Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
Pfizer
ViiV Healthcare
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01276236
First received: December 20, 2010
Last updated: May 16, 2013
Last verified: May 2013
  Purpose

The purpose of this study is to determine whether Maraviroc is effective in the treatment of Kaposi's Sarcoma (KS), when it does not remit with standard antiretroviral drug therapy.


Condition Intervention
Kaposi's Sarcoma
Drug: Maraviroc

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 1 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 1 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 2 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 2 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 4 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 4 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 8 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 8 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 16 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 16 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 36 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 36 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 56 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 56 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 76 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 76 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.

  • Change in Kaposi's Sarcoma Lesion Burden between Baseline and Week 96 [ Time Frame: Evaluations of the lesions will occur at baseline (week 0) and at week 96 ] [ Designated as safety issue: No ]
    The subjects' Kaposi's sarcoma related lesions will be evaluated during each visit for an increase or decrease in the number of lesions and whether the quality of the lesions show improvement or worsening of the condition.


Secondary Outcome Measures:
  • Effects of Maraviroc on CCR5 and KSHV levels in lesional skin. [ Time Frame: Week 0 (baseline), and week 96 or at the end of the therapy if it is discontinued early. ] [ Designated as safety issue: No ]
    A biopsy will be taken from the subjects' lesions at baseline and at the end of the study to determine whether there has been a change in CCR5 receptor levels or KSHV levels.

  • Change in CD4 count, and HIV viral load with Maraviroc from Baseline to Week 4 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 4. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in CD4 count or HIV viral load.

  • Change in CD4 count, and HIV viral load with Maraviroc from Baseline to Week 16 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 16. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in CD4 count or HIV viral load.

  • Change in CD4 count, and HIV viral load with Maraviroc from Baseline to Week 36 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 36. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in CD4 count or HIV viral load.

  • Change in CD4 count, and HIV viral load with Maraviroc from Baseline to Week 56 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 56. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in CD4 count or HIV viral load.

  • Change in CD4 count, and HIV viral load with Maraviroc from Baseline to Week 76 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 76. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in CD4 count or HIV viral load.

  • Change in CD4 count, and HIV viral load with Maraviroc from Baseline to Week 96 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 96. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in CD4 count or HIV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 1 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 1. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 2 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 2. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 4 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 4. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 16 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 16. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 36 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 36. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 56 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 56. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 76 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 76. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects on KSHV Viral Load with Maraviroc treatment from Baseline to Week 96 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline) and 96. ] [ Designated as safety issue: No ]
    Blood and saliva samples will be obtained from the subjects throughout the study at different points to assess if there are any changes in KSHV viral load.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 1 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 1. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 2 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 2. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 4 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 4. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 16 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 16. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 36 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 36. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 56 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 56. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 76 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 76. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Effects of Maraviroc on CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells from Baseline to Week 96 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 96. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in CCR5 receptor expression in T and B lymphocytes, monocytes, and natural killer cells.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 1 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 1. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 2 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 2. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 4 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 4. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 16 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 16. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 36 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 36. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 56 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 56. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 76 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 76. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.

  • Changes in T Cell activation and exhaustion with Maraviroc treatment between Baseline and Week 96 [ Time Frame: Data will be collected on this measure during the subjects' visits on Weeks 0 (baseline), and 96. ] [ Designated as safety issue: No ]
    Blood samples will be obtained from the subjects throughout the study and cryopreserved to assess if there are any changes in T cell activation and exhaustion.


Estimated Enrollment: 10
Study Start Date: February 2011
Estimated Study Completion Date: September 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment Arm (single-arm study)
The subjects in this arm will receive Maraviroc as treatment, while continuing their current antiretroviral medication regimen.
Drug: Maraviroc

FDA Recommended dosing will be used in this study. Subjects on an efavirenz or etravirine-based regimen will be dosed at 600 mg orally, twice per day, for 96 weeks.

Subjects on a ritonavir-boosted protease inhibitor based regimen (except for tipranavir/ritonavir) will be dosed at 150 mg orally, twice per day, for 96 weeks.

Subjects that are on regimens that do not include etravirine, efavirenz, or ritonavir will be dosed at 300mg orally, twice per day, for 96 weeks. These doses are based on the recommendations from the company based on drug-drug interactions.

Other Name: Selzentry(Celsentri outside US)

  Hide Detailed Description

Detailed Description:

Although the advent of antiretroviral therapy (ART) may have greatly decreased the incidence of Kaposi's Sarcoma (KS) in resource rich settings, KS continues to be the most prevalent AIDS-defining malignancy in the world and carries with it significant morbidity and mortality[1]. Indeed, in a recent epidemiological study examining cancers in Kampala, Uganda, KS was found to be second only to prostate cancer in terms of incidence rates[2].

