Antiretroviral Therapy (ART) Alone or With Delayed Chemo Versus ART With Immediate Chemo for Limited AIDS-related Kaposi's Sarcoma

NCT01352117 | Completed Phase 3 Results DMC

• 3 other identifiers: ACTG A52641U01AI068636AMC 067
• Study Type: interventional
• Target: 192
• Locations: 6 countries
• Sites: 8

Brief Summary

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

Conditions

HIV-1 Infection; Kaposi's Sarcoma

Outcome Measures

Primary Outcomes (1)

• Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry

  KS status is a composite, categorical outcome, ordered from worst to best as E1 (Failure: KS progression (PD), initiation of an alternate KS treatment, or no follow-up at Week 48 including death and missed visit), E2 (Stable: in follow-up at Week 48 with no KS PD nor response and without initiation of an alternate KS treatment) and E3 (Response: in follow-up at Week 48, with KS partial or complete response (PR or CR) and without initiation of an alternate KS treatment). Alternate KS treatment was defined as chemotherapy agent other than ET or other treatment triggered by worsening KS. KS outcome status (PR, stable, PR, CR) compared to study entry was evaluated at Week 48 based on 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). Data on initiation of alternate KS treatment, loss to follow-up and dea

  Entry through Week 48.

Secondary Outcomes (24)

• KS Progressive Disease at Week 48 Compared to Study Entry

  Entry and Week 48

• KS Partial Response at Week 48 Compared to Study Entry

  Entry and Week 48

• KS Complete Response at Week 48 Compared to Study Entry

  Entry and Week 48

• KS Partial or Complete Response at Week 48 Compared to Study Entry

  Entry and Week 48

• Premature Study Discontinuation by Week 48

  Entry through Week 48

Study Arms (2)

Arm A: ART alone or with delayed ET

ACTIVE COMPARATOR

Participants were prescribed ART (co-formulated efavirenz/emtricitabine/tenofovir disoproxil fumarate, EFV/FTC/TDF) for 96 weeks. Arm A participants who experienced KS progression on ART alone could receive ET in addition to EFV/FTC/TDF in Step 2 of the study.

Drug: efavirenz/emtricitabine/tenofovir disoproxil fumarate; Drug: etoposide

Arm B: ART with immediate ET

EXPERIMENTAL

Participants were prescribed ART (co-formulated efavirenz/emtricitabine/tenofovir disoproxil fumarate, EFV/FTC/TDF) for 96 weeks with immediate ET for up to 16 weeks.

Drug: efavirenz/emtricitabine/tenofovir disoproxil fumarate; Drug: etoposide

Interventions

efavirenz/emtricitabine/tenofovir disoproxil fumarate DRUG

600 mg efavirenz/200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally at night

Also known as: Atripla®, EFV/FTC/TDF

Arm A: ART alone or with delayed ET; Arm B: ART with immediate ET

etoposide DRUG

50 mg taken orally daily from days 1-7 of each 2-week cycle. For participants without PR or CR after two cycles of therapy and no toxicity greater than Grade 2, the dose of ET was escalated to 100 mg/day orally, days 1-7, every 2 weeks. A cycle could be delayed for a maximum of 14 days. ET could not be initiated prior to 7 days after the last dose in previous cycle. ET could be administered up to a maximum of eight cycles (2 cycles during dose titration and 6 cycles at maximum dose). Participants who could not tolerate escalation of the ET dose to 100 mg/day were treated for a maximum of six cycles.

Also known as: VePesid®, ET

Arm A: ART alone or with delayed ET; Arm B: ART with immediate ET

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.
• Limited stage KS defined as stage T0 and some presentations of stage T1. Stage T0 was confined to skin and/or lymph nodes and/or minimal oral disease defined as non-nodular KS confined to the palate. The following presentations of stage T1 KS were also eligible at the discretion of the site investigator:
• Tumor-associated edema limited to the area(s) of KS without significant functional impairment.
• Oral KS that consists of flat (non-nodular and non-ulcerating) lesions confined to the soft palate, hard palate, gums, and buccal mucosa.
• Asymptomatic gastrointestinal KS (i.e., no unexplained abdominal pain or gastrointestinal bleeding).
• A minimum of 5 cutaneous marker lesions
• Certain laboratory values obtained within 14 days prior to study entry.
• For female participants of reproductive potential, a negative serum or urine pregnancy test performed within 7 days prior to study entry.
• All participants must have agreed not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).
• Participants who are participating in sexual activity that could lead to pregnancy must have agreed to use a combination of TWO of the following methods- Condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, IUD, tubal ligation, and/or hormone-based contraception. For Etoposide, confirmation of lack of reproductive potential was required for all participants. More information on this criterion can be found in the study protocol.
• Ability to swallow oral medications.
• Karnofsky performance score \>= 60 within 30 days prior to entry.
• Ability and willingness of participant or legal guardian/representative to provide informed consent.
• Peripheral blood CD4+ lymphocyte cell count obtained within 30 days prior to study entry at a DAIDS-approved laboratory.

