Study of ORIC-944 in Patients With Metastatic Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to establish recommended Phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) and preliminary antitumor activity of ORIC-944 in patients with metastatic prostate cancer.

Detailed Description
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ORIC-944 is a potent, highly selective, allosteric, orally bioavailable, small molecule inhibitor of PRC2 via binding the embryonic ectoderm development (EED) subunit. This is a first-in-human, open-label, single arm, multicenter, dose escalation followed by dose expansion study to establish the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) and preliminary antitumor activity of ORIC-944 in patients with metastatic prostate cancer, including those with neuroendocrine and/or small cell features, who have exhausted available treatment options. The study will begin with dose finding in patients with metastatic prostate cancer (Dose Escalation); additional dose expansion cohorts (Dose Expansion), with specific histology, treatment history, and/or expression of a specific biomarker, may be initiated via protocol amendment The study will evaluate escalating dose levels of ORIC-944 administered orally, once daily in 28-day cycles following an interval 3+3 design.

Official Title
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An Open-Label, Phase 1/1b, Study of ORIC-944 in Patients With Metastatic Prostate Cancer

Conditions
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Metastatic Prostate Cancer, Neuroendocrine Prostate Cancer

Intervention / Treatment
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* Drug: ORIC-944


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with metastatic prostate cancer, including those with neuroendocrine prostate cancer (NEPC) and/or small cell features Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist to maintain castrate levels of testosterone Any number of prior therapies are allowed, but must have progressed after at least one line of next generation androgen receptor antagonist (abiraterone, enzalutamide, apalutamide, darolutamide) and must not have received more than 2 chemotherapy regimens in the mCRPC setting Evidence of progressive disease by PCWG3 criteria for study entry rising PSA, defined as a minimum of 2 rising values obtained a minimum of one week apart with the latest result being at least 2.0 ng/mL (or 1.0 ng/mL if PSA rise is the only indication of progression), or confirmation of 2 new bone lesions on last systemic therapy, or soft tissue progression per RECIST 1.1 Measurable and/or evaluable disease by RECIST 1.1 Agreement and ability to undergo on-study punch skin biopsies and core tumor biopsies ECOG performance status of 0 or 1 Adequate organ function Exclusion Criteria: History or presence of CNS metastases, unless previously treated and stable History of class III or IV congestive heart failure or severe non-ischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months Known, symptomatic human immunodeficiency virus (HIV) infection Active symptomatic Hepatitis B or C infection; patients with well controlled disease are eligible Active gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, short gut syndrome, etc) or other malabsorption syndromes that would reasonably impact drug absorption per investigator judgement Any other condition or circumstance (eg, clinical, psychological, familial, sociological, inability to swallow oral study drug) that, in the opinion of the investigator, may interfere with protocol compliance or contraindicates participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Interval 3+3 dose escalation design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>ORIC-944 dosed orally on a continuous daily dosing regimen in 28-day cycles | Drug: ORIC-944<br>* ORIC-944 oral once daily for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) | RP2D as determined by interval 3+3 dose escalation design | 12 months | 
| Maximum plasma concentration (Cmax) | PK of ORIC-944 | 28 Days | 
| Time to maximum observed concentration (Tmax) | PK of ORIC-944 | 28 Days | 
| Area under the curve (AUC) | PK of ORIC-944 | 28 Days | 
| Apparent plasma terminal elimination half-life (t1/2) | PK of ORIC-944 | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate (CBR) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Objective response rate (ORR) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Duration of response (DOR) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Progression-free survival (PFS) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PRC2 dysregulation, EED, CRPC