Clinical trial NCT05508906: Phase 1b Combo w/ Ribociclib, Alpelisib, or Everolimus
Official title: A Phase 1b Open-Label Multicenter Study of OP-1250 (Palazestrant) in Combination With the CDK4/6 Inhibitor Ribociclib, With the PI3K Inhibitor Alpelisib, or With the mTOR Inhibitor Everolimus in Adult Subjects With Advanced and/or Metastatic ER Positive, HER2 Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Metastatic Breast Cancer
Advanced Breast Cancer
ER-positive Breast Cancer
HER2-negative Breast Cancer
Breast Cancer
Lead sponsor: Olema Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Novartis
First posted: 2022-08-19
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Treatment Group 1: OP-1250 in combination with ribociclib

Treatment Group 2: OP-1250 in combination with alpelisib

Treatment Group 3: OP-1250 in combination with everolimus
Primary purpose: TREATMENT

Brief summary: This is a Phase 1b open-label, 2-part study in 3 treatment groups. The 3 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).

Treatment Group 3: OP-1250 in combination with everolimus.

Detailed description: Part 1 (Dose Escalation): This part will evaluate the safety and pharmacokinetics of a range of doses of OP-1250 administered orally (PO) daily to subjects in combination with 600 mg of ribociclib administered PO daily for 21 consecutive days followed by 7 days off treatment (Treatment Group 1) or with 300 mg or 250 mg of alpelisib administered PO daily (Treatment Group 2) or with everolimus 10 mg administered PO daily (Treatment Group 3) and determine the RP2D (Recommended Phase 2 Dose) for each treatment group.

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 ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3) and provide an exploratory estimate of anti-tumor activity of the combinations. An additional group of OP-1250 at an alternate dose level in combination with ribociclib (Treatment Group 1b) will be explored to optimize the RP2D of OP-1250.

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 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.
* Evaluable disease with one of the following: 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) OR patients with predominantly bone disease (with or without other non-measurable lesions) are allowed if it is possible to evaluate on radiological examinations (eg. bone scan, PET/CT, CT, MRI) even if lesions are non-measurable according 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 received no more than 2 prior hormonal regimens (Treatment Group 2 and Treatment Group 3) for advanced or metastatic disease. Prior hormonal regimens in combination with CDK4/6 inhibitors are allowed in all treatment groups.
* Has received no more than 1 prior chemotherapy (which includes antibody drug conjugates) 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.
* History of severe cutaneous reaction, such as Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms.
* Has clinically significant co-morbidities, such as active infection, psychiatric disease, or any other condition that could impact the ability of the subject to participate in this study 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).

Primary outcomes:
measure: Dose Limiting Toxicities (DLTs)
timeFrame: The first 28 days of treatment
measure: Characterize the incidence, nature and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) of OP-1250 when administered with ribociclib, alpelisib, or everolimus
timeFrame: Up to 35 days after end of treatment
measure: Pharmacokinetics (PK) of OP-1250 when administered with ribociclib (Treatment Group 1) or alpelisib (Treatment Group 2), or everolimus (Treatment Group 3).
timeFrame: Every 28 days
Secondary outcomes:
measure: Preliminarily assess the anti-tumor activity (ORR) of OP-1250 when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3), as assessed by the investigator using RECIST v1.1.
timeFrame: Up to 1 year
measure: Evaluate clinical benefit rate (CBR) of OP-1250 when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3)
timeFrame: Up to 1 year
measure: Evaluate duration of response (DoR) of OP-1250 when administered with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3)
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: San Francisco
country: United States
facility: University of California San Francisco Health
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Orlando
country: United States
facility: Advent Health Hematology and Oncology
state: Florida
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health
state: Michigan
city: Minneapolis
country: United States
facility: Regents of the University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, School of Medicine
state: Missouri
city: New York
country: United States
facility: Ichan School of Medicine at Mount Sinai
state: New York
city: Charlotte
country: United States
facility: Atrium Health Levine Cancer Institute
state: North Carolina
city: Nashville
country: United States
facility: Henry-Joyce Cancer Clinic, The Vanderbilt Clinic
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Sydney
country: Australia
facility: Macquarie Health
state: New South Wales
city: Nedlands
country: Australia
facility: Breast Cancer Research Center- Western Australia
state: Western Australia
Study officials:
affiliation: Olema Pharmaceuticals, Inc.
name: Mark Shilkrut, M.D., PhD
role: STUDY_DIRECTOR
affiliation: Olema Pharmaceuticals, Inc.
name: Daniela Vecchio, PhD
role: STUDY_DIRECTOR
References: