COLONYVAQ™, a Quantum-Classical Guided Personalized Neoantigen Vaccine for MSS Stage III Colorectal Cancer

Summary

This is an early phase I, single-arm, open-label clinical study designed to evaluate the safety, tolerability, and feasibility of COLONYVAQ-CRC, a physics-aware, quantum-classical AI-guided personalized neoantigen peptide vaccine, administered in combination with standard adjuvant oxaliplatin-based chemotherapy (mFOLFOX6 or CAPOX) and nivolumab 3 mg/kg in patients with completely resected stage III microsatellite-stable (MSS) / proficient mismatch repair (pMMR) colorectal cancer. An initial safety cohort of 12 patients will be enrolled and closely monitored for toxicity attributable to the experimental vaccine preparation. If, among these 12 patients, fewer than 3 develop experimental-preparation-related toxicity greater than grade 2 and no patient develops experimental-preparation-related grade 4 toxicity, the study will expand to enroll a total of 50 patients. Primary objectives focus on safety and tolerability of the combination regimen. Secondary and exploratory objectives characterize neoantigen-specific immune responses, ctDNA dynamics, T-cell receptor (TCR) clonotype evolution, tumor immune microenvironment features, and preliminary disease control (disease-free survival and overall survival) to inform subsequent phase II design.

Eligibility

* Eligibility
* Inclusion Criteria

  * \*\*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).
* Exclusion Criteria

  * \*\*Residual or Metastatic Disease at Baseline\*\*
  * R2 resection or indeterminate margins not clearly R0.
  * Radiologic or histologic evidence of distant metastases (M1) at baseline staging (e.g., liver, lung, peritoneum).
  * Gross residual disease at the primary site.
  * \*\*Mismatch Repair-Deficient / MSI-High / POLE-Ultramutated Disease\*\*
  * Known dMMR/MSI-H CRC or POLE ultramutated tumors for which checkpoint inhibition is standard/preferred.
  * \*\*Prior Anticancer Therapy (Beyond Allowed Neoadjuvant)\*\*
  * Prior systemic therapy for metastatic CRC.
  * Neoadjuvant chemotherapy/chemoradiotherapy that:
  * Was not completed within protocol-defined windows, \*\*or\*\*
  * Led to unresolved Grade ≥2 non-hematologic toxicity (excluding alopecia or clinically insignificant neuropathy, per protocol)
  * Prior tumor vaccine targeting TAAs or neoantigens (peptide, DC, viral, RNA, or DNA).
  * Prior immune checkpoint inhibitor therapy (anti-PD-1, anti-PD-L1, anti-CTLA-4).
  * \*\*Active or Uncontrolled Infections\*\*
  * Systemic infection requiring IV or oral antimicrobials that would interfere with study treatment per investigator judgment.
  * Uncontrolled HIV (e.g., CD4 below protocol threshold or unsuppressed viral load).
  * Active hepatitis B with HBV DNA above predefined limit, or active hepatitis C with detectable HCV RNA not adequately treated.
  * Other clinically significant infections posing excessive risk with immunotherapy, vaccine, or chemotherapy.
  * \*\*Autoimmune Disease / Immunosuppression\*\*
  * Severe/uncontrolled autoimmune disease requiring systemic immunosuppression (e.g., high-dose corticosteroids, biologics), including (examples):
  * Systemic lupus erythematosus
  * Inflammatory bowel disease with recent flares
  * Rheumatoid arthritis requiring biologics
  * Multiple sclerosis
  * Myasthenia gravis
  * Exceptions may include (per protocol):
  * Stable autoimmune thyroiditis on replacement therapy
  * Vitiligo
  * Well-controlled type 1 diabetes
  * Chronic systemic corticosteroids \>10 mg prednisone equivalent daily (or other immunosuppressants) within a protocol-defined window prior to first dose (unless physiologic/adrenal replacement).
  * \*\*Transplant History\*\*
  * Prior allogeneic hematopoietic stem cell transplantation.
  * Prior solid organ transplantation (e.g., kidney, liver, heart).
  * \*\*Hypersensitivity / Drug Intolerance\*\*
  * Severe hypersensitivity (e.g., anaphylaxis) to any of the following:
  * COLONYVAQ-CRC components (peptides/excipients)
  * Poly I:C or similar TLR agonists
  * Nivolumab or other anti-PD-1/PD-L1 agents
  * Oxaliplatin, 5-FU, leucovorin, or capecitabine (including severe DPD deficiency)
  * \*\*Concurrent Malignancy\*\*
  * Active second primary malignancy requiring systemic therapy or expected to require systemic therapy during the trial.
  * Exceptions:
  * Adequately treated basal cell or squamous cell skin carcinoma
  * Cervical carcinoma in situ
  * Other malignancies in complete remission not expected to relapse or require systemic therapy within 5 years, per investigator judgment
  * \*\*Significant Comorbidities\*\*
  * Clinically significant/unstable cardiovascular disease, including:
  * MI within 6 months
  * Unstable angina
  * Uncontrolled arrhythmias
  * CHF NYHA class III-IV
  * Uncontrolled hypertension despite medical therapy
  * Stroke or TIA within 6 months (if risk is increased per investigator judgment).
  * Severe COPD or interstitial lung disease with significant impairment, or prior pneumonitis requiring systemic steroids.
  * Any other serious uncontrolled condition (e.g., poorly controlled diabetes, severe cirrhosis, advanced renal failure) that may compromise safety or adherence.
  * \*\*Pregnancy / Lactation\*\*
  * Pregnant at screening (positive pregnancy test).
  * Breastfeeding (must discontinue lactation before first dose).
  * \*\*Concurrent Investigational Agents / Confounding Therapies\*\*
  * Participation in another interventional trial with systemic investigational agents (unless sponsor/IRB-approved and not confounding).
  * Live attenuated vaccine within a protocol-defined period (e.g., 30 days) prior to first dose of nivolumab or COLONYVAQ-CRC, or during study treatment.
  * \*\*Other Conditions Affecting Compliance or Assessment\*\*
  * Psychiatric illness, cognitive impairment, substance abuse, or social situation limiting adherence to study requirements.
  * Any condition that, in the investigator's opinion, makes the participant unsuitable or interferes with interpretation of safety, immunologic, or clinical outcomes.

Conditions4

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