Evaluation of Dabrafenib, Trametinib, and Imatinib in the Treatment of Rare and Hard-to-Treat Cancers: A Clinical Trial on Drug Repurposing

The primary objective of this study is to describe the **anti-tumour activity** of commercially available targeted anti-cancer drugs in the treatment of patients with rare and hard-to-treat cancers. This is clinically relevant as it aims to provide insights into the effectiveness of existing medications in managing challenging cancer types, potentially leading to improved therapeutic strategies. Additionally, the study seeks to describe serious toxicity related to the study treatment, which is crucial for understanding the safety profile of these drugs in this specific patient population.

Secondary objectives include evaluating the efficiency of the investigational medication in patients who have progressed on standard of care treatment, with a focus on progression-free survival, overall survival, and duration of treatment. These measures are important for assessing the potential benefits of the investigational medication in extending patient survival and improving quality of life.

The clinical trial involves participants diagnosed with **cancer**, specifically targeting those with rare and hard-to-treat forms of the disease. The study population includes both male and female subjects, aged 18 years and older, with no specific vulnerable populations selected. Participants are required to have a pathology-proven locally advanced or metastatic malignant disease with no efficient standard anti-cancer treatment available. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and a life expectancy of at least three months. They should also have acceptable organ function and no known malabsorption syndrome for orally administered drugs. Lifestyle considerations such as diet and physical activity are not detailed in the trial information. The selection criteria emphasize the need for a genomic profile that suggests potential clinical benefit from the targeted anti-cancer therapies included in the study. Participants must also agree to use effective contraception methods due to the potential risks of drug treatment to a developing fetus.

The clinical trial is designed to evaluate the **anti-tumor** activity and safety profile of commercially available targeted anti-cancer drugs in patients with rare and hard-to-treat cancers. This is a phase II trial utilizing marketed and authorized drugs outside of their standard indications. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from February 2025 to February 2039, with the primary objective of assessing disease control at 16 weeks post-treatment initiation and monitoring treatment-related adverse events.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as **ECOG performance status**, life expectancy, and genomic profiling. The inclusion visit will also involve obtaining informed consent. Follow-up visits will be scheduled at regular intervals to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by factors such as unacceptable toxicity, disease progression, or withdrawal of consent.

The expected length of participant involvement is up to 100 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with study protocols, or the participant's decision to withdraw. The trial aims to provide valuable insights into the potential repurposing of existing drugs for earlier lines of treatment in rare cancer cases, with secondary endpoints including progression-free survival and overall survival.

The clinical trial involves the administration of several experimental medications, primarily focusing on the treatment of rare and hard-to-treat cancers. **Dabrafenib** is utilized in multiple formulations, including Tafinlar 50 mg and 75 mg hard capsules, as well as Finlee 10 mg dispersible tablets. These formulations are administered orally, with a maximum daily dose of 300 mg and a total dose limit of 10,000 mg over a treatment period of up to 100 days. The capsules and tablets are produced by Novartis Europharm Limited, and the active substance is of chemical origin. The marketed products have been modified with study-specific labeling for trial use.

**Trametinib** is another key active substance in this trial, available as Mekinist 0.5 mg and 2 mg film-coated tablets, and Spexotras 0.05 mg/ml powder for oral solution. These formulations are also administered orally, with a maximum daily dose of 2 mg and a total dose limit of 10,000 mg over the same treatment period. The products are manufactured by Novartis Europharm Limited, with the active substance being chemically derived. The marketed products have been adapted with labeling for clinical trial purposes.

**Imatinib** is included in the trial as Imatinib Teva 100 mg and 400 mg film-coated tablets. These tablets are administered orally, with a maximum daily dose of 400 mg and a total dose limit of 10,000 mg over the treatment period. The products are manufactured by TEVA B.V, and the active substance is of chemical origin. The labeling of these marketed products has been modified for use in the clinical trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus remains on evaluating the anti-tumor activity and toxicity of these targeted anti-cancer drugs in the specified patient population.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include disease control, defined as objective complete or partial response or stable disease at 16 weeks after treatment initiation, and treatment-related grade ≥3 and serious adverse events for all cohorts. Additionally, treatment-related grade 1-5 adverse events will be evaluated for cohorts with new treatment combinations. Secondary endpoints will focus on progression-free survival, overall survival, and the duration of time on the drug.

The assessment of these endpoints will be conducted according to established response criteria. The trial will utilize marketed and authorized drugs outside of their indication, specifically targeting patients with rare and hard-to-treat cancers. The trial is designed to describe the anti-tumor activity of these targeted anti-cancer drugs and to document any serious toxicity related to the study treatment. The trial is set to run until February 2039, with recruitment starting in February 2025.