A Phase 2, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination With Bevacizumab and FOLFIRI Versus Bevacizumab and FOLFIRI in Previously Treated Advanced Inoperable Metastatic Colorectal Cancer (mCRC)

The primary objectives of this study are to evaluate the **safety** and tolerability of magrolimab in combination with bevacizumab and FOLFIRI (5-fluorouracil, irinotecan, and leucovorin) in a safety run-in cohort, and to determine the recommended Phase 2 dose (RP2D). Additionally, in the randomized cohort, the study aims to assess the efficacy of this combination in previously treated participants with advanced inoperable **metastatic colorectal cancer** (mCRC), as determined by progression-free survival (PFS) through investigator assessment. These objectives are clinically relevant as they address the potential for improved therapeutic strategies in mCRC, a condition with limited treatment options after initial therapies have failed.

The clinical trial involves a total of **81 participants** diagnosed with **metastatic colorectal cancer (mCRC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of adenocarcinoma originating in the colon or rectum, progression on or after one prior systemic therapy, and ineligibility for checkpoint inhibitor therapy. The trial population is characterized by a requirement for measurable disease according to RECIST V1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating a relatively stable general health status. Participants must have a life expectancy of at least 12 weeks and adequate liver and renal function, as well as sufficient blood counts. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **Phase 2**, randomized, open-label study designed to evaluate the safety and efficacy of **magrolimab** in combination with **bevacizumab** and FOLFIRI compared to bevacizumab and FOLFIRI alone in patients with previously treated advanced inoperable **metastatic colorectal cancer** (mCRC). The trial employs a randomized, controlled design to ensure robust data collection and analysis. The study is expected to last approximately 36 months, with an estimated recruitment start date of March 1, 2023, and an estimated end date of September 15, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed adenocarcinoma originating in the colon or rectum, measurable disease per RECIST V1.1 criteria, and an ECOG performance status of 0 or 1. Following the screening, participants will be randomized into either the experimental or control group. The trial includes a safety run-in cohort to evaluate the safety, tolerability, and recommended Phase 2 dose of magrolimab. The primary endpoint for the randomized cohort is progression-free survival as determined by investigator assessment using RECIST Version 1.1.

Study visits will include regular follow-up assessments to monitor safety and efficacy, with data collection on dose-limiting toxicities, adverse events, and laboratory abnormalities according to the NCI-CTCAE Version 5.0. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of the treatment's impact. Participants are expected to be involved for the duration of the trial unless conditions such as unacceptable toxicity, disease progression, or withdrawal of consent necessitate early termination. The trial's design ensures that all data collected will contribute to understanding the potential benefits and risks of the treatment regimen in this patient population.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Magrolimab** is an experimental medication used in this study. It is a **solution for infusion** containing the active substance magrolimab, a humanized monoclonal antibody of the IgG4 kappa isotype targeting CD47. The medication is administered via **intravenous administration**. The maximum daily dose is 31 mg/kg, with a total maximum dose of 2431 mg/kg over a treatment period of up to 36 weeks.

**Bevacizumab**, marketed as Avastin, is another experimental treatment in this trial. It is provided as a **concentrate for solution for infusion** and is administered through **intravenous infusion**. The active substance is bevacizumab, a protein-based therapeutic. The maximum daily dose is 5 mg/kg, with a total maximum dose of 360 mg/kg over the course of the study, which can last up to 36 weeks.

The study also includes the administration of **FOLFIRI**, a combination therapy consisting of **irinotecan hydrochloride trihydrate**, **fluorouracil**, and **leucovorin**. **Irinotecan hydrochloride trihydrate** is provided as a **concentrate for solution for infusion** and administered via **intravenous administration**. The maximum daily dose is 180 mg/m², with a total maximum dose of 12960 mg/m² over 36 weeks. **Fluorouracil** is available as a **solution for injection or infusion** and is also administered intravenously. The maximum daily dose is 1252 mg/m², with a total maximum dose of 201600 mg/m². **Leucovorin**, marketed as Leucovorin-Teva, is provided as a **concentrate for solution for infusion** and administered intravenously, with a maximum daily dose of 400 mg/m² and a total maximum dose of 28800 mg/m² over the study period.

Additional non-experimental treatments include **calcium levofolinate**, marketed as Calcio levofolinato Teva Generics, which is a **solution for infusion** administered intravenously. The maximum daily dose is 200 mg/m², with a total maximum dose of 14400 mg/m² over 36 weeks. **Paracetamol** is provided as **film-coated tablets** for oral administration, with a maximum daily dose of 1000 mg and a total maximum dose of 86000 mg. **Antihistamines for systemic use** and **corticosteroids for systemic use, plain** are also included as auxiliary treatments, with the former administered orally and intravenously, and the latter intravenously. The maximum daily doses for these are 400 mg and 40 mg, respectively, with total maximum doses of 34400 mg and 3440 mg over the study period.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)** in participants with advanced inoperable metastatic colorectal cancer (mCRC). This will be determined by investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. PFS is defined as the time from the date of randomization until the earliest date of documented disease progression or death from any cause, whichever occurs first. The time frame for this assessment is up to 3 years.

In the randomized cohort, the efficacy of the combination of magrolimab with bevacizumab and FOLFIRI will be compared to bevacizumab and FOLFIRI alone. The study will utilize a randomized, open-label design to ensure objective evaluation of the treatment effects. The primary endpoint will be measured at various time points throughout the study duration, with data collection and analysis conducted in accordance with established clinical trial protocols.