Clinical trial NCT01352117: Antiretroviral Therapy (ART) Alone or With Delayed Chemo Versus ART With Immediate Chemo for Limited AIDS-related Kaposi's Sarcoma
Official title: A Randomized Evaluation of Antiretroviral Therapy Alone or With Delayed Chemotherapy Versus Antiretroviral Therapy With Immediate Adjunctive Chemotherapy for Treatment of Limited Stage AIDS-KS in Resource-Limited Settings (REACT-KS) AMC 067
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Kaposi's Sarcoma
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-05-11
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Step 1: 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.

Step 2: Inclusion Criteria

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.

Step 3: Inclusion Criteria

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

Step 1: 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.

Step 2: Exclusion Criteria

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.

There are no exclusion criteria for Step 3.

Primary outcomes:
measure: Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry
timeFrame: Entry through Week 48.
Secondary outcomes:
measure: KS Progressive Disease at Week 48 Compared to Study Entry
timeFrame: Entry and Week 48
measure: KS Partial Response at Week 48 Compared to Study Entry
timeFrame: Entry and Week 48
measure: KS Complete Response at Week 48 Compared to Study Entry
timeFrame: Entry and Week 48
measure: KS Partial or Complete Response at Week 48 Compared to Study Entry
timeFrame: Entry and Week 48
measure: Premature Study Discontinuation by Week 48
timeFrame: Entry through Week 48
measure: Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry
timeFrame: Entry through Week 96.
measure: KS Progressive Disease at Week 96 Compared to Study Entry
timeFrame: Entry and Week 96
measure: KS Partial Response at Week 96 Compared to Study Entry
timeFrame: Entry and Week 96
measure: KS Complete Response at Week 96 Compared to Study Entry
timeFrame: Entry and Week 96
measure: KS Partial or Complete Response at Week 96 Compared to Study Entry
timeFrame: Entry and Week 96
measure: Premature Study Discontinuation by Week 96
timeFrame: Entry through Week 96
measure: Cumulative Incidence of Initial KS Progressive Disease by Week 96
timeFrame: From entry through 96 weeks
measure: Cumulative Incidence of Initial KS Partial or Complete Response by Week 96
timeFrame: From entry through 96 weeks
measure: Cumulative Incidence of Initial KS Partial Response by Week 96
timeFrame: From study treatment initiation to 96 weeks
measure: Cumulative Incidence of Initial KS Complete Response by Week 96
timeFrame: From study treatment initiation to 96 weeks
measure: Number of Participants With Grade 3 or Higher Adverse Events
timeFrame: From study treatment dispensation through up to Week 96, until long-term follow-up began in Step 3 or until study discontinuation.
measure: Cumulative Incidence of KS-IRIS
timeFrame: From study entry to Week 12
measure: Percentage of Participants With Etoposide Dose Modification
timeFrame: From ET dispensation to ET discontinuation (total duration of ET was up to 16 weeks)
measure: Percentage of Participants With HIV-1 RNA Suppression
timeFrame: Entry and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72.
measure: Percentage of Participants With ARV Dose Modification
timeFrame: From treatment dispensation to Week 96
measure: Change in log10 HIV-1 Plasma Viral Load From Entry
timeFrame: Entry and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72.
measure: Change in Peripheral Blood CD4+ Lymphocyte Cell Count
timeFrame: Screening and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72.
measure: Cumulative Incidence of KS Progressive Disease After Initiation of Delayed Etoposide in Arm A
timeFrame: From initiation of etoposide (Step 2 entry) to up to 84 weeks (end of Step 2)
measure: Cumulative Incidence of KS Response After Initiation of Delayed Etoposide in Arm A
timeFrame: From initiation of etoposide (Step 2 entry) to up to 84 weeks (end of Step 2)
Other outcomes:
Locations:
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (12101)
city: Kericho
country: Kenya
facility: Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)
city: Blantyre
country: Malawi
facility: College of Med. JHU CRS (30301)
city: Lilongwe
country: Malawi
facility: University of North Carolina Lilongwe CRS (12001)
city: San Miguel
country: Peru
facility: San Miguel CRS
state: Lima
city: Johannesburg
country: South Africa
facility: Wits HIV CRS
state: Gauteng
city: Durban
country: South Africa
facility: Durban Adult HIV CRS (11201)
city: Kampala
country: Uganda
facility: JCRC CRS
Study officials:
affiliation: University of Colorado Hospital CRS
name: Thomas B Campbell, M.D.
role: STUDY_CHAIR
affiliation: University of North Carolina Lilongwe CRS
name: Mina C Hosseinipour, M.D.
role: STUDY_CHAIR
References:
citation: 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).
citation: 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
citation: 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.
citation: 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.
citation: 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.
citation: 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.