A phase I/II study of abemaciclib, a CDK4/6 inhibitor, in participants with HIV-associated and HIV-negative Kaposi sarcoma.

Abstract

11505 Background: Kaposi sarcoma (KS), caused by Kaposi sarcoma herpesvirus (KSHV), is a multicentric angioproliferative tumor seen in people with and without HIV. Abemaciclib (abema) is an oral cyclin-dependent kinase (CDK) inhibitor that targets CDK4 (cyclin D1) and CDK6 (cyclin D3), and is FDA-approved for breast cancer. In vitro studies of KSHV-infected cells have shown that CDK4/6 inhibitors enhance host immune cell surface expression and T-cell activation induced by these cells. Here, we investigate the safety and activity of abema in participants (pts) with KS. Methods: In this open label, non-randomized, two-stage Phase I/II study of pts with KS, there were two primary objectives. Phase I evaluated the safety and tolerability of abema in pts with KS using a 3+3 dose de-escalation design to identify a maximum tolerated dose (MTD). The first group of pts were treated at dose level 1 (DL) of 200mg twice daily for days 1-28 of a 28-day cycle. Intra-participant dose reductions were permissible for abema-related toxicities. Phase II assessed the overall response rate of abemaciclib of all participants and stratified by prior systemic KS therapy (Arm 1 target: 15 pts with previously treated KS and Arm 2 target: 10 participants with untreated KS). Eligibility criteria included adherence to antiretroviral therapy in people with HIV (PWH) for > 8 weeks prior to enrollment and no concomitant strong CYP3A4 inhibitors. KS response was evaluated using the modified AIDS Clinical Trials Group criteria. Results: Thirty-four pts (33 men) with a median age of 43 years were enrolled. Twenty-five (74%) were PWH and 27 pts had stage T1 KS (6 pts had either gastrointestinal and/or lung involvement). Among PWH, the baseline median HIV viral load was <20 copies/ml and the median CD4 T-cell count was 308 cells/µL (interquartile range: 176-468 cells/µl). In Phase I, 6 pts (4 PWH) were enrolled at 200mg BID with no dose-limiting toxicities. In Phase II, 17 pts (14 PWH) were enrolled to Arm 1, and 11 pts (7 PWH) enrolled to Arm 2. Overall, 3 pts (2 in Arm 1 and 1 in Arm 2) did not proceed after one cycle due to grade 2 anxiety in 2 pts and tremor in 1 pt that were unrelated to study therapy. These pts were replaced as KS response was not evaluable. The most common grade 1/2 adverse events were diarrhea (92%) and creatinine elevation (64%). Neutropenia of all grades was noted in 63% and 13 pts had dose reductions for recurrent grade 3 or grade 4 neutropenia. Among 31 evaluable pts receiving >2 cycles, 24 pts had a partial response (PR) (77% [95% confidence interval (CI): 59-90%]), 4 pts had stable disease and 2 pt had progressive disease. Sixteen of 21 pts who prior KS therapy had a PR (76% [95% CI: 53-92%]) and 8 of 10 pts in Arm 2 with previously untreated KS had a PR (80% [95% CI: 44-98%]). Conclusions: Abema is a novel therapeutic option in KS, with notable activity among pts with previously untreated KS. Adverse events were managed with dose reduction and supportive measures. Clinical trial information: NCT04941274 .