Abstract OT-09-10: A phase I/II open-label, first-in-human, multicenter, dose escalation and dose expansion study of OP-1250 monotherapy in adult subjects with advanced and/or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer
Authors: Hamilton Erika , Alemany Carlos , Lin Nancy U , Klein Pamela M , Le Trinh , Kushner Peter J , Harmon Cyrus , Zujewski Jo Anne , Patel Manish 
Published: February 2021

Abstract
Background: Endocrine therapy has been the primary treatment modality for HR+, HER2- metastatic breast cancer (MBC). Endocrine agents are administered sequentially, either in combination with targeted therapy or as monotherapy. The majority of patients with HR+, HER2- MBC will develop endocrine resistant disease. More effective and less toxic therapies are needed for the treatment of endocrine resistant disease.
OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates Estrogen Receptor (ER), blocks ER-driven transcriptional activity, inhibits ER-driven breast cancer cell growth, and induces degradation of ER. OP-1250 demonstrates anti-cancer activity in vitro and in vivo, including activity against metastases in the brain and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with a favorable pharmacokinetic profile supportive of once-daily dosing. OP-1250 is hypothesized to completely antagonize ER resulting in superior efficacy compared to agents that only have partial antagonism of ER. Its favorable pharmacologic profile makes it an attractive agent for chronic use in patients with MBC.
Trial design: This is a Phase I/II open-label, first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D), to characterize the safety and pharmacokinetic (PK) profile, and to determine the preliminary efficacy of OP-1250 in adult subjects with HR+, HER2- MBC. Treatment will consist of oral, once a day dosing and subject evaluation will be performed in 28-day cycles. This study comprises 2 parts. Part 1 (Dose Escalation) will evaluate the safety and pharmacology of a range of doses of OP-1250 administered orally to subjects and to determine the maximum tolerated dose (if any) and/or the RP2D. Cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for DLTs during the first cycle of study treatment. Part 2 (Dose Expansion) will evaluate the preliminary activity of OP-1250. Patients with and without central nervous system (CNS) disease will be enrolled at the RP2D. This is designed using a Simon 2 Stage Design. Total accrual will be determined by the number of dose levels needed to identify the RP2D.
Eligibility criteria:Males and females, age 18 or older, with ER+, HER2− advanced or MBCPrior treatment with endocrine therapyECOG performance status of 0 or 1For dose expansion the subject must have measurable disease according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1
ObjectivesPart 1 (Dose Escalation)To identify the DLT, MTD and/or RP2D of OP-1250To assess the safety and tolerability of OP-1250To assess the pharmacokinetics of OP-1250
Part 2 (Phase II: Monotherapy Expansion)Objective response rate (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have no evidence of central nervous system (CNS) metastases.To conduct a preliminary assessment of the antitumor activity (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have CNS disease. Assessment of response will be determined according to RECIST 1.1 and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria
Correlative ScienceTo determine biomarker expression, such as, ER, PR, Ki67 and others in the most recently obtained archival tumor tissue sampleTo evaluate whether ESR1 in circulating tumor DNA (ctDNA) can be correlated with response and/or activity of OP-1250To examine ctDNA pre- and post-therapy for mutESR1 and PIK3CA variants, and other relevant markers
For more information, please contact clinical@olemapharma.com
Citation Format: Erika Hamilton, Carlos Alemany, Nancy U Lin, Pamela M Klein, Trinh Le, Peter J Kushner, Cyrus Harmon, Jo Anne Zujewski, Manish Patel. A phase I/II open-label, first-in-human, multicenter, dose escalation and dose expansion study of OP-1250 monotherapy in adult subjects with advanced and/or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-10.