A Phase 1/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of BLU-222 as a Single Agent and in Combination Therapy for Patients with Advanced Solid Tumors

The primary objective of this Phase 1/2 study is to evaluate the **safety** and **tolerability** of **BLU-222** as a monotherapy and in combination with carboplatin, ribociclib, and fulvestrant in patients with advanced solid tumors. In Phase 1, the study aims to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BLU-222. In Phase 2, the focus is on assessing the anticancer activity of BLU-222 at the RP2D. These objectives are clinically relevant as they aim to establish a safe and effective dosage regimen for BLU-222, potentially offering a new therapeutic option for patients with advanced solid tumors, including HR+ breast cancer, CCNE1 amplification, HER2-negative breast cancer, ovarian cancer, endometrial cancer, and gastric cancer.

Secondary objectives include:

• Phase 1: Assessing the anticancer activities of BLU-222 monotherapy and in combination with carboplatin, ribociclib, and fulvestrant; characterizing the pharmacokinetic (PK) profile of BLU-222; evaluating the effect of a high-fat meal on the PK of BLU-222; assessing the relative bioavailability of different generations of BLU-222 capsules; and evaluating treatment-induced modulation of cyclin E/CDK2 pathway biomarkers and CA-125 in ovarian cancer.
• Phase 2: Further characterizing the PK profile of BLU-222; assessing additional measures of anticancer activity at the RP2D in patients with advanced solid tumors; and evaluating treatment-induced modulation of CA-125 in ovarian cancer.

The clinical trial involves a total of **316 participants** diagnosed with various advanced solid tumors, including **HR+ breast cancer**, **HER2-negative breast cancer**, **ovarian cancer**, **endometrial cancer**, **gastric cancer**, and tumors with **CCNE1 amplification**. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on the progression of their disease beyond standard care, with specific criteria for those with HR+ HER2- breast cancer, endometrial and gastric cancer, and platinum-resistant ovarian cancer. The trial includes a vulnerable population, indicating careful consideration of ethical standards. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed to evaluate the **safety**, pharmacokinetics, and efficacy of BLU-222, both as a monotherapy and in combination with other agents, for patients with advanced solid tumors. This trial is structured as a Phase 1/2 study, employing a randomized, double-blind, controlled methodology. The estimated duration of the trial extends from November 2023 to May 2026, with participant involvement expected to last until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as progression beyond standard care for advanced solid tumors or specific cancer types like HR+ HER2-negative breast cancer. Following successful screening, participants will be randomized to receive BLU-222 either alone or in combination with carboplatin, ribociclib, and fulvestrant. The trial will include multiple follow-up visits to monitor safety, tolerability, and therapeutic response, with assessments including vital signs, ECGs, and laboratory parameters. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted.

The primary objectives in Phase 1 are to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BLU-222, while Phase 2 focuses on assessing the anticancer activity at the RP2D. Secondary endpoints include overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the pharmacokinetic parameters and potential correlations with safety and antitumor activity.

The clinical trial involves the administration of **BLU-222**, an investigational medication provided in the form of a hard capsule. The active substance, BLU-222, is of chemical origin and is manufactured by Blueprint Medicines. The medication is administered orally. The study aims to determine the maximum tolerated dose and recommended Phase 2 dose of BLU-222, both as a monotherapy and in combination with other treatments. The frequency of administration and specific dosing schedules are determined based on the study protocol, with compliance monitored through standard clinical trial procedures.

**Kisqali** (Ribociclib) is utilized as a comparator treatment in the study. It is provided in the form of film-coated tablets, each containing 200 mg of the active substance, ribociclib. Manufactured by Novartis Europharm Limited, this medication is also administered orally. The primary container, a blister pack, is repackaged into a child-resistant secondary carton for the trial, ensuring compliance with investigational material labeling requirements. The dosing schedule and administration frequency are aligned with the study's objectives and monitored for participant adherence.

**Fulvestrant STADA** is included in the trial as a non-experimental treatment. It is provided as a solution for injection in a pre-filled syringe, containing 250 mg of the active substance, fulvestrant. This medication, produced by Stadapharm GmbH, is administered via intramuscular injection. The secondary container is over-labeled to meet investigational material labeling requirements. The administration schedule is defined by the trial protocol, with compliance monitored accordingly.

**Carboplatin Hikma** is another non-experimental treatment used in the study. It is supplied as a solution for infusion, with a concentration of 10 mg/ml of the active substance, carboplatin. Manufactured by Hikma Farmacêutica (Portugal), S.A., this medication is administered through intravenous infusion. The primary container, a vial, is over-labeled and placed back into its original secondary container, which is then labeled with investigational material requirements. The dosing and administration are conducted as per the trial's guidelines, with participant compliance closely monitored.

The efficacy of the investigational product **BLU-222** will be assessed in a clinical trial involving patients with advanced solid tumors. The primary endpoints for Phase 1 include the determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of **BLU-222** as a monotherapy and in combination with carboplatin, ribociclib, and fulvestrant. The overall safety profile will be evaluated through the incidence of treatment-emergent adverse events (TEAEs), changes in vital signs, electrocardiograms (ECGs), and clinical laboratory parameters.

In Phase 2, the primary endpoint is the overall response rate (ORR), defined as the proportion of patients achieving a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. Secondary endpoints include duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetic (PK) parameters such as Cmax, Tmax, and AUC. Additionally, correlations between PK parameters and both safety and antitumor activity endpoints will be evaluated. Pharmacodynamic changes in cyclin E/CDK2 pathway biomarker expression levels will also be profiled.

The efficacy assessments will be conducted at various timepoints throughout the trial, with specific measurements and analyses planned to ensure comprehensive evaluation of the investigational product's anticancer activity and safety profile.