There is growing evidence that CCR5 may be involved in the pathogenesis of KS. Kaposi's Sarcoma-associated Herpes Virus (KSHV), an agent found as necessary for KS pathogenesis [10, 11], encodes viral macrophage inflammatory proteins or vMIP [7-9]. vMIP-I and vMIP-II have been found to be ligands for chemokine receptors, and in particular the CCR5 receptor [5, 6], suggesting a potential role in the inflammatory process needed for KS pathogenesis. Further, vMIP-I induces Ca(2+) mobilization in monocytes expressing CCR5, suggesting an agonistic relationship between vMIP-I and the CCR5 receptor [4]. In addition, vMIP has been found to be proangiogenic when expressed in endothelial cells, a key feature of KS tumor survival [12]. As well, CCR5 has been found to be significantly increased in T cells populations of KS patients (from a preliminary study), and in 2 double-blind, placebo-controlled phase 3 studies in which a total of 1049 patients received the randomly assigned drug MVC, there was a trend revealing a lower incidence of KS in MVC arms vs placebo (0.36% vs 1.43%) [3]. This agonistic binding relationship between protein vMIP and CCR5, the proangiogenic activity associated with vMIP, the increased expression of CCR5 in KS, and trend towards lower incidence of KS when patients are taking MVC, suggest CCR5 may play an important role in KS pathogenesis. This involvement of CCR5 in KS pathogenesis implies that MVC may function as a potential therapeutic for KS. To date, there have been no studies examining the effect of MVC on KS.

There is a need for therapeutic development for KS. Standard of care for KS involves initiation or optimization of antiretroviral therapy. A significant proportion of KS cases do not respond to ART alone, with non-response rates ranging from 25-55%, with response times averaging 9 or more months depending on which patient series is identified [13, 14]. In severe or in cases of KS unresponsive to ART, standard of care involves systemic chemotherapy with liposomal doxorubicin [15], which is not without adverse reactions. Adverse reactions to liposomal doxorubicin include cardiac toxicity, nausea, vomiting, diarrhea, abdominal pain, fatigue, and patients may require pre-regime tests of varying costs, along with resources and time needed for intravenous infusion [16]. Nonresponse rates for liposomal doxorubicin hover around 20% [15, 17]. Focal cases may be more amenable to radiation therapy or intralesional velban [18, 19]. However, radiation and intralesional therapies are limited to focal sites, require monitored visits and specialized care, can be given only in limited amounts, and carry various adverse effects [18, 19]. With these nonresponse rates, potential adverse reactions, and resources and time needed for therapeutic delivery, there are clear benefits proferred by an effective oral therapy requiring minimal monitoring, as is the case with MVC.

Maraviroc (MVC) is a member of a new class of antiretroviral compounds known as small molecule CCR5 antagonists that block R5 HIV entry into CD4 cells. Maraviroc has demonstrated selective and reversible binding to CCR5, as well as potent antiviral activity in vitro against a wide range of laboratory adapted strains of R5 HIV from Clades A, B, C, D, E, F, G, J and O. Maraviroc also retains in vitro antiviral activity against clinical isolates resistant to the existing drug classes, but has no activity against viruses that enter CD4+ cells using CXCR4. In vitro studies with approved antiretroviral medications indicate that there is no evidence of antagonism with any members of the other four classes of antiretroviral medications; nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non- nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) or fusion inhibitors.

Although there is growing evidence that CCR5, a potential therapeutic target, is involved in KS pathogenesis [3-9], to date there are no studies examining the effects of a CCR5 inhibitor such as Maraviroc (MVC) on KS. As such, the aim of this study is to examine the effect of Maraviroc, a CCR5 inhibitor, on KS.

  Eligibility

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

Inclusion Criteria:

  • HIV-1 infected, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
  • Active biopsy confirmed KS
  • Screening plasma HIV RNA < 75 copies/mL
  • Patients have unremitting KS. Unremitting is defined as having active biopsy confirmed KS in spite of having had sustained HIV RNA < 75 copies/mL for 24 prior months. Isolated values that are detectable but < 500 copies will be allowed as long as the plasma HIV RNA levels before and after this time point are undetectable.
  • >90% adherence to therapy within the preceding 30 days, as determined by self-report.
  • Both male and female subjects are eligible. Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
  • Ability and willingness of subject or legal guardian/representative to provide informed consent

Exclusion Criteria:

  • Patients who are intending to modify antiretroviral therapy in the next 24 weeks for any reason.
  • Serious illness requiring hospitalization or parental antibiotics within preceding 3 months.
  • Concurrent treatment with immunomodulatory drugs or therapies, or exposure to any immunomodulatory drug or therapy in past 16 weeks.
  • Prior exposure to CCR5 inhibitors
  • Screening absolute neutrophil count <1,000 cells/mm3, platelet count <50,000 cells/mm3, hemoglobin < 8mg/dL, estimated creatinine clearance <40 mL/minute.
  • Elevated transaminases greater than 2.5 times the upper limit of normal.
  • Evidence of cirrhosis
  • Pregnant or breastfeeding women
  • Use of both Tenofovir and Didanosine in current antiretroviral therapy regimen.
  • Local therapy for any KS index lesion in preceding 60 days, unless lesion has clearly progressed with enlargement since the local therapy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01276236

Locations
United States, California
San Francisco General Hospital, Clinical Trials Unit
San Francisco, California, United States, 94110
Sponsors and Collaborators
University of California, San Francisco
Pfizer
ViiV Healthcare
Investigators
Principal Investigator: Patrick Unemori, MD University of California, San Francisco; San Francisco General Hospital (SFGH)
Principal Investigator: Toby Maurer, MD University of California, San Francisco; San Francisco General Hospital (SFGH)
  More Information

Publications:

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01276236     History of Changes
Other Study ID Numbers: 10-02850, 10-02850, 2860798
Study First Received: December 20, 2010
Last Updated: May 16, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
Kaposi's Sarcoma
Maraviroc
CCR5
HIV

Additional relevant MeSH terms:
Sarcoma, Kaposi
Sarcoma
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Vascular Tissue

ClinicalTrials.gov processed this record on April 16, 2014