Pomalidomide for Kaposi Sarcoma in People With or Without HIV

Study Overview
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Brief Summary
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Background: - Pomalidomide is a drug that can treat cancer through several mechanisms. It is taken by mouth (orally). Pomalidomide can help treat cancer by blocking certain factors that promote tumor growth or by stimulating the immune system to attack tumor cells. It also prevents the growth of new blood vessels that help cancer grow. Researchers want to see if pomalidomide can treat Kaposi sarcoma, a rare and potentially fatal skin cancer. Because Kaposi sarcoma may be associated with human immunodeficiency virus (HIV) infection, researchers want to test the drug in people with and without HIV infection. Objectives: - To see if pomalidomide is a safe and effective treatment for Kaposi sarcoma in people with or without HIV. Eligibility: Individuals at least 18 years of age who have Kaposi sarcoma. Participants may or may not have HIV infection. Design: Potential participants will be screened with a medical history and physical exam. Blood and saliva samples will be taken and a chest X-ray will be performed. A skin biopsy of a Kaposi sarcoma lesion may be performed if one has not already been done. Other imaging studies may be performed if needed. Participants will take pomalidomide capsules every day for 3 weeks, followed by a 1-week break. These 28 days are one cycle of treatment. Participants will have up six cycles of treatment, unless the lesions completely resolve sooner. If there are signs of improvement after six cycles but the lesions are not completely gone, up to another six cycles of treatment may be given. Treatment will be monitored with frequent blood tests and other studies including photograph and other imaging of skin lesions. Participants will have regular follow-up visits for 5 years after stopping treatment....

Detailed Description
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Background: Kaposi Sarcoma (KS) is an incurable, multicentric angioproliferative tumor that most frequently involves the skin. It is seen most frequently in people with human immunodeficiency virus (HIV) or other forms of immune compromise. Current therapies are limited by toxicities, including cumulative cardiotoxicity, while effective oral agents, agents deliverable in resource-limited settings, and agents deliverable long-term for relapsing disease are all lacking. Objective: The primary objective of this study is to: Assess the safety, tolerability and pharmacokinetics of pomalidomide in subjects with Kaposi sarcoma, whether HIV associated or not. Eligibility: Age greater than or equal to 18 years Measurable, pathologically confirmed KS Any HIV status; HIV-associated KS subjects must be receiving and able to comply with highly active antiretroviral therapy (HAART) and have achieved an HIV viral load <10,000 copies/mL Hematologic and biochemical parameters within prespecified limits at baseline Willing to use effective birth control, as defined in the full protocol For subjects enrolled in the anti-tumor activity assessment phase, if KS is HIV-associated it must be increasing despite HAART and HIV suppression for greater than or equal to 2 months, or stable despite HAART for greater than or equal to 3 months No symptomatic pulmonary or visceral KS No specific KS therapy within 4 weeks (6 weeks if that therapy was bevacizumab) Neither pregnant nor breast feeding Design: This is an open label single agent phase I/II study of pomalidomide in patients with KS. In the phase I portion, up to six subjects will initially be treated with pomalidomide 5mg daily for 21 days of a 28 day cycle. Subject to toxicity evaluation, this dosage may be deescalated to 3mg daily for 21 days of a 28 day cycle in a second cohort of up to six subjects. If either dose proves tolerable, the study will proceed to the phase II portion, and additional subjects to a goal of 15 HIV positive and 10 HIV negative subjects evaluable for response will be added at the highest tolerable dose to gain preliminary information on activity.

