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

* PDOs are tridimensional multicellular structures expanded in vitro which retain the genotypic and phenotypic features of their tissue or tumor of origin. PDOs can be exposed to a panel of drugs (chemotherapy, hormonal therapy, targeted therapy) in order to study their sensitivity to each agent (or combination of agents) tested ('chemogram'). Recent studies showed that PDOs can accurately predict the response to treatment of solid tumors and could therefore inform clinical decision on the best therapeutic option for each patient.
* ORGANOTREAT is a multicenter prospective study program of organoid-based precision oncology encompassing 3 studies: ORGANOTREAT-01, a pilot study restricted to advanced CRC, and ORGANOTREAT-02A and -2B, two Phase 2 studies in advanced solid cancers.

ORGANOTREAT-01, -02A and -02B

* Patients with advanced, pretreated solid cancers will be enrolled at the beginning of a standard-of-care (SoC) treatment line to allow sufficient time for PDO (tumor-derived organoid) generation and chemogram.
* A biopsy of an easily accessible tumor site will be performed.
* PDO generation, culture and amplification and drug testing will be performed.
* A chemogram report will be prepared.
* The CTB (Chemogram Tumor Board) will make treatment recommendations based on the chemogram report.
* Patients enrolled in ORGANOTREAT-01, ORGANOTREAT-02A and in the experimental arm of ORGANOTREAT-02B will be treated according to the CTB's recommendations after disease progression or unacceptable toxicity while on SoC.
* Patients will be treated at the investigator's discretion until disease progression or unacceptable toxicities. Patient will be followed until death or study termination, whichever occurs first . Note : Provide, as long as necessary (without time limit) the treatments to patient is agreed by all the centers.
* Patients for whom no chemogram can be obtained will be treated according to Soc

Eligibility Criteria:
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: solid cancers of low-to-intermediate incidence and/or with a PDO take-on rate \<50%
  * 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 \>2cm (different from the target lesion) accessible to biopsy without significant risk
* 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 1 (ORGANOTREAT-01 and -2A) or 2 (ORGANOTREAT-02B) validated systemic treatment lines according to approved guidelines:

  * CRC (ORGANOTREAT-01 and -02B stratum 2): 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
  * 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 \>1,000/mm\^3, platelets \>100,000/mm\^3, 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
* Pregnancy or breast-feeding
* Privation of liberty or guardianship
* Geographical, social or psychological reasons precluding study participation and monitoring
* Coagulation abnormality prohibiting a biopsy
* 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