Prospective Multicenter Study Evaluating Feasibility and Efficacy of Tumor Organoid-based Precision Medicine in Patients With Advanced Refractory Cancers

Inclusion Criteria: * Age ≥18 years * ECOG performance status 0-1 * Life expectancy \>3 months * Histologically-confirmed, unresectable, locally advanced or metastatic solid tumor * ORGANOTREAT-01: CRC * ORGANOTREAT-02A: Colorectal adenocarcinoma (CRC) or pancreatic ductal adenocarcinoma (PDAC) * ORGANOTREAT-02B: solid cancers with a PDO take-on rate ≥50%: * Stratum 1: PDAC * Stratum 2: CRC * Other strata: to be added by protocol amendment * ≥1 measurable lesion according to RECIST v1.1 * ≥1 tumor site accessible to biopsy without significant risk, outside from lung lesion * Patients are to be biopsied before the start or within the 3 first weeks of the SoC line. * Failure (disease progression or intolerance) or contraindication to validated treatments in the advanced setting; patients MUST be still eligible for at least 1 (ORGANOTREAT-01 and -2A) or 2 (ORGANOTREAT-02B) validated systemic treatment lines according to approved guidelines: * CRC (ORGANOTREAT-01): failure (disease progression or intolerance) or contraindication to fluoropyrimidines, oxaliplatin, irinotecan, anti-EGFR (in RAS wild-type tumors), anti-BRAF (in BRAF V600E mutated tumors), and antiangiogenics; patients must be still eligible for trifluridine-tipiracil and/or regorafenib * CRC (ORGANOTREAT-2A): failure (disease progression or intolerance) or contraindication to fluoropyrimidines, oxaliplatin, irinotecan, anti-EGFR (in RAS wild-type tumors), anti-BRAF (in BRAF V600E mutated tumors), and trifluridine-tipiracil/bevacizumab; patients must be still eligible for regorafenib * PDAC (ORGANOTREAT-2A): Patients will be included at the beginning of their second line of standard therapy * PDAC (ORGANOTREAT-02B stratum 1): patients will be included at the beginning of their first- or second-line of therapy * Specifications for supplementary tumor strata in ORGANOTREAT-02 will be defined by protocol amendment * Adequate hepatic, renal and hematological functions (AST/ALT \< 2.5 ULN (5 ULN in cases of liver metastases); Total bilirubin \< 1.5 ULN; Albumin \> 30 g/L; International normalized ratio (INR) \<1.5 ULN; Calculated creatinine clearance \>50 mL/min; Absolute neutrophil count \>1000/mm3, platelets \>100 000/mm3, hemoglobin \>9 g/dL) To be performed until 7 days before enrollment * Informed consent signed by the patient or his/her legal representative * Affiliation to or beneficiary of a social security system * A female participant is eligible to participate if she is not pregnant not breastfeeding, and 1. Not a woman of childbearing potential (WOCBP) OR 2. A WOCBP should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * A WOCBP must agree to follow the contraceptive guidance or abstain from heterosexual activity during the treatment period and for at least 180 days, after the last dose of treatment. Exclusion Criteria: * History of other invasive cancer within 5 years prior to entry into the trial other than adequately treated basal-cell skin cancer or in situ carcinoma of the cervix * Concomitant medications/comorbidities that may prevent the patient from being biopsied * Patients with brain or meningeal metastasis, unless definitive therapy occurred more than 6 months ago and with a confirmation of tumoral control and absence of symptoms within 4 weeks of starting study treatment * Pregnancy or breast-feeding * Privation of liberty or guardianship * Geographical, social or psychological reasons precluding study participation and monitoring * Coagulation abnormality prohibiting a biopsy