ROMANCE: "Irinotecan Plus Cetuximab Rechallenge Versus Trifluridine/Tipiracil Plus Bevacizumab in Molecularly Selected Metastatic Colorectal Cancer"

Prior treatment

• Received more than 2 lines of treatment for metastatic disease.
• Previous treatment with trifluridine/tipiracil
• Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
• Known severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 5 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study treatments.

Other illness

• Previous history of malignancy within the last 2 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
• Evidence of bleeding diathesis or coagulopathy.
• Clinically significant cardiovascular disease, active inflammatory bowel disease, active autoimmune disease.
• Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
• Psychiatric or addictive disorders would preclude study participation.

Lab values

• RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT HER2 not amplified status at liquid biopsy analysis during screening.

Other

• ECOG PS ≥2
• Pregnant or lactating women.
• Withdrawal of the consent to take part to the study.

• Male or female aged ≥18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1
• Diagnosis of histologically or cytologically confirmed colorectal cancer.
• At least one measurable lesion according to RECIST1.1
• KRAS/NRAS/BRAFV600E wt status of primary CRC or related metastasis (local laboratory assessment).
• Progression to previous first-line anti-EGFR-containing therapy producing at least a partial response ≥ 6 months.
• Received and progressed to an anti-EGFR and irinotecan free second-line treatment.
• Have an anti-EGFR free interval of at least 4 months.
• Refractory to previous 5-fluorouracil/capecitabine, irinotecan, oxaliplatin, bevacizumab.
• RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT and HER2 not amplified ctDNA at FoundationOne CDx test at baseline.
• Life expectancy of at least 3 months.
• Adequate hematological function defined by white blood cell (WBC) count ≥ 2.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused).
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN for all subjects or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).
• Adequate renal function defined by an estimated creatinine clearance \> 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
• No contraindication to the study drugs.
• No prior treatment with trifluridine/tipiracil.
• Women of childbearing potential\* must have a negative blood pregnancy test at thescreening visit. Subjects and their partners must be willing to avoid pregnancy during the trial.
  • \*A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
• Women of childbearing potential, or male, must agree to use adequate contraception (e.g., abstinence, intrauterine device, oral contraceptive, or double-barrier method), during the study and until at least 6 months after last dose of study treatment administration, based on the judgment of the Investigator or a designated associate.
• Will and ability to comply with the protocol.
• Signed informed consent obtained before screening.