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

A Randomized Comparison of Three Regimens of Chemotherapy With Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings

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).

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Etoposide (ET); Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF); Drug: Bleomycin and Vincristine (BV); Drug: Paclitaxel (PTX)

Detailed Description

The study consisted of four steps. Study duration was up to 240 weeks.

At the study Step 1 entry, participants were randomized with equal probability to each of the three regimens (ET+ART, BV+ART, PTX+ART). The original target sample size was 706. Randomization was stratified by:

1. Screening CD4 lymphocyte cell count (<100, >=100 cells/mm³), and
2. Country.

For participants who had an initial Independent Endpoint Review Committee (IERC) confirmed KS response and subsequent IERC-confirmed KS progression, and who, in the opinion of the investigator and with concurrence of the protocol Clinical Management Committee (CMC), could potentially have benefitted from another course of the same chemotherapy utilized in Step 1, entered Step 2. (Please see details on Step 2 eligibility.)

In Step 3, participants were randomized with equal probability to one of the two chemotherapy arms not utilized in Step 1. (Please see details on Step 3 eligibility.)

In Step 4, participants were assigned to the remaining study-provided chemotherapy not given in Step 1, Step 2 or Step 3. (Please see details on Step 4 eligibility.)

Step 1 visits occurred at screening, entry and weeks 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, 36, 39, 42, 45, 48, 60, 72, 84 and 96 from study entry. Visits for Steps 2, 3 and 4 were scheduled at entry and weeks 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, 36, 39, 42, 45, 48, 60, 72, 84 and 96 from the corresponding step entry date. Key evaluations included targeted physical examination, clinical assessment, KS examination, hematology, chemistry, pregnancy testing (for women of reproductive potential), and pulse oximetry for participants on BV+ART. CD4 count and HIV viral load were obtained every 12 weeks. Assessment of peripheral neuropathy was done at screening, weeks 9 and 21, and for those on BV+ART or PTX+ART, additionally at weeks 3, 6, 15 and 18. KS tumor punch biopsy, serum, plasma and peripheral blood mononuclear cells (PBMCs) were obtained and stored for use in future analyses. Participants also completed ET and ART adherence evaluations and quality of life questionnaires.

Enrollment to ET+ART and initiation of ET+ART in subsequent steps were discontinued in March 2016, based on the recommendation of the Data and Safety Monitoring Board (DSMB) due to ET+ART being less effective than PTX+ART. No safety concerns were identified. ET+ART participants in Step 1 or Step 2, in discussion with the local investigator and in consultation with the protocol CMC, could discontinue ET and enter Step 3. ET+ART participants in Step 3 could discontinue ET and start the remaining chemotherapy regimen in Step 4 in discussion with the local investigator and in consultation with the protocol CMC. Unless otherwise indicated, comparison between ET+ART and PTX+ART was based on the March 2016 data. The study remained open to enrollment and the remaining participants were randomized at Step 1 entry between BV+ART and PTX+ART. The target total sample size was revised to 446.

The DSMB recommended stopping the study in March 2018 due to BV+ART being inferior to PTX+ART. No safety concerns were identified. Study accrual was stopped. Eligible Step 1 PTX+ART participants entered Step 2 to receive PTX+ART; Step 1 and Step 2 BV+ART participants eligible to receive PTX+ART moved to Step 3 to receive PTX+ART. Otherwise, participants permanently transitioned to local care upon arrangement of appropriate oncology and ART, and then went off study. Participants who received ET while on study were followed for 144 weeks after beginning the last cycle of ET.

Comparison between BV+ART and PTX+ART was based on the March 2018 data.

• Study Type: Interventional
• Enrollment (Actual): 334
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 21045
    • Instituto de Pesquisa Clinica Evandro Chagas (12101)
• Kenya
  • Eldoret, Kenya, 30100
    • Moi University International Clnical Trials Unit
  • Kericho, Kenya
    • KMRI / Walter Reed Project Clinical Research Center
  • Kisumu, Kenya, 40100
    • Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)
• Malawi
  • Blantyre, Malawi
    • Univ. of Malawi, John Hopkins Project
  • Lilongwe, Malawi
    • Malawi CRS (12001)
• South Africa
  • Durban, South Africa, 4013 SF
    • Durban Adult HIV CRS (11201)
  • Johannesburg, South Africa
    • University of Witwatersrand
  • West Cape
    • Cape Town, West Cape, South Africa, 7505
      • Family Clinical Research Unit (FAM-CUR) CRS (8950)
• Uganda
  • Kampala, Uganda
    • Uganda Cancer Institute ACTG CRS
• Zimbabwe
  • Harare, Zimbabwe
    • UZ-Parirenyatwa CRS (30313)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / 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: 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
EXPERIMENTAL: BV+ART; Bleomycin and Vincristine (BV) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)	Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF); 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; 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.
ACTIVE_COMPARATOR: PTX+ART; Paclitaxel (PTX) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)	Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF); 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Rate of Progression-Free Survival by Week 48 for ET+ART vs. PTX+ART	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).	From study entry to week 48
Cumulative Rate of Progression-Free Survival by Week 48 for BV+ART vs. PTX+ART	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).	From study entry to week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Rate of Death by Week 48 for ET+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of Death by Week 48 for BV+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of IERC-confirmed KS Progression by Week 48 for ET+ART vs. PTX+ART	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).	From study entry to week 48
Cumulative Rate of IERC-confirmed KS Progression by Week 48 for BV+ART vs. PTX+ART	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).	From study entry to week 48
Cumulative Rate of AIDS-defining Event by Week 48 for ET+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of AIDS-defining Event by Week 48 for BV+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of HIV-1 RNA Virologic Failure by Week 48 for ET+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of HIV-1 RNA Virologic Failure by Week 48 for BV+ART vs. PTX+ART	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.	From study entry to week 48
Number of Participants With Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) for ET+ART vs. PTX+ART	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.	From study entry to week 12
Number of Participants With Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) for BV+ART vs. PTX+ART	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.	From study entry to week 12
Cumulative Rate of KS Progression, Death, or AIDS Defining Event by Week 48 for ET+ART vs. PTX+ART	The Kaplan-Meier estimate of the cumulative rate of KS progression, death, or AIDS defining event by week 48	From study entry to week 48
Cumulative Rate of KS Progression, Death, or AIDS Defining Event by Week 48 for BV+ART vs. PTX+ART	The Kaplan-Meier estimate of the cumulative rate of KS progression, death, or AIDS defining event by week 48	From study entry to week 48
Cumulative Rate of KS Progression, Death, AIDS Defining Event, or Virologic Failure by Week 48 for ET+ART vs. PTX+ART	The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, or virologic failure by week 48	From study entry to week 48
Cumulative Rate of KS Progression, Death, AIDS Defining Event, or Virologic Failure by Week 48 for BV+ART vs. PTX+ART	The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, or virologic failure by week 48	From study entry to week 48
Cumulative Rate of KS Progression, Death, AIDS Defining Event, Virologic Failure, or KS-IRIS by Week 48 for ET+ART vs. PTX+ART	The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, virologic failure, or KS-IRIS.	From study entry to week 48
Cumulative Rate of KS Progression, Death, AIDS Defining Event, Virologic Failure, or KS-IRIS by Week 48 for BV+ART vs. PTX+ART	The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, virologic failure, or KS-IRIS.	From study entry to week 48
Cumulative Rate of Change in KS Treatment by Week 48 for ET+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of Change in KS Treatment by Week 48 for BV+ART vs. PTX+ART	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.	From study entry to week 48
Cumulative Rate of Death for ET+ART vs. PTX+ART	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.	From study entry to week 240
Cumulative Rate of Death for BV+ART vs PTX+ART	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.	From study entry to week 240
Time to IERC-confirmed KS Progression or Death for ET+ART vs. PTX+ART	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.	From study entry to week 240
Time to IERC-confirmed KS Progression or Death for BV+ART vs. PTX+ART	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.	From study entry to week 240
Number of Participants With Objective Response for ET+ART vs. PTX+ART	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).	From study entry up to week 144
Number of Participants With Objective Response for BV+ART vs. PTX+ART	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).	From study entry up to week 144
Duration of Objective Response for ET+ART vs. PTX+ART	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.	From study entry up to week 144
Duration of Objective Response for BV+ART vs. PTX+ART	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.	From study entry up to week 144
Number of Participants With Symptomatic Peripheral Neuropathy (SPN)	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.	Screening, Weeks 3, 6, 9, 12, 15, 18, 21. Assessment of SPN for ET+ART was only done at screening, weeks 9 and 21.
Number of Participants With Peripheral Neuropathy (PN)	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.	Screening, Weeks 3, 6, 9, 12, 15, 18, 21. Assessment of PN for ET+ART was only done at screening, weeks 9 and 21.
Number of Participants With Treatment-related Toxicities and Adverse Events (AEs)	Adverse events classified by the site personnel as possibly, probably or definitely related to ART or chemotherapy.	From study entry to week 240
Changes in CD4+ Lymphocyte Cell Count for ET+ART vs. PTX+ART	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.	Baseline, weeks 12, 24, 48
Changes in CD4+ Lymphocyte Cell Count for BV+ART vs. PTX+ART	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.	Baseline, weeks 12, 24, 48
Self-reported Adherence to ART Therapy	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.	At Weeks 6, 12, 18, 30 and 48
Presence of Oral KS	Funding for oral KS objectives including data and sample collection was withdrawn during the study conduct.	From study entry to week 240
Salivary KSHV	Funding for oral KS objectives including data and sample collection was withdrawn during the study conduct.	Baseline, weeks 60, 120, 180, 240
Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 2	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.	From Step 2 study entry to Step 2 discontinuation, up to 144 weeks
Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 3	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.	From Step 3 study entry to Step 3 discontinuation, up to 144 weeks
Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 4	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.	From Step 4 study entry to Step 4 discontinuation, up to 96 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life Measures	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.	Baseline, weeks 60, 120, 180, 240
Immunohistochemical Evaluations of Viral and Cellular Gene Expression	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.	Baseline, 24-48 hours after 2nd chemo-therapy cycle begins
RNA Levels for KSHV Genes	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.	Baseline, weeks 60, 120, 180, 240
Cellular and Humoral Markers of Immune Function and Activation	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.	Baseline, weeks 60, 120, 180, 240
Plasma KS-associated Herpesvirus (KSHV)	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.	Baseline, weeks 60, 120, 180, 240
Peripheral Blood Mononuclear Cell (PBMC) KSHV	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.	Baseline, weeks 60, 120, 180, 240

