or partial response as best overall KS response. Results are presented by Step 4 treatment arm.


Other Outcome Measures:
  1. Quality of Life Measures [ Time Frame: Baseline, weeks 60, 120, 180, 240 ]
    The protocol did not distinguish between outcome measures essential to the primary publication and those of lesser importance and priority which are not the focus of the study but intended for subsequent publications of exploratory analyses, conditional on primary results and additional funding. This outcome measure was listed under secondary outcome measures in the study protocol but was intended for an exploratory analysis to compare measures of quality of life in ET+ART, BV+ART and PTX+ART.

  2. Immunohistochemical Evaluations of Viral and Cellular Gene Expression [ Time Frame: Baseline, 24-48 hours after 2nd chemo-therapy cycle begins ]
    The protocol did not distinguish between outcome measures essential to the primary publication and those of lesser importance and priority which are not the focus of the study but intended for subsequent publications of exploratory analyses, conditional on primary results and additional funding. This outcome measure was listed under secondary outcome measures in the study protocol but was intended for an exploratory analysis to evaluate the relationship between response of KS to therapy and development of KS-IRIS with immunohistochemical markers of viral and cellular gene expression in KS tumors. The laboratory assays for this outcome measure have not been completed.

  3. RNA Levels for KSHV Genes [ Time Frame: Baseline, weeks 60, 120, 180, 240 ]
    The protocol did not distinguish between outcome measures essential to the primary publication and those of lesser importance and priority which are not the focus of the study but intended for subsequent publications of exploratory analyses, conditional on primary results and additional funding. This outcome measure was listed under secondary outcome measures in the study protocol but was intended for an exploratory analysis to evaluate the relationship between response of KS to therapy and development of KS-IRIS with RNA levels for KSHV genes in tumor biopsies. The laboratory assays for this outcome measure have not been completed.

  4. Cellular and Humoral Markers of Immune Function and Activation [ Time Frame: Baseline, weeks 60, 120, 180, 240 ]
    The protocol did not distinguish between outcome measures essential to the primary publication and those of lesser importance and priority which are not the focus of the study but intended for subsequent publications of exploratory analyses, conditional on primary results and additional funding. This outcome measure was listed under secondary outcome measures in the study protocol but was intended for an exploratory analysis to evaluate the relationship between response of KS to therapy and development of KS-IRIS with cellular and humoral markers of immune function and activation. The laboratory assays for this outcome measure have not been completed.

  5. Plasma KS-associated Herpesvirus (KSHV) [ Time Frame: Baseline, weeks 60, 120, 180, 240 ]
    The protocol did not distinguish between outcome measures essential to the primary publication and those of lesser importance and priority which are not the focus of the study but intended for subsequent publications of exploratory analyses, conditional on primary results and additional funding. This outcome measure was listed under secondary outcome measures in the study protocol but was intended for an exploratory analysis to investigate the relationship between plasma and PBMC KSHV viral load. The laboratory assays for this outcome measure have not been completed.

  6. Peripheral Blood Mononuclear Cell (PBMC) KSHV [ Time Frame: Baseline, weeks 60, 120, 180, 240 ]
    The protocol did not distinguish between outcome measures essential to the primary publication and those of lesser importance and priority which are not the focus of the study but intended for subsequent publications of exploratory analyses, conditional on primary results and additional funding. This outcome measure was listed under secondary outcome measures in the study protocol but was intended for an exploratory analysis to investigate the relationship between plasma and PBMC KSHV viral load. The laboratory assays for this outcome measure have not been completed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01435018


Locations
Layout table for location information
Brazil
Instituto de Pesquisa Clinica Evandro Chagas (12101)
Rio de Janeiro, Brazil, 21045
Kenya
Moi University International Clnical Trials Unit
Eldoret, Kenya, 30100
KMRI / Walter Reed Project Clinical Research Center
Kericho, Kenya
Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)
Kisumu, Kenya, 40100
Malawi
Univ. of Malawi, John Hopkins Project
Blantyre, Malawi
Malawi CRS (12001)
Lilongwe, Malawi
South Africa
Family Clinical Research Unit (FAM-CUR) CRS (8950)
Cape Town, West Cape, South Africa, 7505
Durban Adult HIV CRS (11201)
Durban, South Africa, 4013 SF
University of Witwatersrand
Johannesburg, South Africa
Uganda
Uganda Cancer Institute ACTG CRS
Kampala, Uganda
Zimbabwe
UZ-Parirenyatwa CRS (30313)
Harare, Zimbabwe
Sponsors and Collaborators
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
National Cancer Institute (NCI)
National Institute of Dental and Craniofacial Research (NIDCR)
AIDS Malignancy Consortium
Investigators
Layout table for investigator information
Study Chair: Margaret Borok-Williams, MD University of Zimbabwe
Study Chair: Susan E. Krown, MD AIDS Malignancy Consortium
  Study Documents (Full-Text)

Documents provided by AIDS Clinical Trials Group:
Statistical Analysis Plan  [PDF] September 26, 2018

Additional Information:
Publications of Results:
Other Publications:
Layout table for additonal information
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01435018    
Other Study ID Numbers: ACTG A5263/AMC 066
1U01AI068636 ( U.S. NIH Grant/Contract )
U01CA121947 ( U.S. NIH Grant/Contract )
First Posted: September 15, 2011    Key Record Dates
Results First Posted: April 8, 2019
Last Update Posted: October 20, 2021
Last Verified: September 2021
Additional relevant MeSH terms:
Layout table for MeSH terms
Tenofovir
Emtricitabine
Efavirenz
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Paclitaxel
Etoposide
Vincristine
Bleomycin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers