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.
Histologically or cytologically confirmed prostate cancer (mCRPC).
Must have evidence of metastatic disease on conventional imaging (eg. CT, MRI, technetium bone scan). May have any type or location of metastases (bone, lymph node, visceral). RECIST 1.1 measurable disease is not required; may have bone-only metastases.
Ongoing androgen deprivation therapy (ADT) at time of study enrollment (GnRHR agonist such as leuprolide, goserelin, triptorelin, buserelin, histrelin; GnRHR antagonists such as degarelix or relugolix), or history of surgical castration.
Must have evidence of castrate testosterone levels with baseline serum testosterone level of 50 ng/dL or less at time of study start, and castrate levels should be maintained throughout study.
Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before first dose of study treatment.
Exclusively small cell variant of prostate cancer, or other prostate cancer histology that does not contain adenocarcinoma
Inability to swallow pills.
Presence of a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 calendar days of start of study treatment. Inhaled or topical steroids and adrenal replacement steroid doses < 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
Sequential
(R)-9bMS
Drug(R)-9bMS will be given in clinic on day 1, two doses 12 hours (+/- 30 minutes) apart, and on day 2, 12 hours (+/- 30 minutes) after the second day 1 dose. Patients will be admitted overnight for these first 3 doses. Patient must be fasting 1 hour before and 1 hour after doses for these first 3 doses. (R)-9bMS should be taken with a glass of water. Patients will be dispensed home supply after C1D2 morning dose.
Frequency of dose-limiting toxicities (Dose Escalation only)
Dose-limiting toxicities are defined in the protocol.
Recommended phase 2 dose (RP2D) (Dose Escalation only)
RP2D has traditionally been synonymous with the highest safe dose, or maximum tolerated dose (MTD) as determined based on, but can be lower than MTD based on comprehensive review of all available data from the phase I study (including dose limiting toxicity data, pharmacodynamic (PD)/pharmacokinetic (PK) study and efficacy data).
Number of patients with a prostate specific antigen (PSA) response
PSA response is defined by at least 50% decline in PSA level from baseline measured twice at least 3 weeks apart.
Overall response rate (ORR)
ORR is defined as proportion of patients achieving complete response (CR) and partial response (PR) by RECIST 1.1 or by PCWG3 criteria.
Progression-free survival (PFS)
PFS is defined from date of first treatment to date of progression or death or last follow-up, whichever is earlier.
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TechnoGenesys, Inc.
Lead sponsor
National Cancer Institute (NCI)
Collaborator
Washington University School of Medicine
Collaborator
University of Wisconsin, Madison
Collaborator
