Study of ORIC-101 in Combination With Anticancer Therapy

Inclusion Criteria

• PDAC: Advanced or metastatic PDAC previously treated with and progressed on a fluoropyrimidine-based regimen and a taxane-containing chemotherapy regimen (eg, gemcitabine + nab-paclitaxel). Pancreatic neuroendocrine tumors, lymphoma of the pancreas, acinar pancreatic cancer, or ampullary cancer are not eligible.
• Ovarian Cancer: Advanced or metastatic high grade serous or endometrioid epithelial ovarian, primary peritoneal, fallopian tube cancer or ovarian carcinosarcoma, previously treated with and progressed on a taxane-containing chemotherapy regimen; clear cell, mucinous and borderline histologic subtypes are not eligible; must have received at least one line of therapy with evidence of cancer progression within 6 months after the last dose of platinum-based therapy (ie, having a platinum-free interval of <6 months [platinum resistant]), or progressive disease during or immediately after primary platinum-therapy, (ie, platinum refractory).
• TNBC: Advanced or metastatic ER-negative, PR-negative, HER2-negative primary breast cancer previously treated and progressed on a taxane-based chemotherapy regimen; no previous or synchronous second breast cancer, unless also confirmed ER-, PR- and HER2-negative; must have received at least one line of therapy in the metastatic setting.
• Other Solid Tumor: Other advanced or metastatic solid tumor previously treated with and progressed on a taxane-based chemotherapy regimen, with the exception of metastatic colorectal cancer, primary brain tumors, and neuroendocrine tumors that secrete ACTH or CRH; must have received no more than 4 prior lines of cytotoxic or myelosuppressive therapy Other Key Inclusion Criteria:
• At least 18 years of age
• ECOG performance status 0 or 1
• Measurable disease as assessed centrally using RECIST 1.1
• Treated, stable CNS metastases must be asymptomatic and must not require steroids
• Agreement and ability to undergo two on-study biopsies, one pre-treatment obtained prior to dosing and during Cycle 2
• 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)
• Albumin ≥3.0 g/dL
• 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
• Ability to swallow ORIC-101 intact without chewing or crushing the capsules or tablets
• Adequate gastrointestinal absorption. If the patient has undergone gastric bypass surgery and/or surgery of gastrointestinal or hepatobiliary tract, the patient must demonstrate adequate absorption as evidenced by albumin ≥3.0 g/dL, controlled pancreatic insufficiency (if present), and lack of evidence of malabsorption Expansion Cohorts Part II

Exclusion Criteria

• Any other current or active malignancy
• Prior or current treatment with ORIC-101 or any other GR antagonist (eg, mifepristone, relacorilant)
• Concurrent treatment with any other anticancer therapy including chemotherapy, hormonal therapy, immunotherapy, radiotherapy, chemoembolization, targeted therapy, or an investigational agent within 28 days prior to Cycle 1 Day 1
• Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or incomplete recovery from adverse effects resulting from such procedures; palliative radiotherapy within 1 week of Cycle 1 Day 1
• Systemic, inhaled, or prescription strength topical corticosteroids within 21 days prior to Cycle 1 Day 1; short courses (≤5 days) for non-cancer-related reasons are allowed if clinically required
• Grade 2 (moderate) or higher peripheral neuropathy per CTCAE v5.0; patients with mild peripheral neuropathy may be eligible at the discretion of the investigator in consultation with ORIC
• All other toxicities from prior therapy (except alopecia) that have not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 ≤ Grade 1
• Females: history of unexplained vaginal bleeding in the 8 weeks prior to Cycle 1 Day 1 (given potential for ORIC-101 to exacerbate such bleeding)
• Females: use of hormone replacement therapy; hormone replacement therapy must be discontinued to allow for confirmation of postmenopausal status
• History of Cushing's syndrome or adrenal insufficiency
• Current (within 10 days prior to Cycle 1 Day 1) or expected on-study treatment with specified strong CYP3A4 inhibitors or inducers
• Known human immunodeficiency virus (HIV) infection, unless patient is healthy and has a low risk of AIDS-related outcomes
• Presence of Hepatitis B surface antigen (HBsAg) at screening
• Positive Hepatitis C (HCVAb) antibody test result at screening or within 3 months prior to Cycle 1 Day 1. NOTE: Patients with positive HCVAb due to prior resolved disease can be enrolled if a confirmatory negative Hepatitis C RNA test is obtained
• Positive Hepatitis C RNA test result at screening or within 3 months prior to Cycle 1 Day 1. NOTE: Test is optional and patients with negative HCVAb test are not required to also undergo Hepatitis C RNA testing