Official Title
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A Phase I/II Study of the Safety, Pharmacokinetics and Efficacy of Pomalidomide (CC-4047) in the Treatment of Kaposi Sarcoma in Individuals With or Without HIV

Conditions
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Kaposi Sarcoma, Sarcoma, Kaposi

Intervention / Treatment
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* Drug: Pomalidomide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age greater than or equal to 18 Years. Any human immunodeficiency virus (HIV) status. Kaposi sarcoma pathologically confirmed by Department of Pathology, Clinical Center, National Institutes of Health. At least five measurable Kaposi sarcoma (KS) lesions with no previous local radiation, surgical or intralesional cytotoxic therapy that would prevent response assessment for that lesion. Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2 Life expectancy greater than or equal to 6 months For patients with HIV-associated KS: Must be receiving, and adherent to, a highly active antiretroviral therapy (HAART) regimen consistent with current clinical guidelines. Must have been receiving HAART for at least one month. Must have achieved an HIV viral load (VL) <10,000 copies/mL. The following hematological parameters: Hemoglobin greater than or equal to 10 g/dL Platelets greater than or equal to 75,000 cells/mm(3) Absolute neutrophil count (ANC) greater than or equal to 1000 cells/mm(3) The following biochemical parameters: Estimated or measured creatinine clearance greater than or equal to 45mL/minute Serum alanine aminotransferase (ALT) less than or equal to 2.5 times upper limit of normal Serum aspartate aminotransferase (AST) less than or equal to 2.5 times upper limit of normal Bilirubin less than or equal to 1.5 times upper limit of normal unless the patient is receiving protease inhibitor therapy (e.g., indinavir, ritonavir, nelfinavir, or atazanavir) known to be associated with increased bilirubin, in which case total bilirubin less than or equal to 7.5 mg/dL with direct fraction less than or equal to 0.7 mg/dL. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 14 days prior to and again within 24 hours before starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, and also All study participants must agree to be registered into the mandatory POMALYST Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of the POMALYST REMS program. Females of reproductive potential must be willing to adhere to the scheduled pregnancy testing as required in the POMALYST REMS program. Able to take aspirin 81mg daily or if intolerant of aspirin, able to take a substitute thromboprophylaxis such as low molecular weight heparin at a thromboprophylactic dose (such as enoxaparin 0.5mg/kg once daily). Willing and able to give informed consent. For subjects with HIV-associated entered after a tolerable dose has been determined, KS lesions must be either: Increasing despite HAART and HIV suppression below the limit of detection (48 copies/mL) in the two months prior to screening or Stable despite HAART for at least three months. Stable disease must be symptomatic (examples of symptomatic disease include disease associated with pain, edema, psychological distress and/or social withdrawal). This is to gain preliminary information about pomalidomide activity without confounding due to HAART initiation. EXCLUSION CRITERIA: Symptomatic pulmonary KS. Symptomatic visceral KS (except for non-ulcerating disease restricted to the oral cavity). Specific KS therapy, including cytotoxic chemotherapy but not including HAART, within the past 4 weeks (6 weeks if the therapy was bevacizumab). Use of other anticancer treatments or agents within the past 4 weeks (6 weeks if the therapy was a monoclonal antibody). History of malignant tumors other than KS, unless: In complete remission for greater than or equal to 1 year from the time response was first documented or Completely resected basal cell carcinoma or In situ squamous cell carcinoma of the cervix or anus. History of infection meeting any of the following criteria: Any infection that would be scored as grade 4 by Common Terminology Criteria for Adverse Events (CTCAE) that occurred within six weeks of study screening. Any infection that would be scored as grade 3 by CTCAE that occurred within two weeks of study screening. History of fungal and mycobacterial infections, unless at least six weeks has passed since the completion of induction antimicrobial therapy. Patients may be receiving consolidation therapy for infections of these types. Any abnormality that would be scored as a greater than or equal to grade 3 toxicity by CTCAE, except: Obesity is not considered an abnormality for the purposes of eligibility assessment unless in the opinion of the Principal Investigator or Lead Associate Investigator its clinical consequences in a particular subject places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study. Lymphopenia Asymptomatic hyperuricemia, hypophosphatemia, or creatine kinase (CK) Elevations Direct manifestations of KS Direct manifestations of HIV infection, except for neurologic or cardiac manifestations Direct manifestations of HIV therapy, except for neurologic or cardiac manifestations. History of venous or arterial thromboembolism, unless: Line-related thrombosis without embolus occurring greater than or equal to 1 year prior to screening. Complications resulting from atherosclerotic coronary artery disease, peripheral vascular disease, or cerebrovascular disease (including infarction) are not considered exclusion criteria unless in the opinion of the Principal Investigator or Lead Associate Investigator their clinical consequences in a particular subject places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study Known drug-related, inherited, or acquired procoagulant disorder including prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein S deficiency and antiphospholipid syndrome but not including heterozygosity for the Factor V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria for the antiphospholipid syndrome. Pregnancy. Breast feeding (if lactating, must agree not to breast feed while taking pomalidomide). Prior therapy with pomalidomide. Known hypersensitivity to thalidomide, lenalidomide or pomalidomide. including prior development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide or pomalidomide. Any condition, including the presence of laboratory abnormalities, which in the opinion of the Principal Investigator or Lead Associate Investigator places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Pomalidomide 5mg Daily<br>Up to six subjects will initially be treated with for 21 days of a 28 day cycle | Drug: Pomalidomide<br>* 5 mg by mouth (p.o.) for 21 of 28 days<br>* Other names: POMALYST®;|
| Experimental: Phase 2 Pomalidomide 5mg Daily<br>15 human immunodeficiency virus (HIV) positive and 10 HIV negative subjects evaluable for response will be treated with Pomalidomide 5mg daily for 21 days of a 28 day cycle | Drug: Pomalidomide<br>* 5 mg by mouth (p.o.) for 21 of 28 days<br>* Other names: POMALYST®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grades 1-4 Adverse Events That Are Possibly, Probably, and/or Definitely Attributed to Pomalidomide | Adverse events (AE's) that are possibly, probably, and/or definitely attributed to pomalidomide were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. | During each cycle and 4 weeks after completing therapy, with any continuing AE's observed until resolution, approximately 124 months and 1 day. | 
| Progression Free Survival (PFS) | PFS is defined as time from day 1 of pomalidomide therapy until progression requiring a change in therapy, estimated using the Kaplan-Meier method. Progression was assessed using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group criteria. Progressive disease (PD) involved a 25% or greater increase in total lesions, nodular lesion, or area of the five indicator lesions. | time from day 1 of pomalidomide therapy until progression requiring a change in therapy, an average of 9.97 months | 
| Maximal Plasma Concentration (Cmax) of Pomalidomide | Plasma concentrations of pomalidomide were assayed using high-performance liquid chromatography with fluorescence detection with a lower limit of quantitation of 1 ng/mL and were recorded as observed values. A non-compartmental analysis was used to calculate plasma pharmacokinetic parameters (Pharsight, Mountain View, California). | At pre-dose, 1, 2, 3, 4, 6, and 8 hours after dose on Cycle 1 Day 1, and pre-dose, 1, 2, 3, 4, 6, 8, and 24 hours after dose on Cycle 1 Day 15. | 
| Time to Maximum Observed Serum Concentration of Pomalidomide (Cmax) | Time to maximum observed serum concentration of Pomalidomide was reported. | At pre-dose, 1, 2, 3, 4, 6, and 8 hours after dose on Cycle 1 Day 1, and pre-dose, 1, 2, 3, 4, 6, 8, and 24 hours after dose on Cycle 1 Day 15. | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) to the Last Timepoint (AUCLast) | Area under the plasma concentration versus time curve (AUC) was calculated using the log-linear trapezoidal method. The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | At pre-dose, 1, 2, 3, 4, 6, and 8 hours after dose on Cycle 1 Day 1, and pre-dose, 1, 2, 3, 4, 6, 8, and 24 hours after dose on Cycle 1 Day 15. | 
| Area Under the Curve Extrapolated to Infinity (AUCinf) | AUC is a measure of the serum concentration of Pomalidomide over time. It is used to characterize drug absorption. The AUC extrapolated to infinity was used, unless the percent extrapolated exceeded 25% in which case AUC to the last quantifiable time point (AUCLast) was used. The steady-state exposure on Day 15 of cycle 1 was calculated using AUCLast. | At pre-dose, 1, 2, 3, 4, 6, and 8 hours after dose on Cycle 1 Day 1, and pre-dose, 1, 2, 3, 4, 6, 8, and 24 hours after dose on Cycle 1 Day 15. | 
| Half-Life of Pomalidomide | Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half. | At pre-dose, 1, 2, 3, 4, 6, and 8 hours after dose on Cycle 1 Day 1, and pre-dose, 1, 2, 3, 4, 6, 8, and 24 hours after dose on Cycle 1 Day 15. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Effect of a Second Course of Pomalidomide | Antitumor effect of pomalidomide was assessed at the established tolerated dose after a second course of pomalidomide. Kaposi sarcoma responses were assessed using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group criteria. Complete Response (CR) required clinical resolution of all lesions and tumor-associated phenomenon with biopsy confirmation. Clinical Complete Response (cCR) is resolution of all lesions except for some residual pigmentation but who did not have a biopsy of a representative pigmented area. Partial Response (PR) required ≥ 50% decrease in the number of lesions and/or sum product of the diameters of marker lesions and/or nodularity of lesions, and no new lesions in previously uninvolved areas or criteria. Stable Disease (SD) was assessed for all participants who did not meet criteria doe CR, PR, or PD. And progressive disease (PD) involved a 25% or greater increase in total lesions, nodular lesion, or area of the five indicator lesions. | After completion of 2 cycles of therapy up to 48 weeks after the start of the second course of Pomalidomide | 
