Pomalidomide in Combination With Liposomal Doxorubicin in People With Advanced or Refractory Kaposi Sarcoma

Background:

• Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor that most frequently involves skin, but can also involve lymph nodes, lungs and gastrointestinal tract. It is most common in people with HIV or other forms of immune compromise. Patients with AIDS-associated KS have worse survival than HIV-infected patients without KS.
• Patients may present with advanced disease KS and/or concurrent KSHV-associated multicentric Castleman disease (MCD) or an IL-6 related KSHV-associated cytokine syndrome (KICS). Patients with the latter conditions have poor outcomes when treated with FDA-approved cytotoxic therapies used for KS, and novel approaches are needed.
• A Phase I/II Study demonstrated that pomalidomide 5 mg daily on days 1- 21 of a 28 Day Cycle was safe and tolerable in patients with KS with or without HIV. Increased CD4+ and CD8+ T-cell counts and KS regression were observed.
• Combination of pomalidomide with liposomal doxorubicin may offer a new approach for patients with advanced KS or KS and concurrent KSHV-associated MCD or KICS

Objectives:

• Evaluate the safety and tolerability of various dose combinations of pomalidomide and liposomal doxorubicin in two groups of patients: Group I) KS requiring systemic therapy; Group II) KS with concurrent KSHV-associated MCD or KICS
• To assess the pharmacokinetics (PK) of pomalidomide in combination with liposomal doxorubicin; and for patients with HIV in combination with antiretroviral therapy
• To preliminarily evaluate the antitumor effect of pomalidomide in combination with liposomal doxorubicin against Kaposi sarcoma.

Eligibility:

• Patients with biopsy proven (confirmed in the Laboratory of Pathology, CCR) Kaposi sarcoma (KS)
• Group I: KS requiring systemic therapy (no prior therapy required)
• T1 KS, KS on skin sufficiently widespread that it is not amenable to local therapy, or KS affecting quality of life due to local symptoms or psychological distress

OR

--KS patients with an inadequate response to pomalidomide (either progressive disease or stable disease after 4 months)

OR

• KS patients with an inadequate response to liposomal doxorubicin, paclitaxel, or other systemic chemotherapy (either progressive disease or stable disease after 6 cycles)
• Group I will exclude patients eligible for Group II (below).
• A wash out period off treatment of 3 weeks will be required, except in the case of patients with progressive, severe disease in which delay of treatment cannot be justified (i.e. symptomatic pulmonary KS) -Group II: KS in one of the following high-risk groups (no prior therapy required):
• Concurrent KSHV-associated multicentric Castleman disease (MCD)
• KSHV Inflammatory Cytokine Syndrome (KICS), including those also meeting clinical criteria for KS immune reconstitution syndrome (KS IRIS)
• Patients with primary effusion lymphoma or a large cell lymphoma arising in KSHV-associated MCD are excluded.
• At least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy that would prevent response assessment for that lesion; or other evaluable disease.
• ECOG Performance Status (PS): Group I: less than or equal to 2, Group II: less than or equal to 3, ECOG PS of 4 (with Karnofsky 20%) will be allowed in Group II only if symptoms due to pulmonary KS.
• Measurable disease by the criteria proposed by the AIDS Clinical Trials Group Oncology Committee (for KS).
• Patient or legal guardian must be willing to give informed consent.
• Patients can be HIV positive or negative.
• HAART for HIV+ patients.

Design:

• This is a Phase I study evaluating 2 groups of patients with KS. Patients will receive pomalidomide once a day, days 1-21 of a 28-day cycle, at the various dose levels combined with liposomal doxorubicin IV day 1 of a 28-day cycle until optimal tumor response, unacceptable toxicity, or patient request to discontinue
• Patients with HIV will be prescribed HAART.
• All patients will receive thromboprophylaxis, generally with aspirin 81 mg tablet daily.
• The study will proceed to an antitumor activity phase to assess in a preliminary manner the response of Group I patients to a fixed dose of pomalidomide and liposomal doxorubicin. Up to 30 subjects (HIV positive or negative) evaluable for response will be treated at the highest tolerable combination of pomalidomide and liposomal doxorubicin (determined to be dose level 3: pomalidomide 4mg in combination with 20mg/m^2 liposomal doxorubicin) to gain preliminary information on antitumor activity in an expansion cohort. Based on the observation of positive results in the initial dose expansion of 14 patients evaluated in the expansion cohort, a total of 30 patients will be allowed to be included in this cohort in order to gain additional safety information as well as to improve the precision of the estimate of the response rate in Group I patients.
• The study will also include an antitumor activity phase to assess in a preliminary manner the response of Group II patients to a fixed dose of pomalidomide and liposomal doxorubicin. Up to 10 total patients (HIV positive or negative) evaluable for response will be treated at the highest tolerated dose of pomalidomide for this population (determined to be dose level, 2mg in combination with 20mg/m2 liposomal doxorubicin) to gain preliminary information on KS that occurs concurrently with KSHV-MCD or KICS.
• This study will also evaluate the characteristics of 18fluoro-thymidine (FLT) positron emission tomography (PET) in patients with KS and concurrent KSHV-associated MCD or KICS, and correlate with markers of KSHV-lytic activation.