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

NCT01276236

Last updated date
Study Location
San Francisco General Hospital, Clinical Trials Unit
San Francisco, California, 94110, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Kaposi's Sarcoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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

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Kaposi's SarcomaEffects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)
NCT01276236
  1. San Francisco, California
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)
Official Title  ICMJE Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kaposi's Sarcoma
Intervention  ICMJE 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)
Study Arms  ICMJE Experimental: Treatment Arm (single-arm study)
The subjects in this arm will receive Maraviroc as treatment, while continuing their current antiretroviral medication regimen.
Intervention: Drug: Maraviroc
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 11, 2011)
10
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 2015
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01276236
Other Study ID Numbers  ICMJE 10-02850
10-02850 ( Registry Identifier: IRB Number from UCSF CHR )
2860798 ( Other Identifier: FDA IND Exemption Reference ID )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE
  • Pfizer
  • ViiV Healthcare
Investigators  ICMJE
Principal Investigator:Patrick Unemori, MDUniversity of California, San Francisco; San Francisco General Hospital (SFGH)
Principal Investigator:Toby Maurer, MDUniversity of California, San Francisco; San Francisco General Hospital (SFGH)
PRS Account University of California, San Francisco
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP