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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by AIDS Clinical Trials Group
Sponsor:
Collaborators:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01435018
First received: September 14, 2011
Last updated: April 29, 2014
Last verified: April 2014
  Purpose

This study is being done to compare the safety and efficacy of three combination treatments for Kaposi's Sarcoma and AIDS.


Condition Intervention Phase
HIV-1 Infection
Drug: Coformulated EFV/FTC/TDF
Drug: Etoposide
Drug: Bleomycin and Vincristine (BV)
Drug: Doxorubicin HCL Liposome Injection (PLD)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Comparison of Three Regimens of Chemotherapy With Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Lack of clinical efficacy [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Clinical efficacy is defined as Kaposi's Sarcoma (KS) progression, death by week 48, entry into an additional step prior to week 48, or loss to follow-up.


Secondary Outcome Measures:
  • Death by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • KS progression by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • AIDS-defining event by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • HIV-1 RNA virologic failure by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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.

  • Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • KS tumor response by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Duration of KS tumor response [ Time Frame: Throughout the study (7 years) ] [ Designated as safety issue: No ]
  • KS progression, death, or AIDS defining event by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • KS progression, death, AIDS defining event, or virologic failure by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • KS progression, death, AIDS defining event, virologic failure, or KS-IRIS by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Time to KS progression or death [ Time Frame: Throughout the study (7 years) ] [ Designated as safety issue: No ]
  • Time to death [ Time Frame: Throughout the study (7 years) ] [ Designated as safety issue: No ]
  • Change in KS treatment by week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Chemotherapy-related toxicities and Adverse Events (AEs) (e.g., Peripheral Neuropathy (PN)) [ Time Frame: Throughout the study (7 years) ] [ Designated as safety issue: Yes ]
  • Changes in CD4+ lymphocyte cell count [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]
  • Adherence to therapy [ Time Frame: Weeks 3, 6, 9, 12, 15, 18, 21, 24 ] [ Designated as safety issue: No ]
  • Plasma KS-associated herpesvirus (KSHV) [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]
  • Salivary KSHV [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]
  • Peripheral blood mononuclear cell (PBMC) KSHV [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]
  • Presence of oral KS [ Time Frame: Throughout the study (7 years) ] [ Designated as safety issue: No ]
  • RNA levels for KSHV genes [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]
  • Peripheral neuropathy (PN) [ Time Frame: Througout the study (7 years) ] [ Designated as safety issue: Yes ]
  • Symptomatic peripheral neuropathy (SPN) [ Time Frame: Throughout the study (7 years) ] [ Designated as safety issue: Yes ]
  • Immunohistochemical evaluations of viral and cellular gene expression [ Time Frame: baseline, 24-48 hours after 2nd chemo-therapy cycle begins ] [ Designated as safety issue: No ]
  • Quality of life measures [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]
  • Cellular and humoral markers of immune function and activation [ Time Frame: Baseline, weeks 60, 120, 180, 240, 300, 360 ] [ Designated as safety issue: No ]

Estimated Enrollment: 706
Study Start Date: August 2013
Estimated Study Completion Date: June 2027
Estimated Primary Completion Date: June 2027 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1A: Coformulated EFV/FTC/TDF plus ET Drug: Coformulated EFV/FTC/TDF

The following ART regimens may be 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
Drug: Etoposide

Beginning on day one of the chemotherapy cycle, ET will be given orally in a dose of 50 mg twice daily for 7 consecutive days for the first cycle. If there is no Grade ≥ 2 toxicity attributable to ET after the first cycle, the dose will be 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 is no Grade ≥ 2 toxicity attributable to ET, the dose will be escalated to 100 mg twice daily for 7 days for the third and subsequent cycles.

Treatment with ET will continue for six cycles at the maximum dose achieved or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the A5263/AMC 066 CMC, has determined that alternative therapy is required, whichever occurs first.

Experimental: Arm 1B: Coformulated EFV/FTC/TDF plus BV Drug: Coformulated EFV/FTC/TDF

The following ART regimens may be 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
Drug: Bleomycin and Vincristine (BV)

BV will be administered on day one of each chemotherapy cycle.

