Phase II study evaluating Holmium-166 TARE followed by maIntenance Therapy in liver limited unresectable colorectal cancer patients after first-lIne chemotherapy and target agents: The HAITI study.

Prior treatment

• History of a previous allergic reaction to contrast media that would preclude safe angiography of the hepatic arteries, in the opinion of the treating Interventional Radiologist
• Previous radiotherapy delivered to the liver
• Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer)
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study procedures and treatment administration

Other illness

• Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation
• Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis, or any other contraindications to radioembolization treatment
• Previous history of malignancy within the last 5 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
• Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication

Lab values

• Known hypersensitivity to fluoropyrimidine, anti-VEGF or anti-EGFR MoAb

Other

• Patients with radiological evidence of extra liver distant metastases
• Withdrawal of the consent to take part to the study
• Patients with BRAF mutated and/or MSI-high tumours
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment

• Written informed consent to study procedures
• Renal function: creatinine clearance > 50 mL/min or serum creatinine 1.5 x UNL; no renal disease that would preclude study treatment or follow-up
• Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
• Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as outlined in Section 7.5 – Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy
• Will and ability to comply with the protocol
• RAS/BRAF wild-type and left sided primary tumor (for Cohort A)
• First-line induction chemotherapy regimen permitted up to 6-12 cycles with: FOLFOX or FOLFIRI + anti-EGFR (cetuximab or panitumumab) (for Cohort A)
• RAS mutated and/or right-sided primary tumor (for Cohort B)
• First-line induction chemotherapy regimen admitted up to 6-12 cycles with: FOLFOX/FOLFIRI/XELOX + bevacizumab or FOLFOXIRI + bevacizumab (for Cohort B)
• Age ≥18 years
• Histologically proven diagnosis of colorectal adenocarcinoma, with or without primary tumour in situ
• Liver-only disease at radiological exams involving less than 50% of liver volume
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2
• Patients with partial response or stable disease according to RECIST 1.1 criteria deemed unresectable after 6-12 cycles of induction first-line chemotherapy
• Life expectancy of at least 12 weeks
• Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count ≥100,000/mm3; haemoglobin level ≥ 9 g/dL
• Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase ≤ 5 times ULN; AST ≤ 5 times ULN