Evaluation of Samuraciclib and Elacestrant Combination in Metastatic or Locally Advanced HR+ HER2- Breast Cancer

The primary objective of this study is to determine the recommended Phase 2 dose (**RP2D**) of **samuraciclib** and **elacestrant** in combination during the Phase 1b dose-finding stage. Additionally, in the Phase 2 expansion stage, the study aims to assess the efficacy of this combination in terms of progression-free survival (PFS) as evaluated by local investigators. This is clinically relevant as it seeks to establish an effective dosing regimen and evaluate the potential of the combination therapy to improve outcomes in patients with metastatic or locally advanced hormone-receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

Secondary objectives include: - Characterizing the safety and tolerability of the combination of samuraciclib and elacestrant. - Evaluating the pharmacokinetics (PK) of the combination and exploring any potential drug-drug interactions. - Further assessing the biological and antitumor activity of the combination. - Evaluating correlations between estrogen receptor 1 (ESR1) and tumor suppressor p53 (TP53) mutations and efficacy/safety findings in this participant population.

The clinical trial involves a total of **20 participants** diagnosed with **Breast Cancer**, specifically those with metastatic or locally advanced disease not suitable for curative resection or radiation therapy. The study population includes both male and female subjects, with an age range corresponding to adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of ER-positive and HER2-negative breast cancer, and documented disease progression following prior therapy. The trial does not include vulnerable populations. Participants are expected to have a life expectancy of more than 12 weeks. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to determine the recommended Phase 2 dose of samuraciclib and elacestrant in combination and assess their efficacy in terms of progression-free survival.

The clinical trial is designed as a **Phase 1b/2 open-label study** to evaluate the combination of **samuraciclib** and **elacestrant** in participants with metastatic or locally advanced hormone-receptor-positive and human epidermal growth factor receptor 2-negative **breast cancer**. The trial aims to determine the recommended Phase 2 dose (RP2D) during the Phase 1b dose-finding stage and assess the efficacy in terms of progression-free survival (PFS) during the Phase 2 expansion stage. The study is expected to commence recruitment on November 1, 2023, and conclude by June 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, documentation of ER-positive and HER2-negative status, and prior treatment history. The trial will include regular follow-up visits to monitor safety, efficacy, and pharmacokinetics, with assessments based on local investigator evaluations. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last until disease progression or study conclusion.

Participants are expected to remain in the study for the duration of the trial unless they experience unacceptable toxicity, withdraw consent, or the investigator determines it is in their best interest to discontinue. The primary endpoints include identifying the Phase 2 dose level and measuring PFS, while secondary endpoints focus on safety, clinical benefit response, overall response rate, duration of response, and pharmacokinetic parameters. The trial will adhere to rigorous scientific standards, ensuring that all data collected is reliable and contributes to the understanding of the treatment's efficacy and safety profile.

The clinical trial involves the administration of **ORSERDU 345 mg film-coated tablets**, which contain the active substance **elacestrant**. This pharmaceutical form is a film-coated tablet intended for **oral use**. The dosage and frequency of administration will be determined during the trial, with the aim of establishing the recommended Phase 2 dose (RP2D) in combination with other treatments. The product is manufactured by STEMLINE THERAPEUTICS B.V. and is of chemical origin. Participant compliance with the dosing schedule will be monitored throughout the study.

Another treatment used in the trial is **CT7001**, which is a capsule formulation containing the active substance **samuraciclib**. This medication is also administered orally. The trial will explore the optimal dosing schedule for CT7001 in combination with elacestrant, focusing on its efficacy in terms of progression-free survival in participants with metastatic or locally advanced hormone-receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. The product is developed by CARRICK THERAPEUTICS LIMITED and is of chemical origin.

Additionally, the trial includes the use of **ORSERDU 86 mg film-coated tablets**, which also contain **elacestrant** as the active ingredient. Similar to the 345 mg formulation, these tablets are designed for oral administration. The study will assess the combination of this dosage with other investigational treatments to determine the most effective therapeutic regimen. The tablets are produced by STEMLINE THERAPEUTICS B.V. and are chemically derived. Monitoring of participant adherence to the prescribed dosing regimen will be an integral part of the trial protocol.

The efficacy of the investigational combination of **samuraciclib** and **elacestrant** in participants with metastatic or locally advanced hormone-receptor-positive and human epidermal growth factor receptor 2-negative breast cancer will be assessed primarily through the endpoint of progression-free survival (PFS). PFS is defined as the time from enrollment until disease progression or death, as per local investigator assessment. This endpoint will be evaluated during the Phase 2 expansion of the trial.

Secondary efficacy endpoints include the clinical benefit response (CBR) at 24 weeks, which encompasses a complete or partial response, or stable disease for at least 24 weeks. The overall response rate (ORR) will be determined by the proportion of participants with a reduction in tumor burden, as defined by partial or complete response according to RECIST v1.1 criteria. The duration of response (DOR) will be measured from the documentation of tumor response to disease progression. Additionally, the best percent change in tumor size will be recorded.

Pharmacokinetic parameters, including plasma concentrations of samuraciclib and elacestrant, will be analyzed to explore correlations between ESR1 and TP53 mutations and efficacy/safety findings within the participant population. These assessments will be conducted using validated laboratory tests and methodologies appropriate for the clinical trial setting.