Pomalidomide for Kaposi Sarcoma in People With or Without HIV

Phase 1

Completed

Conditions: Kaposi Sarcoma
Sarcoma, Kaposi

Interventions: Drug: Pomalidomide

Registration Number: NCT01495598

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1 Pomalidomide 5mg Daily	Pomalidomide	Up to six subjects will initially be treated with for 21 days of a 28 day cycle
Phase 2 Pomalidomide 5mg Daily	Pomalidomide	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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grades 1-4 Adverse Events That Are Possibly, Probably, and/or Definitely Attributed to Pomalidomide	During each cycle and 4 weeks after completing therapy, with any continuing AE's observed until resolution, approximately 124 months and 1 day.	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.
Time to Maximum Observed Serum Concentration of Pomalidomide (Cmax)	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 was reported.
Half-Life of Pomalidomide	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.	Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Maximal Plasma Concentration (Cmax) of Pomalidomide	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.	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).
Area Under the Curve Extrapolated to Infinity (AUCinf)	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.	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.
Progression Free Survival (PFS)	time from day 1 of pomalidomide therapy until progression requiring a change in therapy, an average of 9.97 months	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.
Area Under the Plasma Concentration Versus Time Curve (AUC) to the Last Timepoint (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.	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.

Secondary Outcome Measures

Name	Time	Method
Antitumor Effect of a Second Course of Pomalidomide	After completion of 2 cycles of therapy up to 48 weeks after the start of the 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.
Percentage of Participants Who Responded to Each Question on the Self-Reported Health-Related Quality of Life (HRQL): Kaposi Sarcoma (KS) - Specific Questions	Baseline, timepoint 1: after 3 months of therapy, and timepoint 2: 1 month after completion of therapy	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.
Antitumor Effect of a First Course of Pomalidomide	After completion of 2 cycles of therapy up to 48 weeks	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.
Change in Cytokines From Baseline to 4 Weeks, Baseline to 8 Weeks and End of Treatment	Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment	Cytokines were evaluated using MSD 96-Well Multiarray Proinflammatory 7-plex assay (MesoScale Discovery).
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)	Baseline to 4 weeks, baseline to 8 weeks, and baseline to end of treatment	Fluorescence activated cell sorting.
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	Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment	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.
Human Immunodeficiency Virus (HIV) Viral Load	Baseline to 4 weeks, baseline to 8 weeks and baseline to end of treatment	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.
Self-Reported Health-Related Quality of Life (HRQL) Instrument: Functional Assessment of Human Immunodeficiency Virus Infection (FAHI)	Baseline, after 3 months of therapy, and after completion of therapy, up to 48 weeks	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.
Number of Participants Who Responded to Each Question on the Self-Reported Health-Related Quality of Life (HRQL): Kaposi Sarcoma (KS) - Specific Questions	Baseline, timepoint 1: after 3 months of therapy, and timepoint 2: 1 month after completion of therapy	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.