Novel ACK1 Inhibitor (R)-9b in Patients With Prostate Cancer

Summary

TITLE: Phase 1 First in Human Trial to Assess Safety and Tolerability of the Novel ACK1 Inhibitor (R)-9bMS in Patients with Prostate Cancer (PHAROS) STUDY DESCRIPTION: Prostate cancer (PC) patients receive androgen deprivation therapy (ADT), but recalcitrant disease recurs typically within 2-3 years, referred to as the Castration Resistant Prostate Cancer (CRPC). Androgen receptor (AR) targeted therapies, such as Enzalutamide (Enz) or Abiraterone (Abi), are FDA-approved therapeutics for CRPC patients. However, virtually all patients develop resistance. A non-receptor tyrosine kinase, ACK1 act as a novel epigenetic modifier in prostate tumors, regulating AR and its splice variant, AR-V7 expression. A new class of ACK1 small molecule inhibitor, (R)-9bMS, was developed that exhibited excellent drug-like properties. Treatment with (R)-9bMS suppressed Abi and Enz-resistant tumor growth in mice. Robust immune activation against prostate tumors was also reflected in mice treated with ACK1 inhibitor, (R)-9bMS. Importantly (R)-9bMS functionally reinvigorated peripheral blood mononuclear cells (PBMCs) of CRPC patients to mount a robust immune response against CRPC organoids. Collectively, these data indicate that the ACK1 inhibitor, (R)-9bMS, fulfills a unique niche, wherein it not only suppressed AR/AR-V7 within the tumor milieu, but also activated host immune system by overcoming CSK-restrained LCK activity, to mount a robust 'dual' anti-tumor response. OBJECTIVES: Primary Objective: To assess the safety and tolerability of (R)-9bMS in patients with metastatic castration-resistant prostate cancer. Secondary Objectives: To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of (R)-9bMS in patients with CRPC. To determine the pharmacokinetics (PK) of (R)-9bMS in patients after single and multiple dose oral administration. To assess clinical outcomes and anti-tumor activity in patients treated with (R)-9bMS. ENDPOINTS: Primary Endpoint: Frequency of dose-limiting toxicities and toxicity and severe AEs per CTCAE v 5.0. Secondary Endpoints: * RP2D (recommended phase 2 dose) * PK (pharmacokinetics) * PSA responses * Duration of responses * ORR (objective response rate) * OS (overall survival) * PFS (progression free survival) * DSS (disease specific survival) * Toxicity and severe AEs per CTCAE v 5.0 STUDY POPULATION: Approximately 18-30 adult patients with a histologic or cytologic diagnosis of metastatic castration resistant prostate cancer will be enrolled. PHASE: Phase I DESCRIPTION OF SITES: This study will be open to enrollment at the University of Wisconsin Carbone Cancer Center DESCRIPTION OF STUDY INERVENTION: (R)-9bMS will be taken by mouth twice daily until completion of 12 cycles, progression or intolerance STUDY DURATION: 12 months for enrollment + 12 months treatment + 12 months follow-up + 12 months for data analysis = 48 months.

Timeline

Start

2026-03-13

Primary completion

2027-12-30

Completion

2028-03-30

Publications

• Results Sawant M, Mahajan K, Renganathan A, Weimholt C, Luo J, Kukshal V, Jez JM, Jeon MS, Zhang B, Li T, Fang B, Luo Y, Lawrence NJ, Lawrence HR, Feng FY, Mahajan NP. Chronologically modified androgen receptor in recurrent castration-resistant prostate cancer and its therapeutic targeting. Sci Transl Med. 2022 Jun 15;14(649):eabg4132. doi: 10.1126/scitranslmed.abg4132. Epub 2022 Jun 15.
• Results Chouhan S, Sawant M, Weimholt C, Luo J, Sprung RW, Terrado M, Mueller DM, Earp HS, Mahajan NP. TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability. Autophagy. 2023 Mar;19(3):1000-1025. doi: 10.1080/15548627.2022.2103961. Epub 2022 Jul 27.
• Results Sridaran D, Chouhan S, Mahajan K, Renganathan A, Weimholt C, Bhagwat S, Reimers M, Kim EH, Thakur MK, Saeed MA, Pachynski RK, Seeliger MA, Miller WT, Feng FY, Mahajan NP. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nat Commun. 2022 Nov 14;13(1):6929. doi: 10.1038/s41467-022-34724-5.
• Results Mahajan NP, Coppola D, Kim J, Lawrence HR, Lawrence NJ, Mahajan K. Blockade of ACK1/TNK2 To Squelch the Survival of Prostate Cancer Stem-like Cells. Sci Rep. 2018 Jan 31;8(1):1954. doi: 10.1038/s41598-018-20172-z.
• Results Mahajan K, Malla P, Lawrence HR, Chen Z, Kumar-Sinha C, Malik R, Shukla S, Kim J, Coppola D, Lawrence NJ, Mahajan NP. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer. Cancer Cell. 2017 Jun 12;31(6):790-803.e8. doi: 10.1016/j.ccell.2017.05.003.

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