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

NCT ID: NCT01352117

Last Updated: 2019-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 192 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-18
• Study Completion Date: 2018-11-29

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.

Detailed Description

The study consisted of three steps. At the study Step 1 entry, the participants were randomized (1:1) to receive ART alone (Arm A) or ART with immediate ET (Arm B). Study participants in Arm A who experienced KS progression that was confirmed by the Independent Endpoint Review Committee (IERC) could receive etoposide (ET) in addition to ART by entering Step 2 between study weeks 8 and 80. The target sample size was 468, 234 per arm. Randomization was stratified by:

1. Screening CD4 cell count (<200 or ≥200 cells/mm^3) and

2. ART history (naïve or experienced).

The duration of Step 1 or Step 1 and 2 combined was 96 weeks. After 96 weeks on study, participants who received ET (Arm B participants and Arm A participants who entered Step 2) entered Step 3 for a total of 144 weeks of safety follow-up.

Step 1 visits occurred at screening, entry and weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 from study entry. Step 2 visits were scheduled at entry and weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 32, 40, 48, 60, 72, 84 from Step 2 entry until up to 96 weeks on study. The key evaluations included physical examination, clinical assessments, KS exam, CD4 cell count, HIV viral load, hematology, chemistry and pregnancy testing (for women of reproductive potential). Plasma, serum, peripheral blood mononuclear cells (PBMCs), KS tumor punch biopsy were be stored for use in future analyses. Participants also completed ET and ART adherence evaluations and quality of life questionnaires. Step 3 visits were scheduled every 24 weeks and were limited to safety evaluations including targeted physical exam, clinical assessments and hematology.

Study accrual terminated early, based on the Data and Safety Monitoring Board (DSMB) recommendation in March 2016. The participants in Steps 1 and 2 at that time were arranged to enter either Step 3 for safety follow-up after ET or, if they did not receive ET, to be taken off study.

Conditions

HIV-1 Infection; Kaposi's Sarcoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: ART alone or with delayed ET

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.

Group Type: ACTIVE_COMPARATOR

efavirenz/emtricitabine/tenofovir disoproxil fumarate

Intervention Type: DRUG

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

etoposide

Intervention Type: 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.

Arm B: ART with immediate ET

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.

Group Type: EXPERIMENTAL

efavirenz/emtricitabine/tenofovir disoproxil fumarate

Intervention Type: DRUG

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

etoposide

Intervention Type: 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.

Interventions

efavirenz/emtricitabine/tenofovir disoproxil fumarate

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

Intervention Type: DRUG

etoposide

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.

Intervention Type: DRUG

Other Intervention Names

Atripla®; EFV/FTC/TDF; VePesid®; ET

Eligibility Criteria

Inclusion Criteria

1. HIV-1 infection.

2. Biopsy diagnostic of KS at any time prior to study entry.

3. 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).

4. A minimum of 5 cutaneous marker lesions

5. Certain laboratory values obtained within 14 days prior to study entry.

6. For female participants of reproductive potential, a negative serum or urine pregnancy test performed within 7 days prior to study entry.

7. 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).

8. 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.

9. Ability to swallow oral medications.

10. Karnofsky performance score >= 60 within 30 days prior to entry.

11. Ability and willingness of participant or legal guardian/representative to provide informed consent.

12. Peripheral blood CD4+ lymphocyte cell count obtained within 30 days prior to study entry at a DAIDS-approved laboratory.

13. For treatment-experienced patients, the availability of an ART regimen that includes at least two ART drugs that in the opinion of the site investigator are expected to have activity based on historical genotypic testing (if available) and treatment history.

14. For participants who were to receive ART other than EFV/TDF/FTC, the availability of those ART components.

1. KS progression compared to study entry or best response with ART alone while on Step 1, between weeks 8 and 80.

2. Need for ET for treatment of KS progression, in the opinion of the site investigator, after confirmation of KS progression by the IERC.

3. Willingness to receive ET for treatment of KS progression.

4. For female participants of reproductive potential, a negative serum or urine pregnancy test performed within 7 days prior to initiating ET.

5. Karnofsky Performance Score >= 50.

6. Certain laboratory values obtained within 14 days prior to Step 2 entry.

7. Ability to swallow oral medications.

8. 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).

9. 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, 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.

1. Received at least one dose of ET (Arm B participants and Arm A participants who entered Step 2)

Exclusion Criteria

1. Any manifestation of KS which, in the opinion of the site investigator, requires immediate chemotherapy.

2. More than 14 days of ART after onset of KS within 6 months prior to study entry.

3. Biopsy proven KS during previous ART.

4. Breastfeeding.

5. Allergy/sensitivity to any study drug or its formulations.

6. Any prior systemic anti-neoplastic treatment for KS (including chemotherapy, biological therapy, immunotherapy or investigational therapy).

7. Any prior local treatment of cutaneous marker lesions unless there was evidence of a clear-cut progression of the lesion.

8. Receipt of any investigational therapy within 30 days prior to study entry.

9. Current or anticipated receipt of any of the prohibited medications indicated in the study protocol.

10. In the opinion of the site investigator, any psychological or social condition, or addictive disorder that would have precluded compliance with the protocol.

11. 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.

1. 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.

2. Current or anticipated receipt of any of the prohibited medications indicated in the study protocol.

3. Breastfeeding.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas B Campbell, M.D.

Role: STUDY_CHAIR

University of Colorado Hospital CRS

Mina C Hosseinipour, M.D.

Role: STUDY_CHAIR

University of North Carolina Lilongwe CRS

Locations

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, , Brazil

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

Kericho, , Kenya

College of Med. JHU CRS (30301)

Blantyre, , Malawi

University of North Carolina Lilongwe CRS (12001)

Lilongwe, , Malawi

San Miguel CRS

San Miguel, Lima region, Peru

Wits HIV CRS

Johannesburg, Gauteng, South Africa

Durban Adult HIV CRS (11201)

Durban, , South Africa

JCRC CRS

Kampala, , Uganda

Countries

Brazil; Kenya; Malawi; Peru; South Africa; Uganda

References

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).

Reference Type: 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

Reference Type: 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.

Reference Type: BACKGROUND

PMID: 2671281 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11773164 (View on PubMed)

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.

Reference Type: RESULT

PMID: 29365083 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37368929 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31520741 (View on PubMed)

Other Identifiers

1U01AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AMC 067

Identifier Type: OTHER

Identifier Source: secondary_id

ACTG A5264

Identifier Type: -

Identifier Source: org_study_id