Colorectal Cancer Clinical Trials

⁃ \*\*Diagnosis / Histology\*\*

• Histologically confirmed adenocarcinoma of the colon or rectum.

• Pathology report available for central or sponsor review (if requested), including:

• Primary tumor site (colon vs rectum)

• Grade of differentiation

• Resection margins

• \*\*Stage and Surgical Status\*\*

• Pathologic stage III disease (any T, N1-2, M0) per AJCC 8th edition.

• R0 resection of the primary tumor documented by operative and pathology reports (no macroscopic or microscopic residual tumor at margins).

• No evidence of distant metastatic disease (M1) on staging imaging (CT chest/abdomen/pelvis ± MRI/PET per institutional standard) within a protocol-defined window (e.g., ≤8 weeks prior to enrollment).

• Enrollment and treatment initiation planned within a protocol-defined timeframe after surgery (e.g., 4-12 weeks post-resection), allowing appropriate recovery.

• \*\*Molecular Subtype (MSS/pMMR)\*\*

• Tumor confirmed MSS or pMMR by local testing using one or more of the following:

• IHC for MLH1, MSH2, MSH6, and PMS2

• PCR-based MSI panel

• NGS-based MSI/MMR assessment

• No evidence of dMMR/MSI-H status or POLE ultramutated phenotype.

• \*\*High-Risk Recurrence Profile\*\*

• At least one protocol-defined high-risk feature, including one or more of the following:

• Pathologic T4 tumor

• Pathologic N2 nodal status (≥4 positive lymph nodes)

• Positive postoperative ctDNA (MRD) by a validated tumor-informed assay within a protocol-defined window after surgery/chemotherapy initiation

• Other protocol-specified high-risk features (e.g., lymphovascular invasion, perineural invasion, poorly differentiated histology, inadequate lymph node sampling), as defined in the protocol/statistical analysis plan

• \*\*Suitability for Standard Adjuvant Chemotherapy\*\*

• Candidate for oxaliplatin-based adjuvant chemotherapy with one of the following:

• mFOLFOX6 every 14 days for \

‣ 6 months, \*\*or\*\*

• CAPOX (XELOX) every 21 days for \

‣ 3-6 months

• Chemotherapy regimen (mFOLFOX6 vs CAPOX) determined before enrollment and recorded as a stratification factor.

• No contraindications to oxaliplatin, 5-fluorouracil, leucovorin, or capecitabine (e.g., severe DPD deficiency; prior severe 5-FU/capecitabine toxicity).

• \*\*Suitability for Nivolumab\*\*

• Eligible in the investigator's judgment to receive anti-PD-1 therapy (nivolumab 3 mg/kg IV every 2 weeks), including:

• No history of severe (Grade ≥3) immune-related adverse events from prior immunotherapy

• No active autoimmune disease requiring systemic immunosuppression

• \*\*Performance Status\*\*

• ECOG performance status 0-1 at screening.

• \*\*Adequate Organ and Marrow Function\*\* (documented within 14 days prior to enrollment; no transfusions/growth factors solely to meet eligibility)

• \*\*Hematologic\*\*

• ANC ≥ 1.5 × 10⁹/L

• Platelets ≥ 100 × 10⁹/L

• Hemoglobin ≥ 9.0 g/dL (transfusions allowed if clinically indicated, but not solely to qualify)

• \*\*Hepatic\*\*

• Total bilirubin ≤ 1.5 × ULN (≤3 × ULN allowed for known Gilbert's syndrome if direct bilirubin is normal)

• AST and ALT ≤ 2.5 × ULN

• Alkaline phosphatase ≤ 2.5 × ULN (higher thresholds may be allowed for non-malignant causes per protocol)

• \*\*Renal\*\*

• Serum creatinine ≤ 1.5 × ULN \*\*or\*\* creatinine clearance ≥ 50 mL/min (Cockcroft-Gault or institutional standard)

• \*\*Biospecimen Availability (COLONYVAQ)\*\*

• Adequate tumor tissue available from resected primary tumor (and/or metastases if applicable), including one of the following:

• Fresh frozen tissue (preferred), \*\*or\*\*

• FFPE block(s), \*\*or\*\*

• ≥15 unstained slides (or equivalent) suitable for DNA/RNA extraction

• Matched normal sample (peripheral blood) available for germline DNA sequencing.

• Willingness to provide additional blood samples for ctDNA, immune monitoring, and exploratory assays per schedule.

• Pre-existing WES/RNA-seq may be accepted if meeting COLONYVAQ requirements per protocol.

• \*\*Neoantigen Suitability\*\*

• At least one predicted high-quality tumor neoantigen identified by the COLONYVAQ pipeline meeting prespecified criteria, including:

• Strong predicted binding to patient-specific HLA alleles (e.g., Kd in an established binder range)

• Evidence of tumor RNA expression of the source gene/allele

• Prioritization by multi-algorithm immunogenicity scoring and passage through COLONYVAQ quantum-geometric, thermodynamic, and immunogenicity gates

• \*\*OR\*\*

• Availability of pre-manufactured GMP-grade neoantigen peptides with demonstrated in vitro immunogenicity and acceptable safety profile.

• \*\*Life Expectancy\*\*

• Investigator-estimated life expectancy ≥ 3 years in the absence of CRC recurrence.

• \*\*Contraception and Pregnancy\*\*

• \*\*Women of childbearing potential (WOCBP)\*\*

• Negative serum or urine pregnancy test within 7 days prior to randomization

• Agreement to use highly effective contraception during treatment and for a protocol-defined period after last dose (e.g., 5 months after last nivolumab and 6 months after last chemotherapy, or per label/institutional guidance)

• \*\*Men with partners of childbearing potential\*\*

• Agreement to use effective contraception and avoid sperm donation during treatment and for the protocol-defined period after last dose

• \*\*Informed Consent and Compliance\*\*

• Able to understand and voluntarily sign written informed consent.

• Willing and able to comply with all study procedures (visits, imaging, blood draws, follow-up).