Title
A Randomized, Active-Controlled, Double-blind, Multicenter, Phase 3 Clinical Study of Ivonescimab in Combination with FOLFOX versus Bevacizumab in Combination with FOLFOX for the First-line Treatment of Metastatic Colorectal Cancer (HARMONi-GI3)

Description
A Randomized, Active-Controlled, Double-blind, Multicenter, Phase 3 Clinical Study of Ivonescimab in Combination with mFOLFOX6 (Oxaliplatin, Leucovorin and 5-Fluorouracil) versus Bevacizumab in Combination with FOLFOX for the First-line Treatment of Metastatic Colorectal Cancer(HARMONi-GI3)

Objective
Primary Objective
-To compare the PFS as assessed by blinded Independent Radiological Review Committee (IRRC) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, of ivonescimab in combination with mFOLFOX6 to bevacizumab in combination with mFOLFOX6.

Secondary Objectives
-To compare the OS of ivonescimab in combination with mFOLFOX6 to bevacizumab in combination with mFOLFOX6.
-To compare ORR and DOR as assessed by blinded IRRC based on RECIST v1.1, of ivonescimab in combination with mFOLFOX6 to bevacizumab plus mFOLFOX6.
-To compare the safety and tolerability of ivonescimab in combination with mFOLFOX6 to bevacizumab in combination with mFOLFOX6.
-To evaluate the PK profile of ivonescimab in combination with mFOLFOX6.
-To evaluate the immunogenicity of ivonescimab in combination with mFOLFOX6.

Treatment This trial will be performed as a phase 3, randomized, active-controlled, double-blind, multiregional study comparing Ivonescimab in combination with mFOLFOX6 (Oxaliplatin, Leucovorin and 5-Fluorouracil) versus Bevacizumab in combination with mFOLFOX6 in patients with metastatic colorectal cancer who have not previously received systemic therapy for metastatic disease. Approximately 600 patients will be randomly assigned to the 2 treatment groups in a 1:1 ratio. Each enrolled subject will receive an intravenous infusion of the Ivonescimab/Bevacizumab Plus mFOLFOX6 (Q2W, up to 8 cycles) in treatment periods per the randomization schedule. Afterward, Ivonescimab/ Bevacizumab Plus 5-Fluorouracil and Leucovorin will be used for maintenance treatment (administered on Day 1 of each cycle, Q2W) for up to 2 years.

Key Eligibility Inclusion Criteria:

-ECOG performance status score of 0 or 1
-Expected life expectancy >/= 6 months
-Patients with histologically or cytologically confirmed metastatic CRC
-No prior systemic therapy for metastatic CRC
-At least 1 measurable noncerebral lesion

Exclusion Criteria:

-Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) disease
-Known BRAF V600E mutant status
-Current presence of significant radiographic or clinical manifestations of gastrointestinal (GI) obstruction
-Ascites requiring paracentesis within last 30 days
-Patients who have received prior immunotherapy or anti-angiogenic therapy for colorectal cancer
-Active or prior history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea)
-Resectable disease

Applicable Disease Sites
Colon and Rectum

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital