Abstract C031: A randomized Phase 1b study of IGM-8444 in combination with FOLFIRI + bevacizumab compared to FOLFIRI + bevacizumab alone in second line metastatic colorectal cancer
Authors: Ulahannan Susanna , Pelster Meredith , LoRusso Patricia , Falchook Gerald , Wang Judy , Barve Minal , Grewal Jaspreet , Chow Warren , Henry Jason , Cecchini Michael , Subbiah Vivek , Leabman Maya , Hernandez Genevive , Li Yao , Sinclair Angus , Wang Beatrice , Kotturi Maya , Humke Eric , Ahern Sean , Ennis Leslie , Caruano Melaine , Agrawal Sapeck 
Published: December 2023

Abstract
Background: Death receptor 5 (DR5), a member of the tumor necrosis factor (TNF) receptor superfamily that binds to TNF-related apoptosis-inducing ligand and activates the extrinsic apoptotic pathway, is an attractive target for cancer therapies given its upregulated expression in multiple cancers and ability to induce apoptosis. However, key limitations of therapies targeting DR5 are a lack of potency due to an inability to multimerize DR5, and/or clinically significant hepatoxicity. IGM-8444 is an IgM-based DR5 agonist with 10 binding sites that allow multimerization and subsequent activation of DR5. Preclinical studies demonstrate IGM-8444 cytotoxicity as a single agent and in combination in a range of tumors. We discuss our ongoing randomized study of IGM-8444 in combination with FOLFIRI + bevacizumab compared to FOLFIRI + bevacizumab alone in second line metastatic colorectal cancer (mCRC) (NCT04553692).
Methods: This study is a Phase 1b, multicenter, randomized, open-label clinical trial of IGM-8444 in combination with FOLFIRI + bevacizumab compared to FOLFIRI + bevacizumab alone in patients with second line mCRC who have not received prior irinotecan in either the adjuvant, locally advanced, or metastatic setting. Patients will be randomized 1:1 either to Treatment Arm 1: IGM-8444 in combination with FOLFIRI + bevacizumab or Treatment Arm 2: FOLFIRI + bevacizumab. Patients will be stratified by the presence of liver metastases and KRAS mutational status. Patients randomized in Treatment Arm 2 will have the opportunity to crossover to Treatment Arm 1 after confirmed radiographic progression. Patients will receive IGM-8444 on Days 1 and 15 of each 28-day cycle at a dose level of 3 mg/kg. IGM-8444 will be dosed prior to administering FOLFIRI + bevacizumab in Treatment Arm 1. FOLFIRI + bevacizumab will be administered in accordance with prescribing guidelines and institutional standards. Patients will continue this regimen until disease progression or unacceptable toxicity. The primary endpoint will be progression-free survival as determined by study investigators. Secondary endpoints include frequency and severity of adverse events, overall response rate, duration of response, and overall survival as determined by study investigators. The randomized study is currently open with patients actively enrolling. The planned study size is 110 patients. Clinical Trial Registry Number NCT04553692
Citation Format: Susanna Ulahannan, Meredith Pelster, Patricia LoRusso, Gerald Falchook, Judy Wang, Minal Barve, Jaspreet Grewal, Warren Chow, Jason Henry, Michael Cecchini, Vivek Subbiah, Maya Leabman, Genevive Hernandez, Yao Li, Angus Sinclair, Beatrice Wang, Maya Kotturi, Eric Humke, Sean Ahern, Leslie Ennis, Melaine Caruano, Sapeck Agrawal. A randomized Phase 1b study of IGM-8444 in combination with FOLFIRI + bevacizumab compared to FOLFIRI + bevacizumab alone in second line metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C031.