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

NCT01435018 | Completed Phase 3 Results DMC

• 3 other identifiers: ACTG A5263/AMC 0661U01AI068636U01CA121947
• Study Type: interventional
• Target: 334
• Locations: 6 countries
• Sites: 11

Brief Summary

This study was done to compare the safety and efficacy of three combination treatments for Kaposi's Sarcoma (KS) and AIDS:

1. 1.Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) (ET+ART),
2. 2.Bleomycin and Vincristine (BV) plus co-formulated EFV/FTC/TDF (BV+ART),
3. 3.Paclitaxel (PTX) plus co-formulated EFV/FTC/TDF (PTX+ART).

Conditions

HIV-1 Infection

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (37)

• Cumulative Rate of Death by Week 48 for ET+ART vs. PTX+ART

  From study entry to week 48

• Cumulative Rate of Death by Week 48 for BV+ART vs. PTX+ART

  From study entry to week 48

• Cumulative Rate of IERC-confirmed KS Progression by Week 48 for ET+ART vs. PTX+ART

  From study entry to week 48

• Cumulative Rate of IERC-confirmed KS Progression by Week 48 for BV+ART vs. PTX+ART

  From study entry to week 48

• Cumulative Rate of AIDS-defining Event by Week 48 for ET+ART vs. PTX+ART

  From study entry to week 48

Other Outcomes (6)

• Quality of Life Measures

  Baseline, weeks 60, 120, 180, 240

• Immunohistochemical Evaluations of Viral and Cellular Gene Expression

  Baseline, 24-48 hours after 2nd chemo-therapy cycle begins

• RNA Levels for KSHV Genes

  Baseline, weeks 60, 120, 180, 240

Study Arms (3)

ET+ART

EXPERIMENTAL

Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

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

BV+ART

EXPERIMENTAL

Bleomycin and Vincristine (BV) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

Drug: Bleomycin and Vincristine (BV); Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

PTX+ART

ACTIVE COMPARATOR

Paclitaxel (PTX) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

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

Interventions

Etoposide (ET) DRUG

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.

ET+ART

Bleomycin and Vincristine (BV) DRUG

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.

BV+ART

Paclitaxel (PTX) DRUG

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.

PTX+ART

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

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

BV+ART; ET+ART; PTX+ART

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infection
• Biopsy diagnostic of KS at any time prior to study entry.
• Current KS stage T1 using ACTG criteria.
• 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.
• CD4+ lymphocyte cell count obtained within 28 days prior to study entry at a DAIDS-approved laboratory.
• Certain laboratory values, as defined in the protocol, obtained within 14 days prior to study entry.
• 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.
• All participants must agree not to participate in a conception process (active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).
• 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.
• Ability to swallow oral medications and adequate venous access.
• Karnofsky performance status \>= 60 within 28 days prior to entry.
• Ability and willingness of participant or legal guardian/representative to provide informed consent.

You may not qualify if:

• 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.
• Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to entry.
• 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.
• Oxygen saturation less than 90% and/or exercise desaturation greater than 4% within 14 days prior to study enrollment.
• Grade \>=3 peripheral neuropathy (PN) at entry.
• Breastfeeding.
• Receipt of ART for more than 42 days immediately prior to entry.
• Prior or current systemic or locally administered chemotherapy.
• Prior or current radiation therapy.
• Prior or current immunotherapy, e.g., interferon alfa.
• Corticosteroid use at doses above those given as replacement therapy for adrenal insufficiency within the last 30 days prior to study entry.
• Any immunomodulator, HIV vaccine, live attenuated vaccines, or other investigational therapy or investigational vaccine within 30 days prior to study entry.
• Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
• Active drug or alcohol use or dependence that would interfere with adherence to study requirements.
• Current or anticipated receipt of any of the prohibited medications listed in section 5.5.2 of the protocol.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• National Cancer Institute (NCI): collaborator
• National Institute of Dental and Craniofacial Research (NIDCR): collaborator
• AIDS Malignancy Consortium: collaborator

Study Sites (11)

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, 21045, Brazil

Location

Moi University International Clnical Trials Unit

Eldoret, 30100, Kenya

Location

KMRI / Walter Reed Project Clinical Research Center

Kericho, Kenya

Location

Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)

Kisumu, 40100, Kenya

Location

Univ. of Malawi, John Hopkins Project

Blantyre, Malawi

Location

Malawi CRS (12001)

Lilongwe, Malawi

Location

Family Clinical Research Unit (FAM-CUR) CRS (8950)

Cape Town, West Cape, 7505, South Africa

Location

Durban Adult HIV CRS (11201)

Durban, 4013 SF, South Africa

Location

University of Witwatersrand

Johannesburg, South Africa

Location

Uganda Cancer Institute ACTG CRS

Kampala, Uganda

Location

UZ-Parirenyatwa CRS (30313)

Harare, Zimbabwe

Location

Related Publications (3)

• 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.

  PMID: 2671281 BACKGROUND

• 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.

  PMID: 11773164 BACKGROUND

• 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.

  PMID: 32145827 RESULT

Related 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

MeSH Terms

Interventions

Etoposide; Bleomycin; Vincristine; Paclitaxel; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Glycopeptides; Glycoconjugates; Peptides; Amino Acids, Peptides, and Proteins; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Tenofovir; Organophosphonates; Organophosphorus Compounds; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Adenine; Purines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Margaret Borok-Williams, MD

  University of Zimbabwe

  STUDY CHAIR

• Susan E. Krown, MD

  AIDS Malignancy Consortium

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2011
• First Posted: September 15, 2011
• Study Start: October 1, 2013
• Primary Completion: March 13, 2018
• Study Completion: August 29, 2019
• Last Updated: October 20, 2021
• Results First Posted: April 8, 2019

Record last verified: 2021-09

Locations

ZA (3); MA (2); BR (1); UG (1); KE (3); ZI (1)