This is a Phase 1b open-label, 2-part study in 3 treatment groups. The 3 treatment groups are as follows:
Treatment Group 1: Palazestrant (OP-1250) in combination with ribociclib (KISQALI®, Novartis Pharmaceuticals Corporation).
Treatment Group 2: Palazestrant (OP-1250) in combination with alpelisib (PIQRAY®, Novartis Pharmaceuticals Corporation).
Treatment Group 3: Palazestrant (OP-1250) in combination with everolimus.
Treatment Group 4: Palazestrant (OP-1250) in combination with atirmociclib.
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 tissue sample from a metastatic site, using locally accepted criteria by the local pathology report.
Prior or concurrent malignancy whose natural history or treatment may interfere with the safety or efficacy assessment of the investigational regimen.
Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
History of cerebral vascular disease within 6 months prior to the first administration 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.
Parallel
Palazestrant
DrugComplete estrogen receptor antagonist (CERAN)
Ribociclib
DrugAll subjects in Treatment Group 1 will receive palazestrant in combination with ribociclib.
Alpelisib
DrugAll subjects in Treatment Group 2 will receive palazestrant in combination with alpelisib.
Everolimus
DrugAll subjects in Treatment Group 3 will receive palazestrant in combination with everolimus.
Atirmociclib
DrugAll subjects in Treatment Group 4 will receive palazestrant in combination with atirmociclib.
Dose Limiting Toxicities (DLTs)
To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), and/ or recommended dose expansion (RDE) of palazestrant when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3), or atirmociclib (Treatment Group 4). The incidence of DLTs will be assessed in the Dose Escalation part (Part 1) of the study.
Characterize the incidence, nature and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) of palazestrant when administered with ribociclib, alpelisib, everolimus, or atirmociclib.
Characterize the incidence, nature and severity of TEAEs and SAEs of palazestrant when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), everolimus (Treatment Group 3), or atirmociclib (Treatment Group 4) according to NCI-CTCAE version 5.0.
Pharmacokinetics (PK) of palazestrant when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2), everolimus (Treatment Group 3), or atirmociclib (Treatment Group 4) .
To assess the PK of palazestrant (and potential metabolites) in combination with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), everolimus (Treatment Group 3), or atirmociclib (Treatment Group 4). Plasma levels of palazestrant will be assessed at predefined intervals to establish PK parameters (including: Cmax, Cmin, Tmax, AUC, and t1⁄2 as data permit) and palazestrant trough concentration at steady state).
Preliminarily assess the anti-tumor activity Overall Response Rate of palazestrant when administered with ribociclib, alpelisib, everolimus, or atirmociclib as assessed by the investigator using RECIST v1.1.
Tumor response will be evaluated in patients with measurable or evaluable disease using RECISTv1.1 guidelines.
Evaluate clinical benefit rate (CBR) of palazestrant when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3), or atirmociclib (Treatment Group 4).
CBR will be assessed as proportion of subjects achieving complete response (CR), partial response (PR), or stable disease (SD) with duration of at least 24 weeks.
Evaluate duration of response (DoR) of palazestrant when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), everolimus (Treatment Group 3), or atirmociclib (Treatment Group 4).
DoR will be calculated as the number of days from the start date of PR or CR (whichever response is achieved first) to the first date that progressive disease is documented.
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