Metastatic Prostate Cancer
Conditions
Keywords
PRC2 dysregulation, EED, CRPC, mCRPC, ARPI
Brief summary
The purpose of this study is to establish the safety and preliminary antitumor activity of ORIC-944 as a single agent and in combinations with ARPIs in patients with metastatic prostate cancer.
Detailed description
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, multicenter, dose escalation study of ORIC-944 as a single agent (Part I) or in combination with an Androgen Receptor Pathway Inhibitor (ARPI) (Part II) to establish the safety and preliminary antitumor activity of ORIC-944 as a single agent and in combination with ARPIs in patients with metastatic prostate cancer. Part III of the protocol (dose optimization) will explore two potential dose levels of ORIC-944 selected from Part II in combination with ARPIs to select the final RP2D for each combination across two separate patient populations.
Interventions
DRUGORIC-944
Oral, once daily, continuous
DRUGAbiraterone acetate (Zytiga®) 250 mg or 500 mg tablets
Oral, 1000 mg once daily, continuous
Oral, 240 mg once daily, continuous
Oral, 600 mg twice daily, continuous
DRUGEnzalutamide (Xtandi®) 40 mg capsules or 40 mg and 80 mg tablets
Oral, 160 mg once daily, continuous
Sponsors
ORIC Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Interval 3+3 dose escalation design
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with metastatic prostate cancer * Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist to maintain castrate levels of testosterone * Prior therapies: Part I (single agent ORIC-944 dose escalation): Any number of prior therapies are allowed, but must have progressed after at least one line of next generation ARPI (abiraterone, apalutamide, darolutamide, or enzalutamide) and must not have received more than 2 chemotherapy regimens in the mCRPC setting Part II (ARPI combination dose escalation): Must have received only 1 prior line of ARPI (abiraterone, apalutamide, darolutamide, or enzalutamide) in any setting; may have also received up to 1 prior line of chemotherapy in the mCSPC setting Part III (ARPI combination dose optimization): In addition to up to 1 prior line of chemotherapy in the mCSPC setting: * Cohorts A and B: received only one 1 prior line of abiraterone in any setting * Cohorts C and D: received only one 1 prior line of apalutamide, darolutamide, or enzalutamide in any 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) | 12 months | RP2D as determined by interval 3+3 dose escalation design |
| Maximum plasma concentration (Cmax) | 28 Days | PK of ORIC-944 single agent and in combination with an ARPI |
| Time to maximum observed concentration (Tmax) | 28 Days | PK of ORIC-944 single agent and in combination with an ARPI |
| Area under the curve (AUC) | 28 Days | PK of ORIC-944 single agent and in combination with an ARPI |
| Apparent plasma terminal elimination half-life (t1/2) | 28 Days | PK of ORIC-944 single agent and in combination with an ARPI |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical benefit rate (CBR) | 36 months | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
| Objective response rate (ORR) | 36 months | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
| Duration of response (DOR) | 36 months | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
| Progression-free survival (PFS) | 36 months | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
| On-treatment PSA levels and change from baseline | 36 months | Prostate cancer working group 3 criteria (PCWG3) |
Countries
Australia, Spain, United Kingdom, United States
Contacts
Primary ContactORIC Clinical
Outcome results
None listed