This is a Phase II, single-arm, open-label trial evaluating the feasibility, safety, and preliminary activity of neoadjuvant Zanzalintinib (a VEGFR-targeting TKI) and Retifanlimab (an anti-PD-1 antibody) in patients with resectable stage II-III mismatch repair-proficient (pMMR) colon cancer. The study's primary objective is to determine the proportion of patients able to undergo curative-intent surgery within 14-35 days after completing two cycles (6 weeks) of neoadjuvant therapy. Secondary objectives include assessment of safety/tolerability and rates of pathologic response, including tumor regression grade (TRG). Two-year relapse-free survival (RFS) will also be evaluated.

This trial builds on emerging evidence from neoadjuvant immunotherapy studies-including in pMMR tumors-and the recently positive readout of STELLAR-303, which evaluated Zanzalintinib plus a PD-(L)1 inhibitor in refractory metastatic colorectal cancer. With a favorable safety profile, short treatment window, and rapid post-treatment pathologic readout, this study provides a low-risk opportunity to test whether immunotherapy-based neoadjuvant strategies can improve outcomes and potentially redefine management in early-stage, pMMR colon cancer.

Inclusion Criteria:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. A signed informed consent must be obtained prior to conducting any study-specific procedures.
• Male or female adult 18 to 80 years of age on day of signing informed consent.
• Histological-confirmed adenocarcinoma of the colon that is amenable to curative intent resection.
• Only participants with pMMR/MSS CRC are eligible. Microsatellite status should be performed per local standard of practice. (e.g., IHC and/or PCR, next-generation sequencing). Subjects with unknown or indeterminate results for either test at the time of enrollment are not eligible.
• Adequate organ and marrow function as defined below:
• Absolute neutrophil count: ≥ 1,500/mcl
• Platelets: ≥ 100,000/mcL without transfusion within 2 weeks of screening laboratory sample collection
• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). This may be up to 3x ULN if Gilbert's syndrome is documented.
• AST and ALT ≤ 3 x institutional ULN.
• Serum creatinine ≤ 1.5 x ULN and EGFR ≥ 40
• ECOG performance status (PS) 0 or 1.
• Urine protein-to-creatinine ratio ≤ 1mg/mg creatinine.
• INR ≤ 1.5 and aPTT ≤ 1.2 x ULN
• Measurable disease as determined by RECIST v1.1.
• Sexually active fertile subjects and their partners must agree to use highly effective method of contraception during the course of the study and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (listed in addendum), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
• Through 186 days after the last dose of zanzalintinib or 120 days from retifanlimab (whichever is latest) for women of childbearing potential (WOCBP) or through 96 days after the last dose of zanzalintinib or retifanlimab (whichever is latest) for men
• At least T3 disease or with pathologically enlarged local lymph nodes by pre-surgical imaging.

Exclusion Criteria:

• Symptoms of clinical obstruction or impending clinical obstruction including severe constipation, nausea and vomiting, or other as deemed by the principal investigator.
• Tumor invading GI-tract from external viscera
• Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis
• Systemic therapy with immunosuppressive agents within 7 days or use of any investigational drug within 28 days before the start of trial treatment
• Prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy within the last two years.
• Previous malignant disease (other than the target malignancy to be investigated in this trial) within 2 years prior to study treatment initiation unless NED for greater than 2 years or deemed to have no possibility of interference with the current study (such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast).
• Receipt of any organ transplantation, including allogeneic stem cell transplantation
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent, such as rheumatoid arthritis, which in the opinion of the Investigator might impair the subject's tolerance or ability to participate in the trial
• Known severe hypersensitivity reactions to monoclonal antibodies or drug formulation components of retifanlimab or Zanalintinib
• Subject is pregnant or breast feeding or planning to become pregnant while enrolled in the study, up to the final end of treatment visit
• Congestive heart failure ≥ New York Heart Association (NYHA) class III.
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before start of study drug.
• Uncontrolled cardiac arrhythmias.
• Poorly controlled hypertension, defined as a blood pressure consistently above 140/90 mmHg despite optimal medical management.
• Persistent proteinuria of NCI-CTCAE Grade 3 or higher. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is < 3.5 g/24 hr.
• Non-healing wound, non-healing ulcer, or non-healing bone fracture.
• Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or NCI CTCAE Grade ≥ 2 diarrhea of any etiology other then secondary to colon cancer.
• Participants with an active, known or suspected autoimmune disease. -Participants with type I diabetes mellitus (T1DM), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).
• Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted.
• Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate.
• Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate.
• Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedications are permitted.
• Active infections requiring systemic antibiotics or antifungal or antiviral treatment within 7 days before first dose of study treatment
• Has received a live vaccine within 28 days before the planned start of study treatment (mRNA vaccines not considered live vaccines).

Note: Examples of live vaccines include but are not limited to measles, mumps, rubella, varicella-zoster (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines are live, attenuated vaccines and are not allowed

• Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 180 days after the last dose of retifanlimab.
• Participants with laboratory values at screening defined in Table 1.
• Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment
• Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment.

Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen.

Note: Subjects who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator.

• Concomitant anticoagulation with oral anticoagulants and platelets inhibitors including the following Warfarin, Clopidogrel Acceptable anticoagulants include wow molecular weight heparin, aspirin, rivaroxaban, apixaban, edoxaban
• Subjects must have discontinued non-accepted anticoagulant within 3 days or 5 half-lives prior to first dose of treatment (whichever is longer)
• Any medical condition, patient characteristic or past medical history that in the opinion of the principal investigator that would interfere with the patient's safety or compliance while on trial
• Any prior treatment with zanzalitinib or retifanlimab
• Stroke or including TIA, MI, or other ischemic event within 6 months before first dose of study treatment
• Known gastric or esophageal varices
• Ascites, pleural effusions, or pericardial fluid requiring drainage in the last 4 weeks.
• Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml) of red blood, or other history of significant bleeding within 12 weeks before first dose of study treatment
• Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed)
• Lesions invading or encasing any major blood vessels
• Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness with the exception of subjects meeting all of the following criteria: (1) on stable anti-retroviral therapy; (2) CD4+ T cell count ≥ 200/µL; and (3) an undetectable viral load. Note: HIV testing will be performed at screening if and as required by local regulation. Note: In order to be eligible, participants taking CYP inhibitors (eg, zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose.
• Requirement for hemodialysis or peritoneal dialysis.
• Major surgery within 8 weeks, prior laparoscopic nephrectomy within 4 weeks, minor surgery within 5 days. Endoscopy with or without biopsy is not considered minor surgery. Subjects must have complete wound healing before first dose of study treatment.
• Inability to swallow tablets or ingest a suspension either orally or by a NG or PEG tube.
• Known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease.
• Free T4 outside of the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after principal investigator approval.