Evaluation of Petosemtamab Monotherapy and Combination Therapy in Advanced Metastatic Colorectal Cancer and Malignant Solid Tumors

The primary objective of this study is to determine the **Objective Response Rate** and to characterize the safety and tolerability of **petosemtamab** as a single agent and in combination with other treatments in patients with advanced solid tumors, including **colorectal cancer metastatic** and other **malignant solid tumors**. This is clinically relevant as it aims to assess the therapeutic potential and safety profile of petosemtamab, which could inform treatment strategies for these conditions.

Secondary objectives include:

• To characterize the pharmacokinetics (PK) of petosemtamab, which is essential for understanding the drug's absorption, distribution, metabolism, and excretion.
• To evaluate antitumor activity in terms of progression-free survival (PFS) and duration of response (DOR), providing insights into the efficacy of the treatment.
• To evaluate overall survival, which is a critical endpoint in determining the long-term benefits of the therapy.

The clinical trial involves a total of **182 participants** diagnosed with **colorectal cancer metastatic** or other **malignant solid tumors**. The study population includes both male and female subjects, aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their diagnosis of unresectable or metastatic adenocarcinoma of the colon or rectum, with a requirement to be RAS/RAF wild type and naive to prior anti-EGFR therapy. The trial includes individuals who are eligible for pembrolizumab as first-line monotherapy or have progressed on or after anti-PD-(L)1 therapy and platinum-based chemotherapy. All participants must have adequate cardiac and organ function. The trial population is inclusive of vulnerable groups, ensuring a comprehensive assessment of the investigational treatment's safety and efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy and safety of **petosemtamab** in combination with other agents in patients with advanced solid tumors, including **colorectal cancer metastatic** and **malignant solid tumors**. The trial is structured in two phases: Phase 1 involves dose escalation to determine the maximum tolerated dose, while Phase 2 focuses on cohort expansion to further assess the efficacy and safety profile. The trial is expected to run from March 2018 to November 2027, with participant involvement lasting 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 age, performance status, and organ function. Following successful screening, participants will be randomized to receive either the investigational product or a control. Regular follow-up visits will be scheduled to monitor the **objective response rate** and the frequency and severity of adverse events. These visits will also include assessments of pharmacokinetic parameters and overall survival. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted to gather comprehensive data on the treatment's impact.

The expected length of participant involvement is contingent upon the progression of the disease and the individual's response to treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression that necessitates alternative treatment. The trial aims to provide valuable insights into the potential benefits and risks associated with the use of **petosemtamab** in combination therapies for advanced solid tumors.

The clinical trial involves the evaluation of **petosemtamab** (MCLA-158), an experimental medication, administered as a **solution for infusion**. This investigational drug is provided by Merus B.V. and is characterized as a protein of other origin. The administration route is **intravenous**, and the dosing schedule is determined based on the phase of the trial, either as a single agent or in combination with other treatments. Participant compliance is monitored through regular assessments and adherence checks.

**Calcium folinate** is used as a non-experimental treatment in this study. It is administered as a **powder for solution for infusion** via **intravenous administration**. Calcium folinate acts as a Vitamin B9 metabolite and is included to support the chemotherapy regimen. The dosing schedule is aligned with standard clinical practices for its use in combination therapies.

**Fluorouracil** is another non-experimental treatment included in the trial. It is provided as a **solution for injection** and can be administered through **intravenous bolus injection or IV infusion**. As a chemotherapy agent, fluorouracil is used in combination with other drugs to enhance therapeutic efficacy. The administration frequency and dosage are consistent with established chemotherapy protocols.

**Pembrolizumab**, marketed as Keytruda, is included as a comparator treatment. It is a **concentrate for solution for infusion** and is administered via **intravenous administration**. Pembrolizumab is a protein of other origin and is used in the trial to evaluate its efficacy in combination with petosemtamab. The dosing schedule follows the approved guidelines for its use in oncology.

**Irinotecan** is utilized as a chemotherapy agent in the study. It is provided as a **concentrate for solution for infusion** and administered through **intravenous administration**. The inclusion of irinotecan aims to assess its combined effect with the investigational drug. The dosing regimen is based on standard chemotherapy treatment protocols.

**Oxaliplatin** is also part of the chemotherapy regimen in this trial. It is administered as a **concentrate for solution for infusion** via **intravenous administration**. Oxaliplatin's role in the study is to evaluate its synergistic effects when used in combination with other chemotherapy agents. The administration schedule is consistent with its established use in clinical settings.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)**, which measures the proportion of patients with a predefined reduction in tumor size, and the frequency and severity of adverse events, serious adverse events, treatment discontinuations, and modifications. These parameters will provide insights into the therapeutic effectiveness and safety profile of the investigational product, **petosemtamab**, both as a single agent and in combination with other treatments.

Secondary endpoints will further evaluate the efficacy through pharmacokinetic parameters, including CEOI, Cmax, C0h, AUC, CL, Vss, tmax, and t1/2, as well as population pharmacokinetics. Additionally, the trial will assess **Progression-Free Survival (PFS)**, **Duration of Response (DOR)**, and **Overall Survival (OS)**. These endpoints will be measured at various timepoints throughout the study to capture a comprehensive view of the treatment's impact on disease progression and patient survival.