Phase 1b Combo w/ Ribociclib and Alpelisib

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1b open-label, 2-part study in 2 treatment groups. The 2 treatment groups are as follows: Treatment Group 1: OP-1250 in combination with ribociclib (KISQALI®, Novartis Pharmaceuticals Corporation). Treatment Group 2: OP-1250 in combination with alpelisib (PIQRAY®, Novartis Pharmaceuticals Corporation).

Detailed Description
-----------------
Part 1 (Dose Escalation): This part will evaluate the safety and pharmacokinetics (PK) of a range of doses of OP-1250 administered orally (PO) every day (QD) to subjects in combination with either 600 mg of ribociclib administered PO QD (Treatment Group 1) or with 300 mg of alpelisib administered PO QD (Treatment Group 2) to determine the recommended phase 2 dose (RP2D). The dose escalation phase will evaluate 3 to 6 subjects per cohort who are sequentially enrolled and monitored for DLTs during the first cycle of study treatment. Each cohort will be reviewed for safety, PK, and dose-limiting toxicity DLTs. The DLT observation may be extended to 2 cycles. Part 2 (Dose Expansion): This part of the study will further evaluate the safety and PK of OP-1250 at the RP2D in combination with either ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) and provide an exploratory estimate of anti-tumor activity of the combinations.

Official Title
-----------------
A Phase 1b Open-Label Multicenter Study of OP-1250 in Combination With the CDK4/6 Inhibitor Ribociclib or With the PI3K Inhibitor Alpelisib in Adult Subjects With Advanced and/or Metastatic HR Positive, HER2 Negative Breast Cancer

Conditions
-----------------
Metastatic Breast Cancer, Advanced Breast Cancer, HR-positive Breast Cancer, HER2-negative Breast Cancer

Intervention / Treatment
-----------------
* Drug: OP-1250
* Drug: Ribociclib
* Drug: Alpelisib


Participation Criteria
=================
Eligibility Criteria
-----------------
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 MBC HR+/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 Evaluable disease (measurable and non-measurable): Measurable disease, ie, at least 1 measurable lesion as per RECIST 1.1 (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).-Subject must have received at least 6 months of a prior continuous endocrine therapy for locally advanced or metastatic breast cancer 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 2 prior hormonal regimens for advanced or metastatic disease. Prior hormonal regimens in combination with CDK4/6 inhibitors are allowed. Has received no more than 1 prior chemotherapy for locally advanced or metastatic breast cancer. Exclusion Criteria: 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 History of pneumonitis or interstitial lung disease Leptomeningeal disease or spinal cord compression Medical history or ongoing gastrointestinal disorders that could affect absorption of oral therapeutics Known human immunodeficiency virus infection Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (eg, hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment Group 1: OP-1250 in combination with ribociclib Treatment Group 2: OP-1250 in combination with alpelisib
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OP-1250 with Ribociclib<br>Treatment Group 1: OP-1250 in combination with ribociclib (KISQALI®, Novartis Pharmaceuticals Corporation). | Drug: OP-1250<br>* OP-1250 is a small molecule and a CERAN being developed for the treatment of patients with advanced or metastatic HR+ and HER2- breast cancer.<br>Drug: Ribociclib<br>* All subjects in Treatment Group 1 will receive OP-1250 in combination with ribociclib.<br>* Other names: KISQALI;|
| Experimental: OP-1250 with Alpelisib<br>Treatment Group 2: OP-1250 in combination with alpelisib (PIQRAY®, Novartis Pharmaceuticals Corporation) | Drug: OP-1250<br>* OP-1250 is a small molecule and a CERAN being developed for the treatment of patients with advanced or metastatic HR+ and HER2- breast cancer.<br>Drug: Alpelisib<br>* All subjects in Treatment Group 2 will receive OP-1250 in combination with alpelisib.<br>* Other names: PIQRAY;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) | To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2), the incidence of DLTs will be assessed in the Dose Escalation part (Part 1) of the study. | The first 28 days of treatment | 
| Characterize the incidence, nature and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) | Characterize the incidence, nature and severity of TEAEs and SAEs of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) according to NCI-CTCAE version 5.0. | Up to 35 days after end of treatment | 
| Pharmacokinetics (PK) of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) | To assess the PK of OP-1250 in combination with ribociclib or alpelisib, plasma levels of OP-1250 (and potential metabolites) and ribociclib (Treatment Group 1) and plasma levels of OP-1250 (and potential metabolites) and alpelisib (Treatment Group 2) will be assessed at predefined intervals. | Every 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminarily assess the anti-tumor activity of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) | Tumor response will be evaluated in patients with measurable or evaluable disease using RECISTv1.1 guidelines. | Up to 1 year | 
| Evaluate clinical benefit rate (CBR) of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) | 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. | Up to 1 year | 
| Evaluate duration of response (DOR) of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2) | 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. | Up to 1 year |