A Randomized, Active-Controlled, Double-blind, Multicenter, Phase III 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)

The main purpose of this study is to measure the safety and effectiveness with ivonescimab/SMT112 in combination with chemotherapy drugs, i.e., FOLFOX (Oxaliplatin, Leucovorin and Fluorouracil) in the first-line treatment of metastatic colorectal cancer (mCRC) compared to bevacizumab in combination with chemotherapy drugs, i.e., FOLFOX (Oxaliplatin, Leucovorin and 5-Fluorouracil). Ivonescimab/SMT112 is considered investigational and has not been approved by the U.S. Food & Drug Administration/local Regulatory Authority for treatment or sale. Bevacizumab is a different approved drug sold under the brand name Avastin. FOLFOX is a standard chemotherapy regimen made up of the drugs folinic acid (leucovorin, FOL), fluorouracil (5-FU, F), and oxaliplatin (Eloxatin, OX).

For more information, visit: https://clinicaltrials.gov/study/NCT07228832

Inova Schar Cancer Institute
A division of Inova Fairfax Hospital
8081 Innovation Park Drive 
Fairfax, VA 22031

• Age ≥18 at the time of enrollment, both male and female.
• An Eastern Cooperative Oncology Organization Group (ECOG) performance status 
  score of 0 or 1.
•  Expected life expectancy ≥ 6 months.
• Patients with histologically or cytologically confirmed metastatic CRC, not amenable to 
  curative resection.
• At the time of enrollment, the patient has remaining archival formalin-fixed paraffin 
  embedded (FFPE) tumor tissue from his/her CRC diagnostic sample or tumor biopsy.
•  Known BRAF, KRAS and NRAS (extended RAS) mutation status from existing 
  reports, or determined by testing tumor tissue utilizing a clinical assay.
•  No prior systemic therapy for metastatic CRC.
  a. If patients have received systemic therapy or radiotherapy for early-stage disease, 
  >12 months must have elapsed since completion of neoadjuvant therapy and/or 
  adjuvant therapy (including adjuvant oxaliplatin or radiotherapy) and prior to 
  diagnosis of recurrent or metastatic disease.
• At least one measurable tumor lesion according to RECIST v1.1 that is amenable to 
  repeated accurate measurements.

• Known BRAF V600E mutant status; known DPD deficiency (refer to local fluorouracil 
  label or local clinical guidance for DPD status recommendation prior to starting 
  treatment).
• Resectable oligometastastic only disease, with multidisciplinary plan for complete 
  resection of all disease.
• Current presence of significant radiographic or clinical manifestations of gastrointestinal 
  (GI) obstruction.
• Ascites requiring paracentesis within last 30 days.
• Symptomatic central nervous system (CNS) metastases with hemorrhagic features, CNS 
  metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need 
  for CNS radiation within the first cycle, or leptomeningeal disease.
  Note: Patients who have stopped corticosteroids or are on stable corticosteroid therapy 
  (prednisone ≤ 10 mg daily or equivalent) are allowed.
• Presence of brainstem, meningeal metastases, spinal cord metastases, or compression
• Other prior malignancy unless the patient has undergone curative therapy with no 
  evidence of disease recurrence within 3 years prior to randomization.
  The following malignancies will be allowed without the 3-year interval after adequate 
  treatment: basal cell or squamous cell carcinoma of skin, superficial bladder cancer, in 
  situ cervical cancer, other in situ cancers, prostate cancer with a Gleason score ≤6 that 
  does not need therapy or other local tumors that are considered cured.
• Concurrent enrollment in another clinical study, unless it is an observational, 
  non-interventional clinical study or a follow-up period for an interventional study.
• Palliative local therapy for non-target lesions and non-specific immunomodulatory 
  therapy (such as interleukin, interferon, thymus peptide, tumor necrosis factor, etc.) 
  within 2 weeks before the first dose.
• Patients who have received prior immunotherapy or anti-angiogenic therapy for 
  colorectal cancer, including immune checkpoint inhibitors (such as other antiprogrammed cell death-1 or programmed cell death ligand-1 [PD-(L)1]/vascular 
  endothelial growth factor [VEGF] antibodies, anti-CTLA-4 antibodies, anti-TIGIT 
  antibodies, anti-LAG3 antibodies, etc.), immune checkpoint agonists (such as ICOS, 
  CD40, CD137, GITR, OX40 antibodies, etc.), immune cell therapy and any other 
  therapy based on the mechanism of action of tumor immunity or angiogenesis