Ivonescimab and ADG126, Alone, and in Combination With Leucovorin and Fluorouracil or FOLFIRI Regimen for the Treatment of Microsatellite Stable Advanced/Metastatic Colorectal Cancer

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative
* Agreement to blood collection for correlative analysis at baseline, 4 weeks, and 8 weeks, and then every subsequent 8 weeks
* Age: ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) ≤ 1
* Histologically confirmed advanced/metastatic MSS colorectal cancer. MSS status must have been confirmed by a Clinical Laboratory Improvement Amendments (CLIA) certified assay
* Measurable disease by RECIST 1.1
* Fully recovered from the acute, clinically significant, toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
* ARM A ONLY: Patients should not have evidence of hepatic metastatic disease
* ARM A ONLY: Patients should have progressed following irinotecan, oxaliplatin, fluoropyrimidine, and an anti-EGFR if clinically indicated
* ARM B ONLY: Patient is eligible for maintenance 5-FU/LV or 5-FU/LV bevacizumab
* ARM B ONLY: No history of significant toxicity to 5-FU/LV that required dose reduction in infusional 5-FU dosing
* ARM C ONLY: Patient is eligible for FOLFIRI chemotherapy
* ARM C ONLY: No history of significant toxicity to 5-FU/LV or irinotecan that required dose reduction in infusional 5-FU dosing or irinotecan
* ARM C ONLY: No prior progression on prior irinotecan and no prior dose reduction on irinotecan due to toxicity
* Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L

  * NOTE: no blood transfusions or growth factor therapy used within 7 days of the screening complete blood count (CBC)
* Platelets ≥ 100 × 10\^9/L

  * NOTE: no blood transfusions or growth factor therapy used within 7 days of the screening CBC
* Hemoglobin ≥ 9.0 g/dL

  * NOTE: no blood transfusions or growth factor therapy used within 7 days of the screening CBC
* Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); For patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤ 3 × ULN
* Aspartate aminotransferase (AST) ≤ 2.5 x ULN; For patients with liver metastases ≤ 5 x ULN
* Alanine aminotransferase (ALT) ≤ 2.5 x ULN; For patients with liver metastases ≤ 5 x ULN
* Creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥ 30 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (adjustment by body surface area \[BSA\] is not required for eGFR; eGFR can be determined using the calculator from the National Kidney Foundation website \[www.kidney.org\])
* International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN (unless abnormalities are unrelated to coagulopathy). This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose
* Urine protein \< 2+ or 24-hour urine protein quantification \< 1.0 g
* For patients with KNOWN history of HIV, hepatitis C virus (HCV) and/or hepatitis B virus (HBV) seropositivity only, nucleic acid quantitation for their virus must be performed.

  * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load and a cd4 \> 400 are eligible for this trial.
  * Patients with known active hepatitis B are required to have hepatitis B DNA \< 200 IU/ml by polymerase chain reaction (PCR) and on appropriate anti-viral therapy with acceptable tolerability for one month prior to randomization.
  * All patients with known active hepatitis C (hepatitis C virus \[HCV\] antibody positive with HCV RNA levels above the lower limit of detection) are excluded
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 6 months after the last dose of study drug. Unsterilized male patients having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner must agree to use barrier contraception (male condom) for the duration of the treatment period until 6 months after the last dose of study drug. Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception for the duration of the treatment period until 6 months after the last dose of study drug

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Major surgical procedures or serious trauma within 4 weeks prior to study entry, or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to study entry
* Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation
* Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days or five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of protocol therapy
* Strong CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy (Arm C only)
* UGT1A1 inhibitors within 14 days prior to day 1 of protocol therapy (Arm C only)
* Any other anti-cancer therapy is prohibited, including but not limited to antibody-based therapy, retinoids, nitrosourea therapy, mitomycin C, small molecule tyrosine kinase inhibitors, proprietary Chinese medicines with anti-cancer activity, or radiotherapy
* Herbal medications must be cleared by the principal investigator (PI)
* Prior exposure to PD-1 or PD-L1 or CTLA-4 targeting agents
* History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to study entry, including but not limited to:

  * Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots) Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed
  * Nasal bleeding/epistaxis (bloody nasal discharge is allowed)
  * Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to study entry is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution or with the use of factor Xa inhibitors
* Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy
* Active autoimmune or lung disease requiring systemic therapy (eg, with disease modifying drugs, prednisone \> 10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to study entry, however the following will be allowed:

  * Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
  * Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted
* History of major diseases before study entry, specifically:

  * Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association \[NYHA\] classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to study entry, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia)
  * History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before study entry
  * History of any grade arterial thromboembolic event, grade 3 and above venous thromboembolic event, as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to study entry
  * Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before study entry
  * History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to study entry
* Imaging during the screening period shows that the patient has:

  * Radiologically documented evidence of major blood vessel invasion or fistula
* Symptomatic central nervous system (CNS) metastases, CNS metastases with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to study entry, potential need for CNS radiation within the first cycle, or leptomeningeal disease. Note: Patients must have stopped corticosteroids or be on physiologic corticosteroid replacement therapy (prednisone ≤ 10 mg daily or equivalent)
* Live vaccine or live attenuated vaccine within 4 weeks prior to planned study entry, or if scheduled to receive a live vaccine or live attenuated vaccine during the study period. Inactivated vaccines are permitted
* Severe infection within 4 weeks prior to study entry, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection (as determined by the investigator) requiring systemic anti-infective therapy within 2 weeks prior to study entry, (excluding antiviral therapy for hepatitis B or C)
* Has pre-existing peripheral neuropathy that is ≥ grade 2 by CTCAE version 5.0
* Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic or required paracentesis in the last 4 weeks prior to enrollment
* History of non-infectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease
* Active or prior history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea)
* Current use of systemic corticosteroids (\>10 mg daily prednisone or equivalent)
* High risk for bowel perforation such as obstructive gastrointestinal (GI) findings on imaging or symptoms suggesting bowel obstruction (post-prandial cramping, nausea, or vomiting)
* Presence of an enteric stent
* Open non-healing wounds
* History of bowel perforation unless related to the primary tumor and unless the tumor was resected or the patient has been diverted proximal to the tumor
* Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies; history of allergic reactions attributed to compounds of similar chemical or biologic composition to any study agent
* History or current evidence of any condition (medical \[including adverse events from prior anticancer therapy, disorders secondary to tumor\], surgical or psychiatric \[including substance abuse\]), or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, might lead to higher medical risk and/or is not in the best interest of the patient to participate, in the opinion of the treating investigator
* Clinically significant uncontrolled illness
* Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Patient is breastfeeding or plans to breastfeed during the study
* Females only: Pregnant
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)