This is an open-label Phase 2 study to evaluate the safety and efficacy of Tovecimig combined with FOLFIRI in patients who have received one prior line of therapy for advanced or metastatic colorectal cancer (CRC).

Inclusion Criteria:

• Histologically or cytologically confirmed CRC.

• Patient must have undergone resection of his/her primary tumor either as part of treatment for early stage disease with subsequent metastatic progression or due to a tumor related complication in the metastatic setting (e.g. bowel obstruction).

• Measurable disease per RECIST 1.1.

• Patient must have advanced or metastatic disease, and have progressed on one line of standard of care therapy in the advanced/metastatic setting

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 8.0 g/dL
  • Total bilirubin ≤ 1.5 x IULN or ≤ 2.0 mg/dL in presence of liver metastases
  • AST(SGOT)/ALT(SGPT) ≤ 3x IULN or ≤ 5x IULN in presence of liver metastases
  • Creatinine clearance > 50 mL/min by Cockcroft-Gault

• The effects of Tovecimig and FOLFIRI on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after the last dose of Tovecimig or any component of FOLFIRI. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Patients with MSI-H status.

• Intact primary tumor that has not been resected.

• More than one line of prior therapy for advanced or metastatic CRC.

  *If FOLFIRI/FOLFOXIRI was given in the first line, it must have been completed ≥ 6 months before study start date.

• Surgery or major procedure, or systemic anticancer therapy within 4 weeks prior to C1D1.

• Radiation therapy within 2 weeks prior to C1D1.

• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.

• Receipt of any other investigational agents within 4 weeks prior to C1D1, with exception of investigational imaging agents.

• Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression.

• Prior history of diseases/conditions that elevates the patient's risk of hemorrhage, such as a bleeding diatheses, history of prior bowel perforation, or clinically significant active bleeding (i.e. hemoptysis larger than a tablespoon within 3 weeks prior to C1D1).

• Recent history of paracentesis (within 3 weeks prior to C1D1) or current indwelling catheter.

• A history of hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to Tovecimig (i.e. humanized/human monoclonal antibody drugs), FOFLIRI, or other agents used in the study.

• Use of anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylaxis) purpose within 10 days of C1D1.

• Use of aspirin, other NSAIDs (i.e. naproxen, ibuprofen), or other antiplatelet drugs within 10 days of C1D1.

• Uncontrolled intercurrent illness/infection requiring ongoing systemic antibiotics, antivirus drugs, or other uncontrolled active acute infectious diseases.

• A history of CHF (NYHA class II or higher) with 5 years prior to C1D1, LVEF < 50% on screening TTE/MUGA, uncontrolled hypertension (defined as SBP/DBP greater than 140/90 despite best supportive care at any time during screening), pulmonary hypertension, myocardial infarction, uncontrolled arrhythmia, unstable angina, or any significant valvular disease.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of C1D1.

• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.

• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.

• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.