A Clinical Study of Arfolitixorin in Patients With mCRC

Inclusion Criteria:

* Signed ICF and ability to comply with protocol requirements.
* Phase 1b: Histologically confirmed RAS mutant, MSS/pMMR, colorectal adenocarcinoma with metastatic disease, eligible for first-line therapy with 5-FU, oxaliplatin, and bevacizumab regimen.

Phase 2:

Histologically confirmed, colorectal adenocarcinoma with metastatic disease, eligible for first-line therapy with 5-FU based backbones, i.e.:

1. Patients with mutated RAS who are candidates for therapy with FOLFOX or FOLFIRI plus bevacizumab.
2. Patients with WT RAS or WT BRAF and left-sided tumors who are candidates for therapy with FOLFOX or FOLFIRI plus cetuximab or panitumumab.

   * Tumor specimen (formalin-fixed, paraffin-embedded \[FFPE\]) available.
   * Acceptable hematologic laboratory values defined as:

a) Hemoglobin ≥90 g/L. b) Absolute neutrophil count (ANC) ≥1.5 × 109/L. c) Platelets ≥100 × 109/L.

* Adequate organ function as defined by the following laboratory values:

  1. Total serum bilirubin ≤1.5 × upper limit of normal (ULN).
  2. ALT and AST ≤3 × ULN (≤5 × ULN in case of hepatic metastases).
  3. Creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min (as measured according to Cockcroft-Gault equation).
* Age ≥18 years at the time of signing the ICF.
* Radiographically measurable disease per RECIST (version 1.1) within 28 days of treatment allocation.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Life expectancy of \>12 weeks.
* Female patients must be surgically sterile, postmenopausal, or have negative results for a pregnancy test at screening, on a serum or urine sample obtained within 72 hours prior to initiation of study treatment.
* Female patients of childbearing potential must agree to use highly effective contraceptive measures while on study treatment and for at least 15 months (or longer if according to local labels) after study treatment discontinuation. Highly effective methods are those that achieve a failure rate of less than 1% per year when used consistently and correctly (as per the Clinical Trial Coordination Group \[CTCG\] Recommendations related to contraception and pregnancy testing in clinical trials, Version 1.2, 07 Mar 2024).
* Female patients should agree to refrain from egg cell donation while on study treatment and for at least 15 months after the last dose of study treatment.
* Male patients with female partners of childbearing potential must agree to use adequate contraceptive measures while on study treatment and for at least 12 months (or longer if according to local labels) after study treatment discontinuation.
* Male patients should agree to refrain from sperm donation while on study treatment and for at least 12 months after the last dose of study treatment.

Exclusion Criteria:

* Indication for any mCRC surgery or anti-cancer treatment other than study treatment, including but not limited to resection as confirmed by a MTB.
* Concomitant malignancies or previous malignancies with less than a 2-year disease free interval at the time of signing consent. Patients with adequately treated basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer are permitted. Ongoing adjuvant antihormonal therapy after breast or prostate cancer is permitted.
* Prior 5-FU, oxaliplatin, irinotecan, bevacizumab, cetuximab, or panitumumab administration for mCRC.
* More than 6 cycles (3 months) of oxaliplatin exposure during adjuvant treatment.
* Known history of central nervous system (CNS) metastases or carcinomatous meningitis.
* Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest. Note that participation in any other clinical study is not allowed as long as the patient is on study treatment.
* Prior exposure to arfolitixorin.
* Major surgery, or significant traumatic injury within 8 weeks of study treatment initiation.
* Hypersensitivity to arfolitixorin, 5-FU, oxaliplatin or other platinum agent, irinotecan, bevacizumab, cetuximab or panitumumab, or to their excipients.
* Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency test with a Clinical Pharmacogenetics Implementation Consortium (CPIC) activity score \<1.
* Current evidence of any condition that could lead to higher risk or otherwise make participating in this study not in the best interest of the patient, including, but not limited to:

  1. Myocardial infarction or unstable angina within the past 6 months.
  2. Other structural heart disease (e.g., myocarditis, ventricular hypertrophy).
  3. New York Heart Association (NYHA) functional classification Class II or greater.
  4. QT prolongation syndrome \>450 ms.
  5. Slow or irregular ventricular rates; other serious arrhythmias requiring medication for treatment.
  6. Left ventricular ejection fraction (LVEF) \<55%.
  7. Active infection requiring i.v. antibiotics.
  8. Ongoing drug or alcohol abuse.
  9. Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg). Initiation of antihypertensives is permitted provided adequate control is documented over at least 1 week before starting treatment.
* Sensory peripheral neuropathy Grade ≥2.
* Pregnancy or lactation.
* Any medical condition, or ongoing treatment with contraindicated drugs, which in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities, or any psychological, familial, sociological or geographical condition that potentially hampers compliance with the study protocol and follow-up schedule.
* BRAF-mutant or deficient in mismatch repair (dMMR)/microsatellite instability-high (MSI-H) mCRC.
* Eligibility for treatment with FOLFIRINOX regimens.