Pomalidomide for Kaposi Sarcoma in People With or Without... | NCT01495598

ID	Type	Description	Link
12-C-0047

Description Module

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.

Label	Type	Description	Intervention Names
Phase 1 Pomalidomide 5mg Daily	Experimental	Up to six subjects will initially be treated with for 21 days of a 28 day cycle	Drug: Pomalidomide
Phase 2 Pomalidomide 5mg Daily	Experimental	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

Name	Type	Description	Arm Group Labels	Other Names
Pomalidomide	Drug	5 mg by mouth (p.o.) for 21 of 28 days	Phase 1 Pomalidomide 5mg Daily Phase 2 Pomalidomide 5mg Daily

Outcomes Module

Primary Outcomes

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.

Secondary Outcomes

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.

Other Outcomes

Measure	Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Eligibility Module

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.

PubMed Identifier	Type	Citation	Retractions
3132950	Background	Krown SE. AIDS-associated Kaposi's sarcoma: pathogenesis, clinical course and treatment. AIDS. 1988 Apr;2(2):71-80. No abstract available.
7997879	Background	Chang 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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Nov 19, 2021	Aug 8, 2022	Prot_SAP_000.pdf
ICF	No	No	Yes	Informed Consent Form	Nov 30, 2021	Aug 8, 2022	ICF_001.pdf

ID	Term
D006566	Herpesviridae Infections
D004266	DNA Virus Infections
D014777	Virus Diseases
D007239	Infections