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.

• INCLUSION CRITERIA:
• Participants must have Kaposi sarcoma confirmed by the Laboratory of Pathology, NCI
• Measurable disease as follows:

• All participants in Groups 1, 2a, or 2b or 4 should have at least five measurable cutaneous KS lesions per AIDS Clinical Trials Group Oncology Committee (ACTG) criteria with no previous local radiation, surgical or intralesional cytotoxic therapy that would prevent response assessment for that lesion and/or evaluable disease per RECIST criteria.
• Measurable disease by the criteria proposed by the AIDS Clinical Trials Group Oncology Committee.
• Participants in Group 3 must have Stage T1 KS with at least five measurable cutaneous KS lesions per ACTG criteria and/or evaluable disease per RECIST criteria.
• Participants may be HIV positive or negative.
• Participants must be able to swallow oral medications
• For all groups, participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count >1,000/mcL
• Platelets >75,000/mcL
• Hemoglobin >= 8gm/dL
• Total bilirubin <= 1.5 upper limit of normal unless the participant is receiving a protease inhibitor known to be associated with increased bilirubin (e.g. atazanavir), in which case total bilirubin <= 7.5 mg/dL with direct fraction <= 0.7
• AST/ALT <3 X institutional upper limit of normal
• Creatinine within normal institutional limits OR
• Creatinine clearance >45 mL/min/1.73 m^2 as estimated by either Cockroft-Gault or 24-hour urine collection for participants with creatinine levels above institutional normal
• Cardiac ejection fraction > 45% by echocardiogram
• Prior treatment as follows:

• Phase I: Participants must have received at least 1 prior line of systemic therapy for KS with either plateau in response, progressive disease, or inadequate response to treatment. Previous local therapy or radiation is not considered systemic therapy.
• Phase II:

• Group 2a: Individuals must have received at least 1 prior line of systemic therapy for KS with either plateau in response, relapsed disease, progressive disease, or inadequate response to treatment
• Group 2b: Individuals have not received prior systemic therapy for KS. Previous local therapy or radiation is not considered systemic therapy.
• Group 3: Evidence of Stage T1 KS with either a) edema or ulcerated KS and/or b) extensive oral KS and/or c) visceral KS involvement
• Group 4: Participants that received prior treatment with abemaciclib with evidence of response (at least a partial response per ACTG criteria and/or RECIST) to abemaciclib.
• Participants in Cohort 4 must:

• have been previously enrolled in Cohorts 1-3
• have at least prior documentation of PR in prior cohort
• not have come off treatment for any >Grade 3 abemaciclib-related AE.
• Age >18 years
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) <= 2 (Karnofsky >= 60%.
• Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy are eligible for this trial.
• Willingness to adhere to antiretroviral therapy (ART)
• All participants must have received ART for 8 weeks prior to enrollment, with no evidence of KS improvement over the most recent 4 weeks
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV VL must be undetectable on suppressive therapy, if indicated.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV VL.
• No uncontrolled severe concurrent bacterial, viral, or fungal infections.
• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
• Contraception requirements as follows:

• Participants of child-bearing potential (IOCBP) must agree to use a highly effective method of contraception (e.g., intrauterine device [IUD], hormonal, surgical sterilization, abstinence) prior to study entry, for the duration of study participation, and for up to 4 months after completion of abemaciclib administration
• Participants able to father a child must with partners of childbearing potential agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the study treatment for up to 4 months after completion of abemaciclib

administration. Individuals with partners of childbearing potential should ask their partners to be on an effective birth control (hormonal, IUD, surgical sterilization).

• Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing person with abemaciclib, nursing should be discontinued if the nursing person is treated with abemaciclib.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Participants who have had chemotherapy or immunotherapy within 3 weeks prior to entering the study.
• Participants who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and enrollment.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia or neuropathy.
• Participants who are receiving any other investigational agents.
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to CDK inhibitor.
• Participants receiving any ART or other medications that are strong/moderate inhibitors of CYP3A4 must have dose reductions per Strong/Moderate CYP3A4 inhibitors.
• Serious and/or uncontrolled severe intercurrent illness that in the judgement of the investigator would preclude participation in the study.
• No active KSHV-associated multicentric Castleman disease, KSHV-associated inflammatory cytokine syndrome or primary effusion lymphoma.
• Psychiatric illness/social situations that would limit adherence with study requirements.
• Pregnancy
• Prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the regimen are eligible for this trial
• Participants with interstitial lung disease