Evaluation of Efficacy of Trifluridine/Tipiracil Plus an Anti-IL-1α True Human Antibody Versus Trifluridine/Tipiracil Plus Placebo in Metastatic Colorectal Cancer Patients After Failure of Oxaliplatin, Irinotecan, Fluoropyrimidine

Inclusion Criteria:

• Male or female that must have signed a written informed consent prior to any studyspecific procedures

• Aged ≥ 18 years at randomization

• Patient with histologically proven metastatic colorectal cancer previously treatedfor metastatic disease by chemotherapy treatment including oxaliplatin, irinotecan,fluoropyrimidine, antiangiogenic (anti-VEGF: bevacizumab or aflibercept) andanti-EGFR (cetuximab or panitumumab) if indicated (MSI tumor could be included ifpreviously pretreated with anti PD1/PDL1 therapy) n.b:

• a patient treated with oxaliplatin in a neoadjuvant/adjuvant situation with arecurrence of the disease within 6 months following the last administration isconsidered resistant to oxaliplatin and validates the criterion if no administrationof oxaliplatin has been carried out in a metastatic disease situation.

• exception for VEGF if medically contraindicated during previous metastatic diseasetreatment (should be clearly documented in the disease history of the patient) it isallowed to included the patient with or without Bevacizumab.

• Have a performance status of 0 or 1 according to the WHO Easter Cooperative OncologyGroup (ECOG)

• Knowledge of RAS, BRAF, Microsatellite status

• Baseline tumoral evaluation (thoraco-abdomino-pelvic computed tomography) perfromedwithin 21 days before randomization with at least one measurable lesion according toRECIST 1.1 criteria.

• Patient willing and able to comply with protocol for the duration of the studyincluding: scheduled visits and exams, visits during the follow-up and treatmentcompliance.

• Adequat hepatic, renal and bone marrow function within the following limits:

• Total bilirubin ≤ 1,5 times the upper limit of normal (ULN) (unless documentedGilbert's syndrome);

• ASAT et ALAT ≤ 5 times ULN;

• Measured Creatinine clearance (Cockcroft and Gault) > 30 ml / min

• Absolute Neutrophil Count (ANC) > 1,5. 109 / L;

• Platelet count ≥ 150. 109 / L;

• Haemoglobin ≥ 9 g / dL (patients can be included even if they have been transfused)

• Albuminemia ≥ 30 g / L;

• Negative Hepatitis B, C and HIV serologies, or absence of active B or C hepatitis

• Urea protein, urine dipstick should be less than 2 crossese and/or 24 hourproteinuria ≤ 1g/24h

• Availability of tumor material dated less than 5 years with sufficient quantity (15to 20 whithe slides) and quality (Good morphological conservation / Presence oftumor tissue / Histopathology consistent with the indication / More than 100 tumorcells)

• Patient must be affiliated to a social health insurance

• Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients (urine within 72h or serum pregnancy within 14 daysprior to inclusion).

• Women of childbearing potential willing to use adequate contraception method (including the use of a mechanical method of contraception in the event of hormonalcontraceptive treatment) during the treatment period and 6 months following the endof treatment.

• Male patients with a partner of childbearing potential should use effectivecontraception during treatment and for up to 6 months after stopping treatment.

• Normal ECG or ECG without clinically significant findings with QTcF < 470 ms.

Exclusion Criteria:

• Other concurrent malignancies the last 3 years, except adequately treatedcone-biopsied in situ carcinoma (as per exemple of the cervix, basal cell, squamouscell carcinoma of the skin, low risk prostate cancer or other insitu carcinoma jugedeligible according the coordinator). Patient who have had potentially curativetherapy for a prior malignancy are eligible provided there has been no evidence ofdisease for ≥ 3 years and the risk of recurrence is considered low.

• Symptomatic brain metastases

• Estimated prognosis <3 months.

• Mutational status BRAF mutant (V600E only)

• Participation in progress, or in the 30 days preceding the first scheduled day ofdosing in this study, in another therapeutic trial with an experimental molecule orwithin a time interval less than at least 5 half-lives of the investigational agent,whichever is longer.

• Severe unbalanced illness, underlying infection that may prevent the patient fromreceiving treatment. Patients with a clinically important and unresolved Grade 3 or 4 non-haematologic adverse reaction related to previous therapies. Also participantwith any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to priorchemotherapy that persisted > 4 weeks and was related to the most recent treatment.

• Bowel obstruction or sub-obstruction or a history of inflammatory bowel disease orsignificant gasto intestinal disorder

• History of autoimmune or inflammatory disease or interstitial lung disease.

• Patient with congenital galactosemia, total lactase deficiency (lactose intolerance)or glucose-galactose malabsorption syndrome

• Severe arterial thromboembolic events less than 6 months before randomization

• New York Heart Association (NYHA) Class III or IV congestive heart failure,ventricular arrhythmias or uncontrolled blood pressure (defined as ≥ 160/100 mm Hg)

• Clinically significant decrease in performance status (medical records) within 2weeks of intended first dose administration.

• -Contraindication to receive a treatment with trifluridine/tipiracil or ananti-IL-1α (XB2001 True Human antibody) and/or patient already treated bytrifluridine/tipiracil, or an anti-IL-1α.

• Concomitant systemic treatment with immunotherapy, immunosuppressants,corticosteroid therapy ≥ 10 mg equivalent prednisone/prednisolone or hormonetherapy: corticosteroid therapy administered chronically, immunosuppressivetreatment, biotherapy administered as part of the management of an inflammatorydisease (anti-TNF, anti-IL6, anti-IL1, anti PD-1, anti EGFR etc.) and live virusvaccines administered up to 14 days prior the first scheduled dose of treatementadministration.

• Current pregnancy (mandatory pregnancy test at baseline for female of childbearingpotential) or breastfeeding.

• Patient with any psychiatric, psychological, sociological, geographical problem orother severe concomitant disease, disorder or condition that potentiallycompromising the understanding of the information, the safety of the patient, theinterpretation of study results or the conduct of the study compliance with thestudy protocol and follow-up schedule.

• Patient deprived of their liberty or under guardianship, curatorship or safeguard ofjustice.

• Known or suspected history of immunosuppression, including history of invasiveopportunistic infections (e.g tuberculosis, histoplasmosis, listeriosis,coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution.Presence or suspicion of active bacterial, fungal or viral infections, oruncontrolled fever.

• Major surgery within 2 weeks prior to randomization or have an unhealed operationwounds.