• Histology:

‣ Dose escalation part: histologically confirmed non MSI-H or deficient-MMR colorectal cancer, or GIST, or esophageal or gastric carcinoma or hepatobiliary cancers,

⁃ Phase II trials : histologically confirmed

• non MSI-H or deficient-MMR colorectal cancer (cohort A),

∙ or GIST (cohort B). As recommended diagnosis by INCa, patients with GIST must have histologically confirmed by central review, except if it has been already confirmed by the RRePS Network

∙ or esophageal or gastric carcinoma (cohort C),

∙ or hepatobiliary cancers (cohort D),

∙ or soft-tissue sarcoma (STS) (cohort E). As recommended diagnosis by INCa, patients with STS must have histologically confirmed by central review, except if it has been already confirmed by the RRePS Network

∙ or radioiodine-refractory differentiated thyroid cancer \[RR-DTC\] (cohort F),

∙ or neuroendocrine gastroenteropancreatic tumors grade 2 and 3

∙ or Non-small cell lung cancer (cohort H)

∙ or Solid tumors including soft-tissue sarcoma with immune signature (cohort I), i.e. presence of tertiary lymphoid structures on tumor sample as determined by central review.

∙ or urothelial cancer (cohort J)

∙ or HPV-associated cancer (cohort K) with molecular confirmation p16 positive status,

∙ triple negative breast cancer (cohort L)

∙ or TMB-high solid tumors (cohort M) with status TMB-high already known

∙ or MSI-high solid tumors (cohort N) with status MSI-high already known

∙ or Non clear-cell renal carcinoma (cohort O)

∙ or Malignant pleural mesothelioma (cohort P).

• Advanced non resectable / metastatic disease,

• Patients for which either there is no further established therapy that is known to provide clinical benefit, OR (for patients to be treated with 160 mg regorafenib) regorafenib monotherapy is an approved or established therapeutic option,

• Age ≥ 18 years,

• ECOG, Performance status ≤ 1,

• Measurable disease according to RECIST,

• Life expectancy \> 3 months,

• Except for cohorts F and H, ≥ 1 previous line (s) of systemic therapy,

• Adequate hematological, renal, metabolic and hepatic functions:

∙ Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell \[RBC\] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l, lymphocytes ≥ 1000/mm3.

‣ Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement for AP and/or liver metastasis and ≤ 5 x ULN in case of liver metastasis for AST and ALT).

‣ Total bilirubin ≤ 1.5 x ULN.

‣ Albumin ≥ 25g/l.

‣ Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and Gault formula).

‣ Creatine phosphokinase (CPK) ≤ 2.5 x ULN.

‣ INR \< 1.5 x ULN

‣ aPTT ≤ 1.5 X ULN

‣ Lipase ≤ 1.5 X ULN.

∙ Cohort specific criteria: Patients with hepatocellular carcinoma must have a correct hepatocellular function, id est Child-Pugh A.

⁃ No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,

⁃ At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,

⁃ Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment, excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0)),

⁃ Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication,

⁃ Both women and men must agree to use an highly effective method of contraception throughout the treatment period and for eight weeks after discontinuation of treatment. Acceptable methods for contraception are described in protocol section 7.4.1,

⁃ Voluntary signed and dated written informed consents prior to any specific study procedure,

⁃ Patients with a social security in compliance with the French law.

⁃ Documented disease progression (as per RECIST v1.1) before study entry. For patients of cohort E (STS) and cohort I (Solid-tumors - TLS+): this progression will be confirmed by central review on the basis of two CT scan or MRI obtained not less than 6 months in the period of 12 months prior to inclusion. For patients of cohort F (RR-DTC): this progression will be confirmed by central review on the basis of two CT scan or MRI obtained at less than 12 months prior to inclusion.

⁃ For patients in cohort H: subjects with histologically or cytologically confirmed diagnosis of non-squamous NSCLC. Documents disease progression based on radiographic imaging, during or after a maximum of 2 lines of systemic treatment for locally/regionally advanced recurrent, Stage IIIb/IV or metastatic disease. Two components of treatments must have been received in the same line or as separate lines of therapy: a maximum of 1 line of platinum-containing chemotherapy regimen, and a maximum of 1 line of PD(L)1 mAb containing regimen. No EGFR, ALK, ROS1 positive tumor mutations. Subjects with known BRAF molecular alterations must have had disease progression after receiving the locally available SoC treatment for the molecular alteration

⁃ For patients with urothelial cancer (cohort J):

∙ A maximum of 1 line of PD(L)1 mAb containing regimen, and

‣ Patients must have received at least 4 months of PD(L1) mAb treatment.

⁃ For HPV-associated cancer (cohort K), TMB-high solid tumors (cohort M) MSI-high solid tumors (cohort N), Non clear-cell renal carcinoma (cohort O):

⁃ o No previous line of PD(L)1 mAb containing regimen

⁃ For malignant pleural mesothelioma (Cohort P):

∙ A maximum of 1 line of PD(L)1 mAb containing regimen, and

‣ Patients must have received at least 4 months of PD(L1)/ CTLA-4 mAb treatment in the case they received this treatment

⁃ For triple-negative breast cancer patients (Cohort L)

∙ A maximum of 1 line of PD(L)1 mAb containing regimen, and

‣ Patients must have received at least 4 months of PD(L1) mAb treatment

⁃ For TMB-High cancer patients (Cohort M):

∙ TMB-High is defined as TMB score \> 16 mutations /megabase on tissue or blood sample