Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

The MOST Plus study is a two-period phase II clinical trial, conducted in patients with all types of progressive solid tumors after at least 1 prior systemic treatment regimen for advanced disease (in the absence of a validated second line therapy). The main goal of this study is to evaluate for these patients the clinical benefit of a maintenance treatment in patients with stable disease (SD) after induction treatment with a selected therapy (Molecular Targeted Therapy (MTT) or with SD, partial response (PR) or complete reponse (CR) with Immunotherapy (IT)). For MTT, the first period of this trial (induction period) will enable to establish whether the identification of genomic alterations in genes encoding for "actionable" targets in the tumor cells, regardless of the histological subtype, can be used to select efficient treatment targeting the pathway activated by the mutation. For Immunotherapy, induction period with durvalumab + tremelimumab is expected to be an innovative therapy for an efficient tumor control and may allow to identify types of cancer or molecular types of cancer that are more receptive to immunotherapy. For all treatments, the second period (maintenance period) will use a randomized design to evaluate the clinical benefit of a maintenance treatment with the targeted therapy or immunotherapy selected based on tumor molecular profile in patients treated by MTT with SD and in patients treated by IT with SD, PR or CR. Each patient enrolled will receive the matching targeted therapy during 12 weeks (MTT) or 52 weeks (IT). At the end of this induction period: MTT cohorts : * patients with a tumor response (CR: complete response or PR: partial response) will continue the targeted therapy, * patients in progression will discontinue the targeted therapy and will be withdrawn from study and oriented towards standard treatments * patients with a stable disease at 12 weeks will be randomized in order to determine if they continue or stop the therapy. IT cohort : \- patients with SD, PR or CR at 52 weeks will be randomized in order to determine if they continue or stop the therapy. For each MTT treatment group: \~80 patients treated in the first step (induction period), 50 patients randomized in the second step (maintenance period, 25 patients per arm). For IT treatment group: \~125 patients treated in the first step (induction period), 50 patients randomized in the second step (maintenance period, 25 patients per arm). In total (for 7 treatment groups): \~ 900 patients treated in the induction period and 350 patients randomized in maintenance period.

Inclusion Criteria: I1. Male or female patient ≥ 18 years of age. I2. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced and unresectable solid tumor of any type, except for Nilotinib cohort: only pigmented villonodular synovitis are eligible, not amenable to curative treatment. Concerning primitive tumors of the central nervous system (CNS), all histological types of malignant tumors (including parenchymal and meningeal tumors) are eligible (except for IT). I3. Documented disease progression at the time of study entry. I4. At least one prior systemic treatment regimen for locally advanced or metastatic disease - except for Nilotinib cohort : patients can be treated with Nilotinib in first line systemic treatment. Patients who are candidates for a validated second line treatment regimen are not eligible for the study. For patients with a primitive CNS tumor, the absence of other therapeutic options must be validated by the reference committee for the patient's pathology before inclusion. As there is no prior systemic treatment regimen available for locally advanced or metastatic PEComa, these tumors are eligible for a MTT treatment in first line of their advanced or metastatic disease. No previous treatment by immune checkpoint inhibitors (anti-PD1/PDL1, anti-CTLA4, anti-LAG3 etc.) is allowed for IT group. I5. Patient with measurable disease, defined as at least one lesion that can be accurately measured on CT-scan or MRI according to RECIST 1.1. I6. A multidisciplinary molecular board must have recommended one of the investigational MTT available in the study after review of a tumor (or blood for pazopanib, olaparib and immunotherapy cohorts) molecular profiling previously established from a biopsied lesion and/or primitive tumor, and/or from a liquid biopsy, respectively (for pazopanib, olaparib and immunotherapy cohorts). I7. The MTT recommended by the multidisciplinary molecular board after the review of tumor or blood molecular profile is not approved and reimbursed in France for the disease affecting the patient in the same label. I8. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2. I9. Adequate organ system function as assessed by the following minimal laboratory requirements : * Absolute neutrophil count (ANC) ≥ 1 x 109/L (for pazopanib and olaparib: ≥ 1.5 x 109/L) * Platelets ≥ 100 x 109/L * Hemoglobin ≥ 9 g/dL. Transfusion is not allowed within 7 days of screening assessment. (For olaparib: Hemoglobin ≥ 10 g/dL. Transfusion is not allowed within 28 days of screening assessment, no features suggestive of myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) on peripheral blood smear within the 28 days) * For pazopanib: activated partial thromboplastin time (aPTT) ≤ 1.2x Upper limit of normal (ULN) and prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2x ULN; Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation. * Aspartate Aminotransferase (AST) and alanine transaminase (ALT) ≤ 3x ULN in the absence of liver metastases (≤ 5x ULN for patients with liver involvement of their cancer) and total bilirubin ≤ 1.5x ULN. (for pazopanib: AST and ALT ≤ 2.5x ULN; concomitant elevations in bilirubin and AST or ALT above 1x ULN are not permitted; for olaparib and IT: AST and ALT ≤ 2.5x ULN in the absence of liver metastases (≤ 5x ULN for patients with liver involvement of their cancer) and total bilirubin ≤ 1.5x ULN.). * Serum creatinine ≤ 1.5x ULN or creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula, or modification of diet in renal disease (MDRD) formula for patients older than 65 years) (for pazopanib: creatinine clearance ≥ 30 mL/min; for olaparib : creatinine clearance ≥ 51 mL/min; for IT : creatinine clearance ≥ 40 mL/min ) * For pazopanib: Urine Protein to Creatinine ratio (UPC) \