Phase 1b Study of OP-1250 (Palazestrant) in Combination With Ribociclib, Alpelisib, Everolimus, or Atirmociclib in ER+, HER2- Breast Cancer

Inclusion Criteria:

• Female or male aged >18 years.

• Willing and able to participate and comply with all study requirements.

• Histologically- or cytologically-confirmed advanced or metastatic Breast Cancer (mBC).

• ER+/HER2- disease, as determined in the most recently obtained archival tumor tissuesample from a metastatic site, using locally accepted criteria by the localpathology report.

• Evaluable disease with one of the following: Measurable disease, ie, at least 1measurable lesion as per RECIST 1.1 (a lesion at a previously irradiated site mayonly be counted as a target lesion if there is clear sign of progression since theirradiation) OR patients with predominantly bone disease (with or without othernon-measurable lesions) are allowed if it is possible to evaluate on radiologicalexaminations (eg. bone scan, PET/CT, CT, MRI) even if lesions are non-measurableaccording to RECIST 1.1.

• Life expectancy ≥6 months, as judged by the investigator.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

• Has received no more than 1 prior hormonal regimen (Treatment Group 1). Has receivedno more than 2 prior hormonal regimens (Treatment Group 2 and Treatment Group 3) .Has received no more than 2 prior hormonal regimens for metastatic disease in Part 1 (Dose Escalation) and no more than 1 prior hormonal regimes in Part 2 (DoseExpansion) for metastatic disease, regardless of type of endocrine agent (TreatmentGroup 4) for advanced or metastatic disease. Prior hormonal regimens in combinationwith CDK4/6 inhibitors are allowed in all treatment groups. For subjects inTreatment Group 4, no prior chemotherapy for metastatic breast cancer is allowed.

• Has received no more than 1 prior chemotherapy (which includes antibody drugconjugates) for locally advanced or metastatic breast cancer.

Exclusion Criteria:

• Prior or concurrent malignancy whose natural history or treatment may interfere withthe safety or efficacy assessment of the investigational regimen.

• Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormality.

• History of cerebral vascular disease within 6 months prior to the firstadministration of study drug dose.

• History of a pulmonary embolism, or deep venous thrombosis within the last 6 months,or subject has an increased risk of thrombosis as determined by the investigator.

• History of pneumonitis or interstitial lung disease.

• Leptomeningeal disease or spinal cord compression.

• Medical history or ongoing gastrointestinal disorders that could affect absorptionof oral therapeutics.

• Known human immunodeficiency virus infection.

• Known clinically significant history of liver disease consistent with Child-PughClass B or C, including active viral or other hepatitis (eg, hepatitis B orhepatitis C virus), current alcohol abuse, or cirrhosis.

• History of severe cutaneous reaction, such as Stevens-Johnson syndrome, erythemamultiforme, toxic epidermal necrolysis, or drug reaction with eosinophilia andsystemic symptoms.

• Active infection or at a high risk of developing a serious infection (e.g.participants with immunodeficiencies, uncontrolled diabetes mellitus, uncontrolledheart disease, poor general health, poor nutritional status).

• Has clinically significant co-morbidities, such as, psychiatric disease, or anyother condition that could impact the ability of the subject to participate in thisstudy or otherwise has the potential to confound the study results.

• Have received prior treatment with OP-1250.

• Have received prior treatment with approved or investigational PI3K inhibitor (Treatment Group 2) or mTOR inhibitor (Treatment Group 3).