Pomalidomide for Kaposi Sarcoma in People With or Without HIV

Background:

Kaposi Sarcoma (KS) is an incurable, multicentric angioproliferative tumor that most
frequently involves the skin. It is seen most frequently in people with 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
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.

- INCLUSION CRITERIA:

- Age greater than or equal to 18 Years.

- Any HIV status.

- Kaposi sarcoma pathologically confirmed by Department of Pathology, Clinical Center,
National Institutes of Health.

- At least five measurable KS lesions with no previous local radiation, surgical or
intralesional cytotoxic therapy that would prevent response

assessment for that lesion.

- 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 HAART regimen consistent with current
clinical guidelines.

- Must have been receiving HAART for at least one month.

- Must have achieved an HIV 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/mm3

- 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 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 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.

- Known 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.