A Phase 2 interventional study of Maraviroc in Kaposi's Sarcoma, sponsored by University of California, San Francisco. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-03-05.
Sponsored by University of California, San Francisco · Phase 2, Interventional, and Treatment
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.
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.
162 studies on the registry are indexed under Sarcoma, Kaposi; 29 are open to participants now.
This study's enrollment of 13 is below the median of 32 across 114 interventional studies indexed under Sarcoma, Kaposi.
Browse Sarcoma, Kaposi studies →University of California, San Francisco is the lead sponsor of 2,132 studies on the registry; 375 are open to participants now.
Of its 262 completed or terminated interventional studies of FDA-regulated products, 196 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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.
Also known as: Selzentry(Celsentri outside US)
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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 96 weeks
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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to 96 weeks
| Milestone | Treatment Arm (Maraviroc) |
|---|---|
| Started | 13 |
| Week 36 visit | 13 |
| Week 56 visit | 9 |
| Week 76 visit | 8 |
| Completed | 7 |
| Not completed | 6 |
| Withdrew: Lack of efficacy | 2 |
| Withdrew: Withdrawal by subject | 4 |
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.
| Participants | Treatment Arm (Maraviroc) |
|---|---|
| Number of Participants With a Decrease in Kaposi's Sarcoma (KS) Total Surface Area | 11 |
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.
| percentage change | Treatment Arm (Maraviroc) |
|---|---|
| Percent Change in KS Total Surface Area | -28.1 ± 7.9 |
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.
| scores on a scale | Treatment Arm (Maraviroc) |
|---|---|
| Change in Edema Grade | -0.7 ± 0.3 |
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.
No measurements were reported for this outcome.
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
| percentage change | Treatment Arm (Maraviroc) |
|---|---|
| Percent Change in CCR5 Levels on CD4+ T-Cells | 22.8 ± 5.9 |
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
| percentage change | Treatment Arm (Maraviroc) |
|---|---|
| Percent Change in CCR5 Levels on CD8+ T-cells | 21.6 ± 3.5 |
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
| percentage change | Treatment Arm (Maraviroc) |
|---|---|
| Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Positive (DR-CD38+) T-cells | 89.7 ± 48.2 |
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
| percentage change | Treatment Arm (Maraviroc) |
|---|---|
| Percent Change in CD69 Expression in a Subset of Double Negative DR-CD38 Negative (DR-CD38-) T-cells | 50.5 ± 35.9 |
Collected over Up to 96 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treatment Arm (Maraviroc) | 0/13 (0%) | 0/13 (0%) | 12/13 (92.3%) |
| Event | Treatment Arm (Maraviroc) |
|---|---|
| FatigueGeneral disorders | 4/13 |
| CoughRespiratory, thoracic and mediastinal disorders | 3/13 |
| HeadacheNervous system disorders | 2/13 |
| DiarrheaGastrointestinal disorders | 2/13 |
| NauseaGastrointestinal disorders | 1/13 |
| Age, Continuous(years) | Treatment Arm (Maraviroc) |
|---|---|
| Mean | 51.5 ± 3.0 |
| Sex: Female, Male(Participants) | Treatment Arm (Maraviroc) |
|---|---|
| Female | 0 |
| Male | 13 |
| Ethnicity (NIH/OMB)(Participants) | Treatment Arm (Maraviroc) |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 13 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Treatment Arm (Maraviroc) |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 13 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Treatment Arm (Maraviroc) |
|---|---|
| United States | 13 |
| Mean duration of Human Immunodeficiency Virus (HIV) diagnosis(years) | Treatment Arm (Maraviroc) |
|---|---|
| Mean | 18.3 ± 2.5 |
| Mean duration of Kaposi's Sarcoma (KS) diagnosis(years) | Treatment Arm (Maraviroc) |
|---|---|
| Mean | 7.5 ± 2.4 |
| Mean cluster of differentiation 4 (CD4) count(cells in a cubic millimetre (cells/mm3)) | Treatment Arm (Maraviroc) |
|---|---|
| Mean | 578.3 ± 86.3 |
1 further baseline measures are reported on the registry.
Plan to share: No
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University of California, San Francisco