Collaborators and Investigators

• Sponsor: AIDS Clinical Trials Group
• Collaborators: National Cancer Institute (NCI); National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Dental and Craniofacial Research (NIDCR); AIDS Malignancy Consortium
• Investigators: Study Chair: Margaret Borok-Williams, MD, University of Zimbabwe

Publications and helpful links

General Publications

• Krown SE, Metroka C, Wernz JC. Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 1989 Sep;7(9):1201-7. doi: 10.1200/JCO.1989.7.9.1201.
• Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L, Pluda JM, Figg WD, Krown SE, Dezube BJ. Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol. 2002 Jan 1;20(1):153-9. doi: 10.1200/JCO.2002.20.1.153.
• Krown SE, Moser CB, MacPhail P, Matining RM, Godfrey C, Caruso SR, Hosseinipour MC, Samaneka W, Nyirenda M, Busakhala NW, Okuku FM, Kosgei J, Hoagland B, Mwelase N, Oliver VO, Burger H, Mngqibisa R, Nokta M, Campbell TB, Borok MZ; A5263/AMC066 protocol team. Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial. Lancet. 2020 Apr 11;395(10231):1195-1207. doi: 10.1016/S0140-6736(19)33222-2. Epub 2020 Mar 5.

Helpful Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2013
• Primary Completion (ACTUAL): March 13, 2018
• Study Completion (ACTUAL): August 29, 2019

Study Registration Dates

• First Submitted: September 14, 2011
• First Submitted That Met QC Criteria: September 14, 2011
• First Posted (ESTIMATE): September 15, 2011

Study Record Updates

• Last Update Posted (ACTUAL): October 20, 2021
• Last Update Submitted That Met QC Criteria: September 24, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antineoplastic; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Etoposide; Emtricitabine; Paclitaxel; Vincristine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Bleomycin; Efavirenz; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: ACTG A5263/AMC 066; U01CA121947 (U.S. NIH Grant/Contract); 1U01AI068636 (U.S. NIH Grant/Contract)