| Antitumor Effect of a First Course of Pomalidomide | Antitumor effect of pomalidomide was assessed at the established tolerated dose after a first course of pomalidomide. Kaposi sarcoma responses were assessed using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group criteria. Complete Response (CR) required clinical resolution of all lesions and tumor-associated phenomenon with biopsy confirmation. Clinical Complete Response (cCR) is resolution of all lesions except for some residual pigmentation but who did not have a biopsy of a representative pigmented area. Partial Response (PR) required ≥ 50% decrease in the number of lesions and/or sum product of the diameters of marker lesions and/or nodularity of lesions, and no new lesions in previously uninvolved areas or criteria. Stable Disease (SD) was assessed for all participants who did not meet criteria doe CR, PR, or PD. And progressive disease (PD) involved a 25% or greater increase in total lesions, nodular lesion, or area of the five indicator lesions. | After completion of 2 cycles of therapy up to 48 weeks | 
| Self-Reported Health-Related Quality of Life (HRQL) Instrument: Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) | Changes in quality of life in participants receiving pomalidomide. HRQL was analyzed using a mixed-model repeated-measures analysis for FAHI and the marginal homogeneity test for Kaposi sarcoma-specific questions such as physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB), and cognitive functioning (CF). The range of possible scores for each subscale was as follows: PWB and EWB, 0 to 40; FGWB, 0 to 52; SWB, 0 to 32; CF, 0 to 12. The total FAHI score, with possible scores ranging from 0 to 176, was calculated as the sum of all five subscale values, with higher scores indicating better results. Questionnaires completed at early withdrawal visits were not included in the analyses. | Baseline, after 3 months of therapy, and after completion of therapy, up to 48 weeks | 
| Number of Participants Who Responded to Each Question on the Self-Reported Health-Related Quality of Life (HRQL): Kaposi Sarcoma (KS) - Specific Questions | The number of participants responding to each question with the indicated responses is shown. Changes in quality of life in participants receiving pomalidomide. HRQL was analyzed using a mixed-model repeated-measures analysis and the marginal homogeneity test for Kaposi sarcoma-specific questions. Three supplemental questions addressing pain, swelling, and satisfaction with physical appearance was used to collect quality of life data. | Baseline, timepoint 1: after 3 months of therapy, and timepoint 2: 1 month after completion of therapy | 
| Change in Cytokines From Baseline to 4 Weeks, Baseline to 8 Weeks and End of Treatment | Cytokines were evaluated using MSD 96-Well Multiarray Proinflammatory 7-plex assay (MesoScale Discovery). | Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment | 
| Change in Immune Cytokines Cluster of Differentiation 4 (CD4), Cluster of Differentiation 8 (CD8) and Cluster of Differentiation 19 (CD19) Among Participants With and/or Without Human Immunodeficiency Virus (HIV) | Fluorescence activated cell sorting. | Baseline to 4 weeks, baseline to 8 weeks, and baseline to end of treatment | 
| Change Between Timepoints Baseline to 4 Weeks, Baseline to 8 Weeks, and Baseline to End of Treatment in Kaposi Sarcoma-Associated Herpesvirus (KSHV) Viral Load | KSHV viral load in peripheral blood mononuclear cells was assessed by modifying a sandwich enzyme-linked immunosorbent assay (ELISA). Viral load testing may provide useful information on the occurrence of KSHV replication. Undetectable levels is good. | Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment | 
| Human Immunodeficiency Virus (HIV) Viral Load | HIV viral load in peripheral blood mononuclear cells was assessed by quantitative real-time polymerase chain reaction (PCR). The lower limit of detection for HIV viral load is <50 copies mL. | Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment | 
| Percentage of Participants Who Responded to Each Question on the Self-Reported Health-Related Quality of Life (HRQL): Kaposi Sarcoma (KS) - Specific Questions | The percentage of participants responding to each question with the indicated responses is shown. Changes in quality of life in participants receiving pomalidomide. HRQL was analyzed using a mixed-model repeated-measures analysis and the marginal homogeneity test for Kaposi sarcoma-specific questions. Three supplemental questions addressing pain, swelling, and satisfaction with physical appearance was used to collect quality of life data. | Baseline, timepoint 1: after 3 months of therapy, and timepoint 2: 1 month after completion of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Herpesvirus-8/HHV8, Immune Modulation, CC-4047, IMiD, Kaposi Sarcoma