A Study of Samuraciclib and Elacestrant in Participants With Metastatic or Locally Advanced HR+/HER2-negative Breast Cancer

Study Overview
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Brief Summary
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This is an international, multisite, open-label, Phase 1b/2 study, to confirm safety and efficacy of samuraciclib in combination with elacestrant in adult participants with metastatic or locally advanced Hormone Receptor (HR) positive and Human Epidermal Growth Factor Receptor (HER)2-negative breast cancer.

Detailed Description
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This is a multiple cohort study, an initial dose escalation phase is designed to confirm the safe dose of samuraciclib in combination with elacestrant. A Safety Review Committee (SRC) will monitor the safety, tolerability, and PK data during this phase. Once ascertained, an expansion cohort will be opened to explore the efficacy of samuraciclib in combination with elacestrant.

Official Title
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A Phase 1b/2 Open-label Study of Samuraciclib in Combination With Elacestrant in Participants With Metastatic or Locally Advanced Hormone Receptor-positive and Human Epidermal Growth Factor Receptor 2-negative Breast Cancer

Conditions
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Metastatic Breast Cancer, Locally Advanced Breast Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Samuraciclib
* Drug: Elacestrant Dihydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of ER-positive, HER2-negative locally advanced or metastatic breast cancer. Documented objective disease progression while on or within 6 months after the end of the most recent therapy. Received prior AI in combination with a CDK4/6i as the last therapy Known TP53 and ESR1 mutation status. Participants must have measurable disease or bone only disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Pre/peri-menopausal participants must have commenced treatment with a luteinizing hormone-releasing hormone (LHRH) agonist at least 4 weeks prior to first dose of study intervention. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 with no deterioration over the past 2 weeks. Expected life expectancy of >12 weeks in the judgement of the treating investigator. Exclusion Criteria: Inflammatory breast cancer. Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. More than 1 line of endocrine treatment for locally advanced or metastatic disease treatment. Inadequate hepatic, renal, and bone marrow function. Clinically significant cardiovascular disease. Any current or prior central nervous system metastases, carcinomatous meningitis, or leptomeningeal disease. Pregnant or breastfeeding women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Up to 6 evaluable participants will receive samuraciclib 240 mg in combination with elacestrant 300 mg in cycles of 28 days (Cycle 1 to 6), 56 days (Cycle 7 to 9) and up to 84 days (Cycles 10 onwards). | Drug: Samuraciclib<br>* Samuraciclib capsules by mouth once a day<br>Drug: Elacestrant Dihydrochloride<br>* Elacestrant tablets by mouth once a day<br>* Other names: ORSERDU;|
| Experimental: Cohort 2<br>Up to 6 evaluable participants will receive samuraciclib in combination with elacestrant at the SRC recommended dose (anticipated 360mg samuraciclib, 300 mg elacestrant) in cycles of 28 days (Cycle 1 to 6), 56 days (Cycle 7 to 9) and up to 84 days (Cycles 10 onward). | Drug: Samuraciclib<br>* Samuraciclib capsules by mouth once a day<br>Drug: Elacestrant Dihydrochloride<br>* Elacestrant tablets by mouth once a day<br>* Other names: ORSERDU;|
| Experimental: Cohort 3<br>Up to 6 evaluable participants will receive samuraciclib in combination with elacestrant at the SRC recommended dose (anticipated 360mg samuraciclib, 400 mg elacestrant) in cycles of 28 days (Cycle 1 to 6), 56 days (Cycle 7 to 9) and up to 84 days (Cycles 10 onward). | Drug: Samuraciclib<br>* Samuraciclib capsules by mouth once a day<br>Drug: Elacestrant Dihydrochloride<br>* Elacestrant tablets by mouth once a day<br>* Other names: ORSERDU;|
