Abstract 2045: Relationship of venetoclax dose and exposure to response in relapsed or refractory chronic lymphocytic leukemia and non-Hodgkin's lymphoma subjects
Authors: Freise Kevin J. , Jones Aksana K. , Eckert Doerthe , Mensing Sven , Wong Shekman , Humerickhouse Rod , Awni Walid , Salem Ahmed H. 
Published: July 2016

Abstract
Venetoclax is a selective, potent, orally bioavailable, small molecule, B-cell lymphoma-2 (Bcl–2) inhibitor that restores apoptosis in cancer cells. Clinical efficacy of venetoclax has been observed in a variety of hematological malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkins lymphoma (NHL). The objective of this research was to characterize the relationship between venetoclax exposures and efficacy in relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL) subjects, as well as safety in R/R CLL/SLL and NHL subjects. A total of 272 and 444 subjects from 4 clinical studies were included in the exposure-efficacy and exposure-safety analyses, respectively. Characteristics evaluated for their impact on efficacy and safety included: demographics (bodyweight, sex, etc.), baseline disease characteristics (e.g. lymphocyte count, tumor size, 17p del somatic mutation), and select co-medications. Model based simulations indicated that a venetoclax dosage of 400 mg daily maximized the probability of a typical subject with R/R CLL/SLL achieving an objective response (OR) by 6 months of venetoclax treatment with estimated OR rates of 80.9% (95% confidence interval [CI]: [77.5% - 84.0%]), 84.8% (95% CI: [81.5% - 88.0%]), and 85.5% (95% CI: [82.6% - 88.4%]) at the 200, 400, and 600 mg dosage regimens, respectively. The 17p deletion was not identified in any of the exposure-efficacy analyses to be related to the responsiveness of R/R CLL/SLL subjects to venetoclax. Therefore, subjects with the 17p deletion chromosomal aberration appear to be as sensitive to the effects of venetoclax as subjects who do not have the 17p deletion, consistent with its Bcl-2 inhibitor mechanism of action that bypasses the signaling events associated with the 17p deletion. The safety analyses of the adverse events (Grade ≥ 3) of neutropenia and infection in R/R CLL/SLL and NHL subjects both indicated that higher average venetoclax concentrations were associated with a decrease in adverse events, indicating that these evaluated safety endpoints are not dose-limiting. Sensitivity analyses supported that increasing venetoclax concentration did not increase these adverse events. It is hypothesized that the association is driven by disease improvement with venetoclax treatment and not by directly affecting neutrophils or granulocyte progenitor cells. Overall, the exposure-response-safety analyses indicated that a venetoclax dosage regimen of 400 mg daily maximizes (&gt;80%) the probability of achieving objective response in R/R CLL/SLL subjects with minimal probability of neutropenia or infection.
Citation Format: Kevin J. Freise, Aksana K. Jones, Doerthe Eckert, Sven Mensing, Shekman Wong, Rod Humerickhouse, Walid Awni, Ahmed H. Salem. Relationship of venetoclax dose and exposure to response in relapsed or refractory chronic lymphocytic leukemia and non-Hodgkin's lymphoma subjects. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2045.