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

March 3, 2021 updated by: University of California, San Francisco
The purpose of this pilot 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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. 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.

There is growing evidence that C-C chemokine receptor 5 (CCR5) may be involved in the pathogenesis of KS. Kaposi's Sarcoma-associated Herpes Virus (KSHV), an agent found as necessary for KS pathogenesis, encodes viral macrophage inflammatory proteins or vMIP. 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. In addition, vMIP has been found to be proangiogenic when expressed in endothelial cells, a key feature of KS tumor survival. 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%). 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. In severe or in cases of KS unresponsive to ART, standard of care involves systemic chemotherapy with liposomal doxorubicin, 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. Nonresponse rates for liposomal doxorubicin hover around 20%. Focal cases may be more amenable to radiation therapy or intralesional velban. 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. With these nonresponse rates, potential adverse reactions, and resources and time needed for therapeutic delivery, there are clear benefits proffered 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 cluster of differentiation 4 (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, 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.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94110
        • San Francisco General Hospital, Clinical Trials Unit

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment Arm (Maraviroc)
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 Names:
  • Selzentry(Celsentri outside US)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With a Decrease in Kaposi's Sarcoma (KS) Total Surface Area
Time Frame: Up to 96 weeks
To assess improvements in disease, up to five bi-dimensionally measurable cutaneous KS lesions were selected as marker lesions. The collective surface area of the marker lesions was evaluated over the course of the study for either an increase or decrease in the total surface area of lesions using the modified AIDS Clinical Trials Group (ACTG) Oncology Committee Staging Criteria.
Up to 96 weeks
Percent Change in KS Total Surface Area
Time Frame: Up to 96 weeks
Up to five bi-dimensionally measurable cutaneous KS lesions were selected as marker lesions and the the collective surface area of the marker lesions was evaluated over the course of the study. The percent decrease or increase in the total surface area of lesions was calculated from comparing measurements at baseline and through week 96, or at the last assessment if participant withdrew from the study prior to week 96.
Up to 96 weeks
Change in Edema Grade
Time Frame: Up to 96 weeks
The presence and extent of lower extremity edema was assessed and graded on a scale from 0 to 2 in patients with a higher grade indicating a greater level of edema using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS Adverse Events (AE) Grading Table), Version 1.0. Edema grade was recorded at baseline was compared with edema grades recorded at week 96, or at last assessment if participant withdrew from study prior to week 96 and an change in grade was calculated to examine whether or not a decrease in overall grade was observed. A negative value would indicate an overall decrease in the grade of lower extremity edema, and positive value would indicate an overall increase in lower extremity edema.
Up to 96 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Kaposi's Sarcoma-associated Herpesvirus (KSHV) Viral Load
Time Frame: Up to 96 weeks
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.
Up to 96 weeks
Percent Change in CCR5 Levels on CD4+ T-Cells
Time Frame: Up to 96 weeks
Maraviroc works by binding to the C-C chemokine receptor 5 (CCR5) on T-cells and thereby blocking viral entry into CD4+ T-cells. Peripheral blood mononuclear cells (PBMC) were obtained from blood draws at each visit and T-cell immunophenotyping was performed from the baseline visit and final follow-up visit to determine the percent change in CCR5 levels on CD4+ T-Cells
Up to 96 weeks
Percent Change in CCR5 Levels on CD8+ T-cells
Time Frame: Up to 96 weeks
Maraviroc works by binding to the C-C chemokine receptor 5 (CCR5) on T-cells and thereby blocking viral entry into CD8+ T-cells. Peripheral blood mononuclear cells (PBMC) were obtained from blood draws at each visit and T-cell immunophenotyping was performed from the baseline visit and final follow-up visit to determine the percent change in CCR5 levels on CD8+ T-Cells
Up to 96 weeks
Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Positive (DR-CD38+) T-cells
Time Frame: Up to 96 weeks
Peripheral blood mononuclear cells (PBMC) were obtained from blood draws at each visit and T-cell immunophenotyping was performed from the baseline visit and final follow-up visit to determine the percent change in CD69 expression in a subset of double negative DR-CD38 positive (DR-CD38+) T-cells
Up to 96 weeks
Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Negative (DR-CD38-) T-cells
Time Frame: Up to 96 weeks
Peripheral blood mononuclear cells (PBMC) were obtained from blood draws at each visit and T-cell immunophenotyping was performed from the baseline visit and final follow-up visit to determine the percent change in CD69 expression in a subset of double negative DR-CD38- T-cells
Up to 96 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

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)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 9, 2011

Primary Completion (Actual)

January 31, 2015

Study Completion (Actual)

April 30, 2015

Study Registration Dates

First Submitted

December 20, 2010

First Submitted That Met QC Criteria

January 11, 2011

First Posted (Estimate)

January 13, 2011

Study Record Updates

Last Update Posted (Actual)

March 5, 2021

Last Update Submitted That Met QC Criteria

March 3, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11351 (DAIDS ES)
  • 2860798 (Other Identifier: FDA IND Exemption Reference ID)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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