Clinical Trial of an Anti-cancer Drug, CA-4948 (Emavusertib), in Combination With Chemotherapy Treatment (FOLFOX Plus Bevacizumab) in Metastatic Colorectal Cancer

PRIMARY OBJECTIVES: I. To assess dose-limiting toxicities (DLTs) and determine the recommended phase 2 dose (RP2D) of CA-4948 (emavusertib) in combination with leucovorin (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab in first-line treatment for patients with advanced or metastatic non-operable colorectal cancer (mCRC). II. To evaluate the safety and tolerability of the combination of CA-4948 (emavusertib) and FOLFOX plus bevacizumab. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate ribonucleic acid sequencing (RNAseq) data to examine the impact of interleukin 1 receptor associated kinase 4 (IRAK4) inhibition on downstream signaling in tumor samples. EXPLORATORY OBJECTIVES: I. To evaluate pharmacodynamic (PD) effect of CA-4948 (emavusertib) in combination with chemotherapy. II. To evaluate pharmacokinetics (PKs) of CA-4948 (emavusertib) in combination with chemotherapy. III. To explore biomarkers and genomic alterations associated with treatment response. IV. To evaluate if certain gene mutations alone or in combination are associated with response, progression free survival (PFS), and/or overall survival (OS). OUTLINE: This is a dose-escalation study of CA-4948 in combination with FOLFOX plus bevacizumab followed by a dose-expansion study. Patients are assigned to 1 of 2 groups. GROUP A: Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-14 of each cycle, bevacizumab intravenously (IV) over 30-90 minutes on day 1 of each cycle beginning in cycle 1, and oxaliplatin IV over 120 minutes, leucovorin calcium (leucovorin) IV over 2 hours, and fluorouracil IV bolus (optional) followed by continuous IV infusion over 46 hours on day 1 of each cycle. Cycles repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After treatment for 2 years, patients may continue treatment after discussion with the study chair. Patients also undergo blood sample collection and computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT throughout the trial. Patients may also undergo tumor biopsy throughout the trial. GROUP B: Patients receive CA-4948 PO BID on days 1-14 of each cycle, bevacizumab IV over 30-90 minutes on day 1 of each cycle beginning in cycle 2, and oxaliplatin IV over 120 minutes, leucovorin IV over 2 hours, and fluorouracil IV bolus (optional) followed by continuous IV infusion over 46 hours on day 1 of each cycle. Cycles repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After treatment for 2 years, patients may continue treatment after discussion with the study chair. Patients also undergo blood sample collection and CT, MRI, or PET/CT throughout the trial. Patients also undergo tumor biopsy throughout the trial. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 12 months after end of treatment.