Evaluation of Safety and Efficacy of Telisotuzumab Adizutecan Combinations in Metastatic Colorectal Cancer: A Phase 2 Open-Label Randomized Study

The primary objectives of this Phase 2, open-label, randomized study are to evaluate the **efficacy** of telisotuzumab adizutecan combinations compared to standard of care treatment in patients with **metastatic colorectal cancer** (mCRC), assess the safety and tolerability of these combinations, and optimize the telisotuzumab adizutecan dose in combination regimens to determine the recommended Phase 3 dose (RP3D) in applicable substudies. These objectives are clinically relevant as they aim to establish a potentially more effective treatment regimen for mCRC, which could improve patient outcomes and inform future clinical practice.

Secondary objectives include evaluating additional efficacy endpoints of telisotuzumab adizutecan combinations in mCRC and assessing the pharmacokinetics (PK) of telisotuzumab adizutecan in combination regimens. These objectives are important for understanding the broader impact of the treatment on disease progression and the drug's behavior in the body, which can further guide clinical decision-making and optimize therapeutic strategies.

The clinical trial involves a total of **120 participants** diagnosed with **Metastatic Colorectal Cancer**. 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 inclusion criteria, such as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and possessing histologically or cytologically confirmed metastatic colorectal cancer. The trial also considers individuals with measurable disease as per RECIST v1.1 guidelines. The study population includes a vulnerable group, indicating careful consideration of ethical standards. Lifestyle factors such as diet and physical activity are not specified, but participants must meet cardiac health criteria, including a QTc interval of less than 470 msec and no significant cardiac abnormalities. The trial aims to evaluate the efficacy and safety of telisotuzumab adizutecan combinations compared to standard care, with a focus on optimizing dosage for future studies.

The clinical trial is designed as a **randomized**, open-label, master protocol study to evaluate the safety and efficacy of multiple treatment combinations with **telisotuzumab adizutecan** in subjects with **metastatic colorectal cancer**. The trial aims to compare the efficacy of telisotuzumab adizutecan combinations against standard care treatments, assess safety and tolerability, and optimize dosing for future studies. The trial is expected to run until March 2028, with recruitment starting in June 2025. Participants will be involved for a maximum treatment period of 13 weeks, with the possibility of early termination if adverse events or disease progression occur.

The study involves several key visits: an initial **screening visit** to confirm eligibility based on criteria such as **ECOG performance status** and measurable disease per RECIST v1.1, followed by regular treatment visits where participants receive intravenous infusions of the investigational products. These products include **bevacizumab**, **fluorouracil**, **folinic acid**, **oxaliplatin**, and **panitumumab**, alongside the test product, telisotuzumab adizutecan. Follow-up visits will monitor the participants' response to treatment, with assessments of objective response, progression-free survival, and overall survival. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing health concerns are addressed.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it in their best interest. The study's primary endpoint is the objective response rate, with secondary endpoints including progression-free survival, duration of response, overall survival, and disease control. The trial's design ensures rigorous assessment of the investigational treatments' impact on metastatic colorectal cancer, contributing valuable data to the field of oncology.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Telisotuzumab adizutecan**, also known as ABBV-400, is the primary experimental medication. It is an antibody-drug conjugate (ADC) provided as a **solution for infusion**. The active substance, telisotuzumab adizutecan, is of protein origin. The medication is administered **intravenously**. The dosing schedule and frequency are determined by the study protocol, with a maximum treatment period of 13 weeks. Participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen.

**Bevacizumab** is one of the comparator treatments used in the study. It is a concentrate for solution for infusion, with the active substance being a protein of other origin. Bevacizumab is administered intravenously, and the treatment period is up to 13 weeks. The medication is sourced locally by investigational sites or provided by AbbVie.

**Fluorouracil** is another comparator treatment, classified as an antineoplastic agent. It is provided as a solution for injection and administered intravenously. The active substance is of chemical origin, and the treatment duration is also up to 13 weeks. The medication is sourced locally or provided by AbbVie.

**Folinic acid** is used in two formulations within the trial, both as a solution for injection/infusion. It serves as a supportive treatment in combination with other antineoplastic agents. The active substance is of chemical origin, and the administration route is intravenous. The treatment period is up to 13 weeks, with local sourcing or provision by AbbVie.

**Oxaliplatin** is included as a comparator treatment, provided as a concentrate for solution for infusion. It is an antineoplastic agent of chemical origin, administered intravenously. The treatment period is up to 13 weeks, with the medication sourced locally or provided by AbbVie.

**Panitumumab** is another comparator treatment, classified as an antineoplastic agent. It is a concentrate for solution for infusion, with the active substance being a structurally diverse substance - immunoglobulin. Panitumumab is administered intravenously, with a treatment period of up to 13 weeks. The medication is sourced locally or provided by AbbVie.

The efficacy of the investigational treatment combinations involving **telisotuzumab adizutecan** in subjects with metastatic colorectal cancer will be assessed using several primary and secondary endpoints. The primary endpoint is the objective response rate, which includes confirmed Complete Response (CR) or Partial Response (PR) as assessed by the investigator according to RECIST version 1.1. A repeat assessment must confirm the response at least 28 days from the first documented response.

Secondary endpoints include Progression-Free Survival (PFS), Duration of Response (DOR), Overall Survival (OS), and Disease Control. PFS is defined as the time from the first dose of study treatment to the first occurrence of radiographic progression or death from any cause. DOR is the time from the first documented CR or PR to the first occurrence of radiographic progression or death. OS is defined as the time from the first dose of study treatment to death from any cause. Disease Control is assessed as the best overall response of confirmed CR, PR, or Stable Disease (SD) based on RECIST version 1.1.