Phase III Randomized, Double-Blind Study of Camizestrant and Palbociclib Versus Anastrozole and Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer

The primary objective of this study is to demonstrate the superiority of **AZD9833** plus **palbociclib** compared to anastrozole plus palbociclib by assessing progression-free survival (PFS) in patients with **estrogen receptor-positive, HER2-negative advanced breast cancer** who have not received any systemic treatment for advanced disease. This is clinically relevant as it aims to establish a more effective treatment regimen that could potentially improve patient outcomes in this specific cancer subtype.

Secondary objectives include:

• To demonstrate the superiority of AZD9833 plus palbociclib relative to anastrozole plus palbociclib by assessing overall survival (OS) and second progression-free survival.
• To estimate the effectiveness of AZD9833 plus palbociclib relative to anastrozole plus palbociclib by assessing objective response rate (ORR), duration of response (DoR), clinical benefit rate at 24 weeks, time to chemotherapy, time to first subsequent therapy or death, and time to second subsequent therapy or death.
• To assess the steady-state pharmacokinetics (PK) of AZD9833 in combination with palbociclib in all participants who receive at least one dose of AZD9833 per the protocol, for whom there is at least one reportable PK concentration.
• To assess symptoms, functioning, and health-related quality of life in participants treated with AZD9833 plus palbociclib compared with anastrozole plus palbociclib using the EORTC QLQ-C30 and EORTC QLQ-BR45 questionnaires.

The clinical trial involves a total of **822 participants** diagnosed with **Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer**. The study population includes both female and male subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically or cytologically documented diagnosis of ER+, HER2-negative breast cancer, and being previously untreated with systemic anti-cancer therapy for their locoregionally recurrent or metastatic ER+ disease. The trial includes individuals with an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ and marrow function and must demonstrate willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. The trial also considers lifestyle factors, as pre-/peri-menopausal women or men must be amenable to treatment with concomitant, approved LHRH agonists for the study's duration. The trial population includes a vulnerable population, ensuring comprehensive representation in the study.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of AZD9833 (camizestrant) plus **palbociclib** compared to **anastrozole** plus palbociclib in patients with **Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer**. The primary objective is to demonstrate the superiority of the AZD9833 combination by assessing progression-free survival (PFS) as the primary endpoint. Secondary endpoints include overall survival, progression-free survival 2, objective response rate, duration of response, and other clinical measures. The trial is expected to run from May 2021 to February 2029, with a maximum treatment period of 26 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically documented ER+, HER2- negative breast cancer, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, as well as to collect data on secondary endpoints. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

Participant involvement is expected to last up to 26 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will ensure compliance with scheduled visits, treatment plans, and study procedures to maintain the integrity of the data collected. The study will utilize a placebo to match camizestrant and Arimidex to maintain blinding, ensuring unbiased results. The trial's design and methodology adhere to rigorous scientific standards to provide reliable and valid results for the treatment of advanced breast cancer.

The clinical trial involves the administration of several treatments, including **camizestrant**, **palbociclib**, **anastrozole**, **goserelin acetate**, and **leuprorelin acetate**, as well as corresponding placebos. **Camizestrant** is provided in the form of film-coated tablets, with a maximum daily dose of 75 mg. It is administered orally once daily for a maximum treatment period of 26 weeks. The active substance in camizestrant is chemically derived, and the product is manufactured by AstraZeneca AB. Compliance with the dosing schedule is monitored throughout the trial.

**Palbociclib** is available in various formulations, including 75 mg, 100 mg, and 125 mg hard capsules, as well as 75 mg, 100 mg, and 125 mg film-coated tablets. The maximum daily dose for palbociclib is 125 mg, administered orally. The treatment period extends up to 26 weeks. Palbociclib is a chemical substance produced by Pfizer Europe MA EEIG, and the product is relabelled for clinical trial use. Participant adherence to the dosing regimen is closely monitored.

**Anastrozole** is administered as 1 mg film-coated tablets, with a maximum daily dose of 1 mg. The tablets are taken orally once daily for up to 26 weeks. Anastrozole is a chemical compound provided by Laboratoires Juvisé Pharmaceuticals. For blinding purposes, the clinical trial presentation of anastrozole is identical to the commercial formulation, except for specific modifications to the tablet's appearance and packaging.

**Goserelin acetate** is delivered as an implant in a pre-filled syringe, with a maximum daily dose of 0.12 mg. The administration route is subcutaneous, and the treatment duration is up to 26 weeks. Goserelin acetate is a chemical substance, and participant compliance is monitored to ensure adherence to the treatment protocol.

**Leuprorelin acetate** is provided as a powder and solvent for prolonged-release suspension for injection, with a maximum daily dose of 0.13 mg. It is administered intramuscularly, with a treatment period of up to 26 weeks. Leuprorelin acetate is a chemical compound, and compliance with the administration schedule is tracked throughout the study.

Placebos are used to match camizestrant and anastrozole, ensuring blinding in the trial. The placebo for camizestrant is administered orally, while the placebo for anastrozole is also administered orally. Both placebos are designed to match the appearance and administration route of their respective active treatments, maintaining the integrity of the double-blind study design.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**, as evaluated by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This primary endpoint aims to demonstrate the superiority of AZD9833 plus palbociclib compared to anastrozole plus palbociclib in patients with estrogen receptor-positive, HER2-negative advanced breast cancer. Secondary endpoints include overall survival (OS), progression-free survival 2 (PFS2), objective response rate (ORR), duration of response (DoR), time to second subsequent therapy (TSST), time to chemotherapy (TTC), time to first subsequent anti-cancer therapy (TFST), clinical benefit rate at 24 weeks (CBR24), plasma concentration of AZD9833 at specified timepoints, and changes from baseline in EORTC QLQ-C30 and EORTC QLQ-BR45 scales.

The efficacy parameters will be collected and analyzed at various timepoints throughout the study, with specific attention to the progression of the disease as defined by RECIST criteria. The trial is designed to ensure rigorous assessment of these parameters to provide a comprehensive evaluation of the treatment's efficacy. The study will be conducted over an estimated period, with recruitment starting in May 2021 and expected to conclude by February 2029. The trial will involve a double-blind, randomized, multicenter approach to ensure the reliability and validity of the results.