Kaposi's SarcomaPhase 2NCT01276236
Effects of Maraviroc (MVC) on HIV-related Kaposi's Sarcoma (KS)
A Phase 2 study testing Maraviroc in people with Kaposi's Sarcoma, run by University of California, San Francisco at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Kaposi's Sarcoma
- What is being tested?
- Maraviroc
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- 9 Mar 2011to 30 Apr 2015
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
San Francisco General Hospital, Clinical Trials Unit
San Francisco, California, 94110
About this study
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.
Read the 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.
- Conditions
- Kaposi's Sarcoma
- Being tested
- Maraviroc
- Keywords
- Kaposi's Sarcoma, Maraviroc, CCR5, HIV
- Medical subject headings
- Sarcoma, Kaposi
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MaravirocDrug
Also called Selzentry(Celsentri outside US)
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.
| Study group | Role | What they receive |
|---|---|---|
| Treatment Arm (Maraviroc) | Experimental | The subjects in this arm will receive Maraviroc as treatment, while continuing their current antiretroviral medication regimen. Receives: Drug: Maraviroc |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With a Decrease in Kaposi's Sarcoma (KS) Total Surface Area
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.
Measured: Up to 96 weeks
Percent Change in KS Total Surface Area
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.
Measured: Up to 96 weeks
Change in Edema Grade
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.
Measured: Up to 96 weeks
Secondary outcomes (5)
Change in Kaposi's Sarcoma-associated Herpesvirus (KSHV) Viral Load
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.
Measured: Up to 96 weeks
Percent Change in CCR5 Levels on CD4+ T-Cells
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
Measured: Up to 96 weeks
Percent Change in CCR5 Levels on CD8+ T-cells
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
Measured: Up to 96 weeks
Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Positive (DR-CD38+) 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 CD69 expression in a subset of double negative DR-CD38 positive (DR-CD38+) T-cells
Measured: Up to 96 weeks
Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Negative (DR-CD38-) 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 CD69 expression in a subset of double negative DR-CD38- T-cells
Measured: Up to 96 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2011 (estimated)
- Study start9 Mar 2011
- Primary completion31 Jan 2015
- Study completion30 Apr 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Kaposi's SarcomaStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Pfizer, ViiV Healthcare
- Responsible party
- Sponsor
- Investigators
- Patrick Unemori, MD, Principal investigator, University of California, San Francisco; San Francisco General Hospital (SFGH)Toby Maurer, MD, Principal investigator, University of California, San Francisco; San Francisco General Hospital (SFGH)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01276236
- Sponsor's protocol ID
- 11351
- Other IDs
- 2860798
- Status last verified
- Mar 2021
- First submitted
- 20 Dec 2010
- Last updated
- 5 Mar 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, Biggar RJ; HIV/AIDS Cancer Match Study. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS. 2006 Aug 1;20(12):1645-54. doi: 10.1097/01.aids.0000238411.75324.59.
PubMed 16868446Parkin DM, Nambooze S, Wabwire-Mangen F, Wabinga HR. Changing cancer incidence in Kampala, Uganda, 1991-2006. Int J Cancer. 2010 Mar 1;126(5):1187-95. doi: 10.1002/ijc.24838.
PubMed 19688826Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, Nadler J, Clotet B, Karlsson A, Wohlfeiler M, Montana JB, McHale M, Sullivan J, Ridgway C, Felstead S, Dunne MW, van der Ryst E, Mayer H; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008 Oct 2;359(14):1429-41. doi: 10.1056/NEJMoa0803152.
PubMed 18832244Nakano K, Isegawa Y, Zou P, Tadagaki K, Inagi R, Yamanishi K. Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded vMIP-I and vMIP-II induce signal transduction and chemotaxis in monocytic cells. Arch Virol. 2003 May;148(5):871-90. doi: 10.1007/s00705-002-0971-7.
PubMed 12721796Navenot JM, Wang ZX, Trent JO, Murray JL, Hu QX, DeLeeuw L, Moore PS, Chang Y, Peiper SC. Molecular anatomy of CCR5 engagement by physiologic and viral chemokines and HIV-1 envelope glycoproteins: differences in primary structural requirements for RANTES, MIP-1 alpha, and vMIP-II Binding. J Mol Biol. 2001 Nov 9;313(5):1181-93. doi: 10.1006/jmbi.2001.5086.
PubMed 11700073Shao W, Fernandez E, Sachpatzidis A, Wilken J, Thompson DA, Schweitzer BI, Lolis E. CCR2 and CCR5 receptor-binding properties of herpesvirus-8 vMIP-II based on sequence analysis and its solution structure. Eur J Biochem. 2001 May;268(10):2948-59. doi: 10.1046/j.1432-1327.2001.02184.x.
PubMed 11358512Nicholas J, Ruvolo VR, Burns WH, Sandford G, Wan X, Ciufo D, Hendrickson SB, Guo HG, Hayward GS, Reitz MS. Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. Nat Med. 1997 Mar;3(3):287-92. doi: 10.1038/nm0397-287.
PubMed 9055855Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, Siani MA, Sasaki T, Williams TJ, Gray PW, Moore PS, Chang Y, Weiss RA. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science. 1997 Oct 10;278(5336):290-4. doi: 10.1126/science.278.5336.290.
PubMed 9323208Kledal TN, Rosenkilde MM, Coulin F, Simmons G, Johnsen AH, Alouani S, Power CA, Luttichau HR, Gerstoft J, Clapham PR, Clark-Lewis I, Wells TN, Schwartz TW. A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9. doi: 10.1126/science.277.5332.1656.
PubMed 9287217Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without HIV infection. N Engl J Med. 1995 May 4;332(18):1181-5. doi: 10.1056/NEJM199505043321801.
PubMed 7700310Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865-9. doi: 10.1126/science.7997879.
PubMed 7997879Cherqui S, Kingdon KM, Thorpe C, Kurian SM, Salomon DR. Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo. Mol Ther. 2007 Jul;15(7):1264-72. doi: 10.1038/sj.mt.6300183. Epub 2007 May 1.
PubMed 17505479Dupont C, Vasseur E, Beauchet A, Aegerter P, Berthe H, de Truchis P, Zucman D, Rouveix E, Saiag P. Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. CISIH 92. Centre d'information et de soins de l'immunodeficience humaine. AIDS. 2000 May 26;14(8):987-93. doi: 10.1097/00002030-200005260-00010.
PubMed 10853980Nguyen HQ, Magaret AS, Kitahata MM, Van Rompaey SE, Wald A, Casper C. Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: characterizing the predictors of clinical response. AIDS. 2008 May 11;22(8):937-45. doi: 10.1097/QAD.0b013e3282ff6275.
PubMed 18453853Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma. Oncologist. 2007 Jan;12(1):114-23. doi: 10.1634/theoncologist.12-1-114.
PubMed 17227906