You may not qualify if:

• Any manifestation of KS which, in the opinion of the site investigator, requires immediate chemotherapy.
• More than 14 days of ART after onset of KS within 6 months prior to study entry.
• Biopsy proven KS during previous ART.
• Breastfeeding.
• Allergy/sensitivity to any study drug or its formulations.
• Any prior systemic anti-neoplastic treatment for KS (including chemotherapy, biological therapy, immunotherapy or investigational therapy).
• Any prior local treatment of cutaneous marker lesions unless there was evidence of a clear-cut progression of the lesion.
• Receipt of any investigational therapy within 30 days prior to study entry.
• Current or anticipated receipt of any of the prohibited medications indicated in the study protocol.
• In the opinion of the site investigator, any psychological or social condition, or addictive disorder that would have precluded compliance with the protocol.
• Chronic, acute, or recurrent infections that were serious, in the opinion of the site investigator, for which the participant had not completed at least 14 days of therapy prior to study entry and/or was not clinically stable.
• Chronic, acute, or recurrent infections that were serious, in the opinion of the site investigator, for which the participant had not completed at least 14 days of therapy prior to initiating ET and/or was not clinically stable.
• Current or anticipated receipt of any of the prohibited medications indicated in the study protocol.
• Breastfeeding.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (8)

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, 21045, Brazil

Location

Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)

Kericho, 20200, Kenya

Location

College of Med. JHU CRS (30301)

Blantyre, Malawi

Location

University of North Carolina Lilongwe CRS (12001)

Lilongwe, Malawi

Location

San Miguel CRS

San Miguel, Lima region, Peru

Location

Wits HIV CRS

Johannesburg, Gauteng, South Africa

Location

Durban Adult HIV CRS (11201)

Durban, 4013 SF, South Africa

Location

JCRC CRS

Kampala, Uganda

Location

Related Publications (7)

• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

  BACKGROUND

• Manual for Expedited Reporting of Adverse Events to DAID, Version 2.0, January 2010. http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual

  BACKGROUND

• 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

• Hosseinipour MC, Kang M, Krown SE, Bukuru A, Umbleja T, Martin JN, Orem J, Godfrey C, Hoagland B, Mwelase N, Langat D, Nyirenda M, MacRae J, Borok M, Samaneka W, Moses A, Mngqbisa R, Busakhala N, Martinez-Maza O, Ambinder R, Dittmer DP, Nokta M, Campbell TB; A5264/AMC-067 REACT-KS Team. As-Needed Vs Immediate Etoposide Chemotherapy in Combination With Antiretroviral Therapy for Mild-to-Moderate AIDS-Associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 Randomized Clinical Trial. Clin Infect Dis. 2018 Jul 2;67(2):251-260. doi: 10.1093/cid/ciy044.

  PMID: 29365083 RESULT

• Epeldegui M, Chang D, Lee J, Magpantay LI, Borok M, Bukuru A, Busakhala N, Godfrey C, Hosseinipour MC, Kang M, Kanyama C, Langat D, Mngqibisa R, Mwelase N, Nyirenda M, Samaneka W, Hoagland B, Campbell TB, Martinez-Maza O, Krown SE; A5264/AMC-067 team. Predictive Value of Serum Biomarkers for Response of Limited-Stage AIDS-Associated Kaposi Sarcoma to Antiretroviral Therapy With or Without Concomitant Chemotherapy in Resource-Limited Settings. J Acquir Immune Defic Syndr. 2023 Oct 1;94(2):165-173. doi: 10.1097/QAI.0000000000003236.

  PMID: 37368929 DERIVED

• Kang M, Grund B, Hunsberger S, Glidden D, Volberding P. Interim monitoring in a treatment strategy trial with a composite primary endpoint. Contemp Clin Trials. 2019 Nov;86:105846. doi: 10.1016/j.cct.2019.105846. Epub 2019 Sep 11.

  PMID: 31520741 DERIVED

MeSH Terms

Conditions

Sarcoma, Kaposi

Interventions

Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Etoposide

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue

Intervention Hierarchy (Ancestors)

Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

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

• Thomas B Campbell, M.D.

  University of Colorado Hospital CRS

  STUDY CHAIR

• Mina C Hosseinipour, M.D.

  University of North Carolina Lilongwe CRS

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• 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: March 3, 2011
• First Posted: May 11, 2011
• Study Start: November 18, 2011
• Primary Completion: March 16, 2016
• Study Completion: November 29, 2018
• Last Updated: November 14, 2019
• Results First Posted: July 31, 2017

Record last verified: 2019-11

Locations

MA (2); PE (1); BR (1); UG (1); KE (1); ZA (2)