Clinical trial NCT01495598: Pomalidomide for Kaposi Sarcoma in People With or Without HIV
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Kaposi Sarcoma
Sarcoma, Kaposi
Keywords: Human Herpesvirus-8/HHV8
Immune Modulation
CC-4047
IMiD
Kaposi Sarcoma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-12-20
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Number of Participants With Grades 1-4 Adverse Events That Are Possibly, Probably, and/or Definitely Attributed to Pomalidomide
timeFrame: During each cycle and 4 weeks after completing therapy, with any continuing AE's observed until resolution, approximately 124 months and 1 day.
measure: Progression Free Survival (PFS)
timeFrame: time from day 1 of pomalidomide therapy until progression requiring a change in therapy, an average of 9.97 months
measure: Maximal Plasma Concentration (Cmax) of Pomalidomide
timeFrame: 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.
measure: Time to Maximum Observed Serum Concentration of Pomalidomide (Cmax)
timeFrame: 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.
measure: Area Under the Plasma Concentration Versus Time Curve (AUC) to the Last Timepoint (AUCLast)
timeFrame: 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.
measure: Area Under the Curve Extrapolated to Infinity (AUCinf)
timeFrame: 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.
measure: Half-Life of Pomalidomide
timeFrame: 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 outcomes:
measure: Antitumor Effect of a Second Course of Pomalidomide
timeFrame: After completion of 2 cycles of therapy up to 48 weeks after the start of the second course of Pomalidomide
measure: Antitumor Effect of a First Course of Pomalidomide
timeFrame: After completion of 2 cycles of therapy up to 48 weeks
measure: Self-Reported Health-Related Quality of Life (HRQL) Instrument: Functional Assessment of Human Immunodeficiency Virus Infection (FAHI)
timeFrame: Baseline, after 3 months of therapy, and after completion of therapy, up to 48 weeks
measure: Number of Participants Who Responded to Each Question on the Self-Reported Health-Related Quality of Life (HRQL): Kaposi Sarcoma (KS) - Specific Questions
timeFrame: Baseline, timepoint 1: after 3 months of therapy, and timepoint 2: 1 month after completion of therapy
measure: Change in Cytokines From Baseline to 4 Weeks, Baseline to 8 Weeks and End of Treatment
timeFrame: Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment
measure: 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)
timeFrame: Baseline to 4 weeks, baseline to 8 weeks, and baseline to end of treatment
measure: 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
timeFrame: Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment
measure: Human Immunodeficiency Virus (HIV) Viral Load
timeFrame: Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment
measure: Percentage of Participants Who Responded to Each Question on the Self-Reported Health-Related Quality of Life (HRQL): Kaposi Sarcoma (KS) - Specific Questions
timeFrame: Baseline, timepoint 1: after 3 months of therapy, and timepoint 2: 1 month after completion of therapy
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: Date treatment consent signed to date off study, approximately 124 months and 1 day.
measure: Number of Dose-limiting Toxicities
timeFrame: First 8 weeks (2 cycles) of drug administration
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Robert Yarchoan, M.D.
role: PRINCIPAL_INVESTIGATOR
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citation: Polizzotto MN, Uldrick TS, Wyvill KM, Aleman K, Peer CJ, Bevans M, Sereti I, Maldarelli F, Whitby D, Marshall V, Goncalves PH, Khetani V, Figg WD, Steinberg SM, Zeldis JB, Yarchoan R. Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study. J Clin Oncol. 2016 Dec;34(34):4125-4131. doi: 10.1200/JCO.2016.69.3812. Epub 2016 Oct 31.
citation: Ramaswami R, Polizzotto MN, Lurain K, Wyvill KM, Widell A, George J, Goncalves P, Steinberg SM, Whitby D, Uldrick TS, Yarchoan R. Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection. Clin Cancer Res. 2022 Mar 1;28(5):840-850. doi: 10.1158/1078-0432.CCR-21-3364.