A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors.

Inclusion criteria

• Male or female patients aged of at least 18 years on day of signing informed consent.
• Patients with histologically confirmed diagnosis of metastatic disease or unresectable locally advanced malignancy that is resistant or refractory to standard therapies or for which standard therapies does not exist or is/are not considered appropriate by the investigator.
• A multidisciplinary molecular board must have recommended the specific MTT based on the following documented actionable alterations:

• Cohort HDM201-Ribociclib : amplification of CDK6 and/or CDK4, and/or CDKN2A homozygous deletion, and/or amplification of CCND1 and/or CCND3 with no deletion/losses more than single copy of RB1 by copy number and P53 wild-type.
• Cohort Cabozantinib : AXL, MET, VEGFR, VEGF, RET, ROS1, MER, TRKB, TIE-2 and/or Tyro3 activating mutations and/or amplification, and/or NTRK translocation and/or ROS1 translocation, and/or MET translocation.
• Cohort Alectinib : Activating ALK alterations: translocation, or selected mutations, or activating rearrangements following validation by central molecular tumor board of Centre Léon Bérard.
• Cohort Regoranib : Activating mutation and/or amplification and/or rearrangement of VEGFR1-3, TIE-2, KIT, RET, RAF1, BRAF (other than V600 mutations), CRAF, HRAS, PDGFR, FGFR1-2, FLT3 and/or CSFR1, and/or amplification of the ligands, and/or biallelic inactivation of SMAD4, following validation by central molecular tumor board of Centre Léon Bérard.
• Cohort Trametinib : Activating mutation and/or amplification of KRAS (except all KRAS G12 mutations), NRAS, HRAS and/or MAP2K; and/or biallelic inactivation of NF1; and/or activating mutation PTPN11; and/or amplification or translocation of BRAF, and/or translocation RAF1
• Cohort Trametinib + Dabrafenib : BRAF V600 mutation and/or rearrangement of BRAF following validation by central molecular tumor board of Centre Léon Bérard.
• Cohort Avapritinib : Activating mutations of KIT exon 17 or PDGFRA exon 18 associated or not to mutation on KIT exon 11 or PDGFRA exon 12/14
• Previously treated by at least one prior line of treatment in the advanced/metastatic setting except for specific tumor type with no standard treatment approved and reimbursed in France following sponsor approval.
• Documented radiological disease progression as per RECIST v1.1 and presence of at least one measurable lesion according to RECIST 1.1 criteria based on screening tumor assessment.
• Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• Adequate organ function
• Adequate cardiovascular function
• Specific toxicities related to any prior anti-cancer therapy must have resolved to grade ≤1 , except for alopecia (all grades), grade 2 neuropathy or anemia.
• Unless infertility is proven, men must agree to use effective contraception
• Women of child-bearing potential must have a negative serum pregnancy test within 7 days of first dose of study drug and agree to use effective contraception
• Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study procedures as per protocol.
• Patient must be covered by a medical insurance.

Exclusion criteria

• Patients amenable to therapy with curative intent.
• Patients participating to another clinical trial with a medicinal product.
• Patients previously treated with similar MTT meaning any agent targeting the same signaling pathways components.
• Patients unable to swallow oral medication.
• Patients with known hypersensitivity to excipients
• Patients with symptomatic central nervous system (CNS) metastasis who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.
• Patients with secondary malignancy unless this malignancy is not expected to interfere with the evaluation of study endpoints and is approved by the sponsor. Examples of the latter include: basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, localized prostate cancer, prior malignancy and no evidence of recurrence for ≥ 2 years.
• Patients using, or requirement to use while on the study, or not respecting the minimal wash-out period of medications
• Any clinically significant and/or uncontrolled medical disease that could compromise the patient's ability to tolerate study drug or would likely interfere with study procedures or results.
• Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Patients who are pregnant or breastfeeding women or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through after the last dose of trial treatment (depanding on cohort).