Phase 1 First in Human Trial to Assess Safety and Tolerability of the Novel ACK1 Inhibitor (R)-9b in Patients with Prostate Cancer

Abstract Prostate cancer (PC) is one of the leading cause of cancer deaths among American men. Advanced PC patients often receive androgen deprivation therapy, but, the recalcitrant disease recurs within 2-3-years, referred to as the Castration Resistant Prostate Cancer (CRPC). Androgen Receptor (AR) antagonists such

as enzalutamide (Enz) or abiraterone (Abi) are currently favored therapeutics for PC patients, however, virtually all patients develop resistance. Post-CRPC state, therapeutic options for the recurrent disease are limited. We discovered a non-receptor tyrosine kinase, ACK1, as a novel epigenetic modifier in prostate

tumors, regulating AR/AR-V7 expression. Enthused with these data, we developed a new class of ACK1 small molecule kinase inhibitor, (R)-9b. (R)-9b inhibits ACK1 and downregulates AR and prostate specific antigen (PSA) expression to suppress prostate xenograft tumor growth. Moreover, in immune competent

mouse models, (R)-9b induces significant CD4+ and CD8+ T cell activation against syngeneic prostate tumors. Employing ex vivo 3-D assays, we confirmed that (R)-9b functionally reinvigorates peripheral blood mononuclear cells (PBMCs) of the CRPC patients to mount a robust immune response against human CRPC

organoids. Together, these data indicated that ACK1 inhibitor, (R)-9b with tumor-intrinsic and tumor-extrinsic activities in the host tumor microenvironments is a novel class of inhibitor with much needed immunomodulatory activity. Prolonged (R)-9b treatment exhibited normal histology suggesting that it is not

associated with toxicity, further underscoring the importance of targeting ACK1 to overcome resistance to AR-targeted therapies. We have completed an extensive pre-Investigational New Drug (IND) studies including pharmacokinetic, pharmacodynamic and metabolism studies in mouse/rat/canine models, which

revealed that (R)-9b possessed excellent drug-like properties. These data is submitted to FDA (IND#167907). This proposal is directed towards phase I clinical trial for ACK1 inhibitor (R)-9b in CRPC patients to examine its ability to overcome CRPC resistance by cytotoxic and immunomodulatory activity.

Specifically, we will: Specific Aim 1: To assess the safety/tolerability, pharmacokinetics, and anti-tumor activity of (R)-9b in CPRC patients Specific Aim 2: To evaluate peripheral blood and tissue markers of anti-tumor and immune response after (R)-9b exposure. Overall, successful completion of this study will open a new therapeutic modality for CRPC patients who

have developed resistance for Enzalutamide and Abiraterone, which is a critical unmet need.