Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma

Background:

• Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor, caused by Kaposi sarcoma-associated herpesvirus, that most frequently involves the skin, but may also involve lymph nodes, lungs, bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV-associated KS have worse survival than HIV-infected patients without KS.
• As it is a relapsing and remitting condition, patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS.
• Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins, including cyclin D kinases (CDKs), cyclins and retinoblastoma (Rb)-E2F signaling pathway.
• Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1.
• KS is an endothelial tumor, and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 microM.
• Published Phase I/II studies demonstrated that abemaciclib led to clinical responses in patients with metastatic breast cancer and other tumor types, such as glioblastoma, colorectal cancer, and melanoma.
• Abemaciclib is a therapy licensed for use in metastatic breast cancer both as monotherapy and in combination with other cancer therapies and the safety and efficacy profiles of this agent are very well known. We hypothesize that abemaciclib will be well-tolerated and participants with KS who have received prior therapies will derive some clinical benefit.

Objectives:

• Phase I: To assess the safety and tolerability of abemaciclib in participants with KS
• Phase II: To assess the overall response rate (ORR) of abemaciclib of all participants and by prior KS therapy (untreated KS vs. previously treated KS), and by Stage T1 KS

Eligibility:

• Age >=18 years
• Histologically confirmed Kaposi sarcoma (KS)
• KS requiring systemic therapy, with either no prior systemic therapy or history of at least 1 prior line of systemic therapy:
• 3 weeks from last chemotherapy
• 3 weeks from last immunotherapy
• Measurable disease consisting of at least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy to these measurable lesions; or, in the absence of measurable cutaneous lesions or less than 5 lesions, evaluable KS by RECIST criteria would be required.
• ECOG Performance Status (PS) <= 2
• Participant must be willing to give informed consent.
• Participants can be HIV positive or negative.
• Antiretroviral therapy (ART) for HIV+ participants
• Participants receiving other investigational agents will not be eligible.

Design:

• This is a Phase I/II study assessing the safety and efficacy of abemaciclib in participants with previously untreated or treated KS.
• In the Phase I portion of the study, up to 18 KS participants treated with prior therapy will be enrolled in a 3+3 dose de-escalation schema using 2 dose de-escalation levels.
• Following identification of an optimal dose and schedule, an expansion phase (Phase II) will be initiated. The Phase II will involve multiple groups: up to 25 previously untreated or treated KS participants will be enrolled; and, up to 23 KS participants with Stage T1 disease.
• Up to 25 additional KS participants who were previously treated with abemaciclib and discontinued the drug after reaching a plateau in clinical benefit-potentially entering an observation phase and/or discontinuing the study due to KS recurrence requiring alternative therapy-may be eligible for re-enrollment and retreatment with abemaciclib.
• Abemaciclib will be administered as an oral planned starting dose of 200 mg twice daily (in the morning and evening) without regard to meals. Abemaciclib will be given continuously; one cycle equals 28 days.
• Participants will receive therapy until optimal tumor response, unacceptable toxicity, the participant s request to discontinue therapy, or Principal Investigator (PI) decision. Participants with disease progression will have the option of an additional 12 weeks of treatment, if the PI feels that they are deriving clinical benefit.