Evaluation of Geriatric Assessment-Guided Dose Optimization of CDK 4/6 Inhibitors in Vulnerable Elderly Patients with Advanced Breast Cancer

The primary objective of the IMPORTANT trial is to evaluate the **time to treatment failure (TTF)** in vulnerable or frail older patients with advanced breast cancer. This study compares the efficacy of a lower initial dose of CDK 4/6-inhibitors combined with endocrine therapy against the standard recommended full dose. Understanding TTF is clinically significant as it provides insights into the optimal dosing strategy that could potentially enhance treatment outcomes and minimize adverse effects in this patient population.

Secondary objectives include:

• Comparing the two treatment arms in terms of overall survival (OS).
• Assessing progression-free survival (PFS) as evaluated by investigators.
• Evaluating the time to initiation of chemotherapy.
• Determining overall treatment utility (OTU), which integrates efficacy, tolerability, quality of life (QoL), and patient acceptability.
• Assessing treatment tolerability.
• Evaluating patients' quality of life (QoL).
• Analyzing cost-effectiveness of the treatment regimens.

The clinical trial focuses on **advanced breast cancer** in older patients, specifically targeting individuals aged 70 years and above. The study population includes both male and female participants, with no specific vulnerable populations selected. Participants must have a histologically or cytologically confirmed diagnosis of HR-positive, HER2-negative breast cancer that is advanced, either locoregionally recurrent or metastatic, and not amenable to curative treatment. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are required to have adequate organ function and must be able to swallow capsules. Lifestyle considerations such as diet and physical activity are not detailed in the trial data. The selection criteria emphasize the need for participants to have no prior systemic treatment for advanced disease, although certain prior treatments are permissible under specific conditions. The trial aims to investigate the time to treatment failure in this demographic when treated with a lower initial dose of CDK 4/6-inhibitors plus endocrine therapy compared to the recommended full dose.

The clinical trial is designed to evaluate the **time to treatment failure** in older patients with advanced breast cancer, specifically those who are vulnerable or frail. The study employs a **randomized, controlled** methodology to compare the effects of a lower initial dose of CDK 4/6-inhibitors plus endocrine therapy against the standard full dose. The trial is structured as a **double-blind** study to ensure unbiased results. The estimated duration of the trial is from November 15, 2023, to November 15, 2031, allowing for comprehensive data collection and analysis over an extended period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of HR-positive, HER2-negative breast cancer, and adequate organ function. Following the screening, participants will be randomized into treatment groups. Regular follow-up visits will be scheduled to monitor treatment efficacy, safety, and any adverse effects. These visits will also assess secondary endpoints, including overall survival, progression-free survival, and quality of life (QoL). The end-of-study visit will conclude the participant's involvement, summarizing the treatment outcomes and any long-term effects observed.

The expected length of participant involvement is up to 60 months, depending on individual response and treatment tolerance. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The trial aims to provide valuable insights into optimizing treatment regimens for older breast cancer patients, potentially improving therapeutic outcomes and quality of life.

The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The experimental medications include **Kisqali** (ribociclib), **IBRANCE** (palbociclib), and **Verzenios** (abemaciclib). Kisqali is provided as 200 mg film-coated tablets, administered orally with a maximum daily dose of 600 mg. The treatment period is up to 60 days. IBRANCE is available in hard capsule form with dosages of 75 mg, 100 mg, and 125 mg, also administered orally. The maximum daily dose for IBRANCE is 125 mg, with a treatment period of up to 60 days. Verzenios is available in film-coated tablets with dosages of 50 mg, 100 mg, and 150 mg, administered orally with a maximum daily dose of 300 mg, and a treatment period of up to 60 days.

Non-experimental treatments include **Faslodex** (fulvestrant), **Aromasin** (exemestane), **Femara** (letrozole), and **Arimidex** (anastrozole). Faslodex is provided as a 250 mg solution for injection, with a maximum daily dose of 500 mg, administered via injection over a treatment period of up to 60 days. Aromasin is available as 25 mg coated tablets, administered orally with a maximum daily dose of 25 mg, and a treatment period of up to 60 days. Femara is provided as 2.5 mg film-coated tablets, administered orally with a maximum daily dose of 2.5 mg, and a treatment period of up to 60 days. Arimidex is available as 1 mg film-coated tablets, administered orally with a maximum daily dose of 1 mg, and a treatment period of up to 60 days.

All medications are of chemical origin and are administered according to the specified dosing schedules. Participant compliance is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to optimize the dosing of CDK 4/6 inhibitors in older breast cancer patients, comparing lower initial doses with the recommended full doses in combination with endocrine therapy.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Time to Treatment Failure (TTF)** in vulnerable or frail older patients with breast cancer. This parameter will be evaluated in patients treated with a lower initial dose of CDK 4/6-inhibitors plus endocrine therapy compared to those receiving the recommended full dose. Secondary endpoints include Overall Treatment Utility, Overall Survival, Progression-Free Survival, Time to Chemotherapy Initiation, Toxicity, Quality of Life (QoL), Time to QoL Deterioration, and Cost-effectiveness.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial duration, which is estimated to conclude by November 15, 2031. The trial is designed to be a low interventional study, focusing on optimizing the dose of CDK 4/6-inhibitors in the specified patient population. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The trial's primary and secondary endpoints will be analyzed to determine the efficacy of the treatment regimens under investigation.