Clinical trial NCT01276236: Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)
Official title: Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Kaposi's Sarcoma
Keywords: Kaposi's Sarcoma
Maraviroc
CCR5
HIV
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Pfizer
name: ViiV Healthcare
First posted: 2011-01-13
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With a Decrease in Kaposi's Sarcoma (KS) Total Surface Area
timeFrame: Up to 96 weeks
measure: Percent Change in KS Total Surface Area
timeFrame: Up to 96 weeks
measure: Change in Edema Grade
timeFrame: Up to 96 weeks
Secondary outcomes:
measure: Change in Kaposi's Sarcoma-associated Herpesvirus (KSHV) Viral Load
timeFrame: Up to 96 weeks
measure: Percent Change in CCR5 Levels on CD4+ T-Cells
timeFrame: Up to 96 weeks
measure: Percent Change in CCR5 Levels on CD8+ T-cells
timeFrame: Up to 96 weeks
measure: Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Positive (DR-CD38+) T-cells
timeFrame: Up to 96 weeks
measure: Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Negative (DR-CD38-) T-cells
timeFrame: Up to 96 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: San Francisco General Hospital, Clinical Trials Unit
state: California
Study officials:
affiliation: University of California, San Francisco; San Francisco General Hospital (SFGH)
name: Patrick Unemori, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco; San Francisco General Hospital (SFGH)
name: Toby Maurer, MD
role: PRINCIPAL_INVESTIGATOR
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