A phase 1/2 dose escalation and expansion study of OP-1250 in adults with advanced and/or metastatic hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer

Background: Endocrine therapy administered sequentially as monotherapy or in combination with targeted therapy is the primary treatment for HR+, and HER2- metastatic breast cancer (MBC). Most patients with HR+, HER2- MBC will develop resistance to available therapies. More effective therapies are needed for HR+, HER2- MBC and for the treatment of endocrine therapy-resistant disease. OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates ER, blocking the activity of both the AF1 and AF2 transcriptional activation functions, inhibits ER-driven breast cancer cell growth, and induces ER degradation. OP-1250 demonstrates anti-cancer activity in vitro and in vivo, including activity against mouse models of metastases in the brain and tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with a favorable pharmacokinetic (PK) profile enabling once-daily dosing. OP-1250’s complete ER antagonism is hypothesized to result in superior efficacy compared to agents that only partially antagonize and/or degrade but do not completely antagonize ER. Trial design: Goals of this phase 1/2 are to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), to characterize the safety and PK profile, and to determine the preliminary activity of OP-1250 in subjects with HR+, HER2- MBC. Ph 1 (Dose Escalation) will evaluate escalating doses of orally administered OP-1250 to determine the safety, pharmacology, MTD (if any) and/or the RP2D. Cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for DLTs during cycle 1. Eligibility criteria include males, and both pre- and post-menopausal females, age 18 or older, with ER+, HER2- advanced or MBC (pre-menopausal women must be on an LHRH antagonist); prior CDK4/6 and SERD and fulvestrant are permitted; ECOG of 0 or 1. The objectives of the phase 1 are: identification of the DLT, MTD and/or RP2D and assessment of the safety and tolerability and PK of OP-1250. Objectives of the phase 2 are to assess the objective response rate (ORR) of OP-1250 in 1) subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have no evidence of central nervous system (CNS) metastases, 2) in patients with non-measurable disease, and 3) in patients with CNS disease. Correlative analyses include ER, PR, Ki67 in tumor biopsies and ctDNA pre- and post-therapy for activating mutations in ESR1. Summary: OP-1250, a complete estrogen receptor antagonist (CERAN), is currently being evaluated in a phase 1/2 study in ER+, HER2- MBC. For more information, please contact clinical@olema.com (NCT04505826) Citation Format: Carlos Alemany, Manish Patel, Zahi Mitri, Joseph Sparano, Virginia Borges, Della Makower, Pam Klein, Julia Lawrence, Trinh Le, Jo Anne Zujewski, Erika Harmilton. A phase 1/2 dose escalation and expansion study of OP-1250 in adults with advanced and/or metastatic hormone receptor-positive (HR+), HER2-negative (HER2−) breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P037.