A Study of OP-1250 in Combination with the CDK4/6 Inhibitor Palbociclib in Adult Subjects with Advanced or Metastatic hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) Breast Cancer

OP-1250 is a small molecule being developed as a Complete Estrogen Receptor Antagonist (CERAN) for the treatment of patients with advanced or metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC. Palbociclib is a commercially available kinase inhibitor indicated for the treatment of adult subjects with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC advanced or metastatic breast cancer in combination either with an aromatase inhibitor as initial endocrine-based therapy or fulvestrant in patients who have received prior therapy. The study consists of two parts: Part 1 (Dose Escalation Phase) planned dose: • Dose level 1: 30 mg • Dose level 2: 60 mg • Dose level 3: 90 mg • Dose level 4: 120 mg •Dose level 5: 150 mg •Dose level 6: 210 mg OP-1250 is dosed orally once daily in continuous 28-day cycles. All subjects will receive OP-1250 doses in combination with oral palbociclib 125 mg once daily for 21 days in continuous 28-day cycles In the absence of unacceptable treatment-related toxicity or disease progression, subjects may receive study treatment for up to 1 year and beyond 1 year with the agreement of the Investigator and the Sponsor. Subjects who discontinue OP-1250 must also discontinue palbociclib within the context of this protocol. Each cohort will be administered to a distinct group of subjects. Subjects in each cohort will continue to receive treatment as per above, at the assigned dose level, or at a reduced dose if required based on any toxicities that occur after the end of the DLT period. Intra-subject dose escalation is not permitted during dose escalation. However, once a RP2D is determined, subjects enrolled on the Phase I part of the study may be treated at the RP2D with approval of the Medical Monitor, if the PI or designee considers this in the best interest of the subject after discussion with the Medical Monitor. The DLT period is one cycle (Cycle 1). 3 patients are required per cohort (unless the cohort is required to be expanded to replace a subject who is not evaluable for dose escalation, or for a DLT). The last of the subjects in the cohort is to have completed the DLT period before the safety review is performed, and decision made to escalate to the next cohort. The actual number of days is dependent upon a number of factors including extraction of listings from the database for safety review, availability of members for safety review meeting etc. One week between cohorts is a reasonable assumption. Subjects are provided with a Dosing Diary to record daily administration of their study treatment. This would include any missed doses. This is reviewed by the study team at each clinic visit and any deviations from dosing schedule discussed with the subject. Also, empty bottles and any unused capsules/tablets are returned at every clinic visit for a pill count to be performed by the study team to check compliance. This will be reconciled against the subject dosing diary. Part 2 (Dose Expansion): This portion of the study further explores the safety and Pharmacokinetics of OP-1250 in combination with Palbociclib and to determine the recommended Phase II dose (RP2D) of OP-1250. The MTD is defined as the highest feasible dose tested in which greater than 33% (ie, less than or equal to 1 of 6) subjects experienced a DLT attributable to the study drug, when at least 6 subjects were treated at that dose and were assessable for toxicity. The RP2D will be determined after review of all the available safety and PK data. Additionally, there is an ongoing dose escalation/expansion study of OP-1250 monotherapy that may also be used to inform the decision re RP2D that will be used in Part 2. OP-1250 is dosed orally once daily in continuous 28-day cycles. As for Part 1; ongoing in the absence of unacceptable treatment-related toxicity or disease progression/whilst the patient is deriving clinical benefit per investigator discretion, for up to 12 months or longer if agreed by the investigator and sponsor. Part 2 will commence when the RP2D (dose to be taken into Part 2) has been determined. This will occur after the end of the DLT period for the last dose escalation cohort to be evaluated. The exact time between study parts will depend upon availability of all safety and PK data needed to make the dose determination. Delays are not anticipated Participant groups between study parts are distinct.