Study of ORIC-101 in Combination With Enzalutamide

Study Overview
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Brief Summary
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The purpose of this study is to establish the recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ORIC-101 in combination with enzalutamide (Xtandi®) when administered to patients with metastatic prostate cancer progressing on enzalutamide.

Detailed Description
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ORIC-101 is a small molecule GR antagonist being developed for the treatment of patients with solid tumor malignancies. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the pro-survival signals mediated by the activated nuclear receptor. This is an open-label, single arm, multicenter, dose escalation followed by dose expansion study to assess the safety and preliminary antitumor activity of ORIC-101 in combination with enzalutamide in patients progressing on enzalutamide. Patients deemed eligible will receive treatment with ORIC-101 in addition to continuing their current enzalutamide therapy. Escalating dose levels of ORIC-101 will be administered orally, once daily in combination with enzalutamide 160 mg. Parallel enrollment for assessment of PK/PD modulation in up to 3 additional patients presenting with tumors expressing high levels of GR (GR-high) may be performed at each dose level after the dose level has cleared the initial dose-limiting toxicity evaluation period; these additional patients may serve as supplemental patients for selection of the maximum tolerated dose and/or RP2D. Dose expansion will further evaluate the safety and preliminary antitumor activity of ORIC-101 in patients presenting with different levels of GR expressing-tumors.

Official Title
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An Open-Label Phase 1b Study of ORIC-101 in Combination With Enzalutamide in Patients With Metastatic Prostate Cancer Progressing on Enzalutamide

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: ORIC-101
* Drug: enzalutamide 40 MG oral capsule [Xtandi]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Metastatic prostate cancer currently being treated with enzalutamide (Xtandi®) 160 mg once daily plus surgical or ongoing chemical castration, with baseline testosterone level <50 ng/dL Must have been on treatment with enzalutamide for at least 3 months prior to documented evidence of PSA progression defined as per PCWG3: minimum of 2 rising values (3 measurements) 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) Agreement and ability to undergo on-study core biopsies, as follows, through a procedure that is deemed to be clinically feasible and not carry significant risk: one pre-treatment tumor biopsy obtained while on treatment with enzalutamide prior to enrollment on this study; and one post-treatment tumor biopsy during Cycle 2 one end of treatment tumor biopsy (optional) ECOG performance status 0 or 1 Life expectancy of at least 3 months Adequate organ function as defined by the following criteria: ANC ≥1500 cells/mm3 (1.5 × 103 cells/mm3) Platelets ≥100,000 /µL (100 × 109 /L) Hemoglobin ≥9.0 g/dL (90 g/L) AST (SGOT) or ALT (SGPT) ≤2.5 × ULN, ≤5.0 × ULN for patients with liver metastases Bilirubin ≤1.5 × ULN; patients with a known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible QTcF ≤480 msec Capable of giving signed informed consent Exclusion Criteria: No intervening therapy between enzalutamide treatment and enrollment on this study Any other active malignancy, with the exception of adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 solid tumor malignancies without evidence of disease, or other solid tumors curatively treated with no evidence of disease for ≥5 years from enrollment Current treatment on another therapeutic clinical trial Prior or current treatment with ORIC-101 or any other GR antagonist (eg, CORT-125281, mifepristone, relacorilant) Prior chemotherapy in the metastatic castration-resistant prostate cancer setting Prior treatment with a second-generation AR modulator (eg, apalutamide, abiraterone, darolutamide) History of Cushing's syndrome or adrenal insufficiency History or presence of CNS metastases History of seizures or condition that may predispose to seizures Current (at C1D1) or requirement for chronic use of systemic corticosteroids with the exception of inhaled, topical, intraocular, intranasal, or intraarticular corticosteroids Current (within 10 days prior to first dose of ORIC-101) or expected on-study treatment with specified strong CYP3A4 inhibitors or inducers Receiving any other anticancer therapy, including radiotherapy within 21 days prior to C1D1. Patients must have recovered from all toxicities from prior anticancer therapies and/or radiotherapy Major surgery within 21 days prior to C1D1 or incomplete recovery from adverse effects resulting from such procedure Known human immunodeficiency virus (HIV) infection, unless patient is healthy and has a low risk of AIDS-related outcomes Active Hepatitis B or C infection 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Modified interval 3+3 dose escalation design, followed by dose expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>ORIC-101 dosed orally, once per day in combination with enzalutamide (160 mg) of each 28-day cycle. | Drug: ORIC-101<br>* ORIC-101 once daily in each 28-day cycle<br>Drug: enzalutamide 40 MG oral capsule [Xtandi]<br>* 160 mg once daily in each 28-day cycle<br>|
| Experimental: Dose Expansion<br>RP2D dose | Drug: ORIC-101<br>* ORIC-101 once daily in each 28-day cycle<br>Drug: enzalutamide 40 MG oral capsule [Xtandi]<br>* 160 mg once daily in each 28-day cycle<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 3+3 dose escalation design | 12 months | 
| PSA Response Rate | ≥50% decline from baseline at 8 weeks per Prostate Cancer Working Group 3 (PCWG3) criteria | 36 months | 
| PSA Progression | From study start until PCWG3 criteria is met | 36 months | 
| Number of Participants with Adverse Events | Safety and tolerability of ORIC-101 in combination with enzalutamide | 36 months | 
| Number of Participants with Abnormal Laboratory Values | Safety and tolerability of ORIC-101 in combination with enzalutamide | 36 months | 
| Number of Participants with Abnormal 12-lead ECG | Safety and tolerability of ORIC-101 in combination with enzalutamide | 36 months | 
| Number of Participants with Abnormal Vital Signs | Safety and tolerability of ORIC-101 in combination with enzalutamide | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) | PK of ORIC-101 in combination with enzalutamide | 28 Days | 
| Minimum plasma concentration (Cmin) | PK of ORIC-101 in combination with enzalutamide | 36 months | 
| Time of maximum observed concentration (Tmax) | PK of ORIC-101 in combination with enzalutamide | 28 Days | 
| Area under the curve (AUC(0-24)) | PK of ORIC-101 in combination with enzalutamide | 28 Days | 
| Elimination half-life (T1/2) | PK of ORIC-101 in combination with enzalutamide | 28 Days | 
| Circulating tumor cells (CTCs) conversion | ≥5 cells/7.5 mL of blood to 0 (zero) (CTC0), as well as from unfavorable (≥5 cells/7.5 mL of blood) to favorable (<5 cells/7.5 mL of blood) | 36 months | 
| Objective response rate (ORR) | Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and PCWG3 criteria | 36 months | 
| Duration of response (DOR) | Radiographic progression using RECIST v1.1 | 36 months | 
| Progression-free survival (PFS) | Time from first dose to first documentation of radiographic progression or death | 36 months | 
| Overall survival (OS) | Time from first dose to death | 36 months | 
| Number of Participants with GR Expression by IHC | Level of GR expression by IHC in tumor tissue samples | 36 months |