Vincristine sulfate will be 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 will be followed by bleomycin as detailed below.

Bleomycin sulfate will be administered at a dose of 15 units/m2 over 10 minutes every 3 weeks.

Treatment with BV will continue for six cycles, or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the A5263/AMC 066 CMC, has determined that alternative therapy is required, whichever occurs first.

Experimental: Arm 1C: Coformulated EFV/FTC/TDF plus PLD Drug: Coformulated EFV/FTC/TDF

The following ART regimens may be 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
Drug: Doxorubicin HCL Liposome Injection (PLD)

Doxorubicin HCL liposome will be administered by IV infusion in 250 mL of 5% dextrose at a dose of 20 mg/ m2 body surface area every 3 weeks. The initial infusion rate should not exceed 1 mg/minute. The entire dose should be infused within 1 hour.

Treatment with doxorubicin HCL liposome will continue for six cycles, or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the A5263/AMC 066 CMC, has determined that alternative therapy is required, whichever occurs first.


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Step 1:

  • 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 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.
  • Cardiac ejection fraction of greater than or equal to 50% 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 at least 50 mIU/mL performed within 24 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 6 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.

Exclusion Criteria for Step 1:

  • Current chronic, acute, or recurrent serious infections for which the participant has not completed at least 14 days of therapy prior to Step 2 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 (CAT).
  • 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 28 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.
  • In the opinion of the investigator, any psychological or social condition, or addictive disorder that would preclude compliance with the protocol.
  • New York Heart Association Functional Class II-IV heart failure.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01435018

Locations
Brazil
Instituto de Pesquisa Clinica Evandro Chagas (12101) Recruiting
Rio de Janeiro, Brazil, 21045
Contact: Sandra W. Cardoso    552-125-644933    sandra.wagner@bol.com.br   
Principal Investigator: Beatriz Grinsztejn, MD, PhD         
Kenya
Moi University International Clnical Trials Unit Recruiting
Eldoret, Kenya, 30100
Contact: Kipruto Kirwa    254-53-20-60850    kkr380@yahoo.com   
KMRI / Walter Reed Project Clinical Research Center Recruiting
Kericho, Kenya
Contact: Hellen Ngeno    (254 52) 30686    hngeno@wrp-kch.org   
Malawi
Univ. of Malawi, John Hopkins Project Recruiting
Blantyre, Malawi
Contact: Sima TM Berendes, MPH    265-018-60132    sberendes@jhu.medcol.mw   
Principal Investigator: Johnstone Kumwenda, MD         
South Africa
Durban Adult HIV CRS (11201) Recruiting
Durban, South Africa, 4013 SF
Contact: Fawzia Williamson    27 31 260 4365    amodf1@nu.ac.za   
Principal Investigator: Umesh Gangaram Lalloo, MD, FRCP         
University of Witwatersrand Recruiting
Johannesburg, South Africa
Contact: Pauline S Vunandlala, BSc.    27 11 717 2810    idsyndicate@witshealth.co.za   
Uganda
Uganda Cancer Institute ACTG CRS Recruiting
Kampala, Uganda
Contact: Jackson Orem, MB, ChB, MMED    256-414540410      
Zimbabwe
UZ-Parirenyatwa CRS (30313) Recruiting
Harare, Zimbabwe
Contact: Jimijika Batani, B.A.    263-912272818    jbatani@uz-ucsf.co.zw   
Principal Investigator: James Hakim, MD, MSc, FRCP         
Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Margaret Borok-Williams, MD University of Zimbabwe
Study Chair: Susan E Krown, MD AIDS Malignancy Consortium
  More Information

No publications provided

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01435018     History of Changes
Other Study ID Numbers: ACTG A5263, 1U01AI068636, U01CA121947
Study First Received: September 14, 2011
Last Updated: April 29, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Bleomycin
Doxorubicin
Liposomal doxorubicin
Etoposide
Vincristine
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on August 28, 2014