Early efficacy evaluation of ORIN1001, a first in class IRE1 alpha inhibitor, in advanced solid tumors.
Authors: Rimawi Mothaffar F. , Hamilton Erika P. , Hurvitz Sara A. , Marks Douglas Kanter , Elias Anthony D. , Pluard Timothy J. , Gabrail Nashat Y. , Patterson John , Greene Stephanie , Zeng Qingping 
Published: June 2023

1092 Background: ORIN1001 is a first-in-class small molecule targeting a novel enzyme with a unique mode of inhibition that selectively blocks the Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum. ORIN1001 is now undergoing Phase 1/2 clinical testing in advanced solid tumors. Methods: In a Phase 1 dose escalation trial (3+3 design), ORIN1001 was administered PO daily as a single agent in patients (pts) with advanced solid tumors and in combination with Abraxane in pts with relapsed, refractory breast cancer. Safety, tolerability, pharmacokinetics, and preliminary efficacy of ORIN1001 was evaluated and a RP2D determined. Results: As of Jan, 2023, 30 patients with advanced cancer have received ORIN1001 as a single agent at doses up to 650 mg per day in 21-day continuous cycles and 13 patients with breast cancer have received ORIN1001 at doses up to 400 mg in combination with Abraxane in 28-day continuous cycles. For single agent, DLTs consisting of thrombocytopenia were observed at 200 mg (2 pts) and 650 mg (2 pts) and, rash was observed at 200 mg (1 pt) and 500 mg (1 pt). For combination treatment, DLTs consisting of thrombocytopenia were observed at 300 mg (1 pt), fatigue/ rash at 400 mg (1 pt), febrile neutropenia/low WBC at 400/500 mg (1 pt at each dose). Common ( > 15%) adverse events were predominantly nausea and/or vomiting (Grade 1-2 in severity). ORIN1001 exposure increased in a dose proportional manner with a mean T1/2 at steady state of approximately 20 hours. For single agent, best response per RECIST 1.1 was partial response (PR) in 2 of 30 pts. These PRs included a stage IV colon cancer pt exceeding 44 months on treatment at 100 mg, and stage IV ER-/PR-/HER2+ breast cancer pt with 5 months on treatment at 500 mg. Stable disease (SD) was observed in a total of 16 of 30 pts with breast, colorectal, mesothelioma, liver, prostate, kidney or ovarian cancer. For combination therapy with Abraxane, a PR was observed in one ER+/PR-/HER2- breast cancer pt at 300 mg ORIN1001 and SD was observed in 5 of 13 pts. SD included both triple negative and ER+/HER2- breast cancer pts at 300 or 400 mg with ongoing treatment exceeding 5 months. Of note, in a separate Phase 1 oncology basket trial in China, there were 2 PRs; 1 pt with stage IV NSCLC at 300 mg and 1 pt with metastatic castrate resistant prostate cancer at 100 mg exceeding 9 and 5 months of treatment with ORIN1001 in combination with Abraxane, respectively. Conclusions: Phase 1 clinical evaluation of ORIN1001 has demonstrated tolerability and dose proportional PK. The proposed RP2D is estimated to be 500 mg and 300 mg ORIN1001 for single agent and in combination with Abraxane, respectively. Early efficacy data with ORIN1001 demonstrate clinical responses (SD and PR) in multiple pts with heavily-pretreated advanced solid tumors as a single agent or in combination with Abraxane in breast cancer patients. Clinical trial information: NCT03950570 .