| Experimental: Cohort 4 Expansion<br>Up to 30 evaluable participants will receive samuraciclib in combination with elacestrant at the SRC recommended dose (anticipated 360mg samuraciclib, 400 mg elacestrant) in cycles of 28 days (Cycle 1 to 6), 56 days (Cycle 7 to 9) and up to 84 days (Cycles 10 onward). | Drug: Samuraciclib<br>* Samuraciclib capsules by mouth once a day<br>Drug: Elacestrant Dihydrochloride<br>* Elacestrant tablets by mouth once a day<br>* Other names: ORSERDU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b (Dose-finding) | Identification of Samuraciclib + Elacestrant combination, Phase 2, expansion dose level. Incidence and severity of adverse events as graded by the National Cancer Institute Common Terminology Criteria for Adverse events (NCI-CTCAE) v5.0. Safety will be assessed by monitoring treatment - emerged severe and dose limiting adverse events and clinically relevant changes in vital signs and clinical laboratory results | From the date of first dose of any study intervention (Day 1 Cycle 1) and through 28 days after the last dose of any study intervention | 
| Phase 2 (Expansion) | Progression Free Survival (PFS) is defined as the time from the date of first dose of IMP (Cycle 1 Day 1) to the date of the first documentation of objective progressive disease (PD) or death due to any cause, whichever occurs first. | From the date of first dose of any study intervention (Cycle 1 Day 1) until the first documentation of disease progression, death, withdrawal of consent, or start of new anticancer therapy (assessed up to week 48) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Emergent Adverse Events and Laboratory Abnormalities (Safety and Tolerability) | Type, incidence, severity (as graded by CTCAE v5.0), seriousness and relationship to study medications of AEs and any laboratory abnormalities. Safety will be assessed by monitoring adverse events and clinically relevant changes in vital signs and clinical laboratory results. | From the date of first dose of any study intervention through 28 days after the last dose of any study intervention | 
| Clinical Benefit Response (CBR) | CBR is defined as the overall complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks according to RECIST version 1.1 recorded from enrolment until disease progression, or death due to any cause. | From the date of first dose of any study intervention (Cycle 1 Day 1) to ≥ 24 weeks or until disease progression or death to any cause (assessed up to week 24) | 
| Overall response rate (ORR) | ORR is defined as the proportion of participants with a reduction in tumor burden with CR or PR according to RECIST version 1.1. ORR will be estimated for participants who received at least 1 dose of IMP, had measurable disease at baseline and had a postbaseline tumor assessment. | the date of first dose of study intervention (Cycle 1 Day 1) until the first documentation of disease progression, death, withdrawal of consent, or start of new anticancer therapy (assessed up to week 48) | 
| Duration of Response (DOR) | DOR is defined as the time from the date of first documentation of objective tumor response (CR or PR) to the earliest documented disease progression per RECIST version 1.1 | From the date of first dose of study intervention (Cycle 1 Day 1) until the first documentation of disease progression, death, withdrawal of consent, or start of new anticancer therapy (assessed up to week 48) | 
| Best percent change in tumor size. | Best percent change in tumor size is defined as the percentage change in the sum of the longest diameters of target lesions | From the date of first dose of study intervention (Cycle 1 Day 1) until the first documentation of disease progression, death, withdrawal of consent, or start of new anticancer therapy (assessed up to week 48) | 
| Samuraciclib plasma exposure: Cmax | Plasma concentration for Samuraciclib | Day 1 of Cycles 1 and Cycle 2 (each cycle is 28 days) | 
| Elacestrant exposure: Cmax | Plasma concentrations for Elacestrant | Day 1 of Cycles 1 and Cycle 2 (each cycle is 28 days) | 
| Samuraciclib plasma exposure: Ctrough |  | Cycle 1 Day 2 and 15; Day 2 of Cycle 2; Day 1 of Cycles 3-6 and end of treatment within 28 days of last dose of IMP and prior to the initiation of a new anticancer therapy (each cycle is 28 days)] | 
| Elacestrant exposure: Ctrough |  | Cycle 1 Day 2 and Day 15; Cycle 2 Day 2 of Cycle 2 and Day 1 of Cycles 3-6 and at end of treatment within 28 days of the last dose of IMP and prior to the initiation of a new anticancer therapy (each cycle is 28 days) | 
| Genotyping for ESR1 and TP53 mutations | Genotyping for ESR1 and TP53 mutations to evaluate correlations between ESR1 and TP53 mutations and efficacy/safety findings | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Breast Cancer, Advanced Breast Cancer, Breast Cancer, HR Positive, HER2-Negative