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)