A Prospective, Randomized, Multicenter, Comparative Study of the Efficacy of Imatinib Resumption Combined With Atezolizumab Versus Imatinib Resumption Alone in Patients With Unresectable Advanced Gastrointestinal Stromal Tumors (GIST) After Failure of Standard Treatments

INCLUSION CRITERIA : I1. Male or female ≥ 18 years at the day of consenting to the study; I2. Patients must have histologically confirmed diagnosis of GIST (within the French Reference Network in Pathology of Sarcomas - RRePS network); I3. Locally advanced or metastatic disease confirmed as measurable according to the RECIST V1.1 (Appendix 1); I4. Patients who previously failed to at least imatinib, sunitinib and then regorafenib. Failure is defined for Imatinib as progressive disease, and for sunitinib and regorafenib as progressive disease and/or intolerance; I5. Performance Status of the ECOG of 0 or 1; I6. Adequate bone marrow and organ function defined by the following laboratory results: a. Bone marrow: i. Hemoglobin ≥ 9.0 g/dl, ii. Absolute Neutrophils Count (ANC) ≥ 1.5 G/l, iii. Lymphocytes count ≥ 0.5 G/l, iv. Platelets ≥ 100 G/l; b. Coagulation: i. Prothrombin time ≤ 1.5 x Upper Limit of the Normal (ULN) for patients without therapeutic anticoagulation. Patients with therapeutic anticoagulation must have stable dose of treatment. c. Hepatic function: i. Total serum bilirubin ≤ 1.5 x ULN (except patients with Gilbert's syndrome who must have total serum bilirubin ≤ 3.0 x ULN), ii. Transaminases (ASAT/ALAT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN in case of documented liver metastases) iii. Alkaline Phosphatases ≤ 2.5 x ULN (or ≤ 5.0 x ULN in case of documented bone metastases), d. Renal function: i. Serum creatinine ≤ 1.5 x ULN or Cr. Cl. ≥ 40ml/min/1.73m² (MDRD or CKD-EPI formula); I7. Willingness and ability to comply with the study requirements; I8. Signed and dated informed consent indicating that the patient has been informed of all the aspects of the trial prior to enrolment; I9. Women of childbearing potential are required to have a negative serum pregnancy test within 72 hours prior to study treatment start. A positive urine test must be confirmed by a serum pregnancy test; I10. Women of childbearing potential and male patients must agree to use adequate highly effective contraception for the duration of study participation (Appendix 3); I11. Patient must be covered by a medical insurance; EXCLUSION CRITERIA : E1. Prior malignancy within the last 3 years except for locally curable disease with no sign of relapse; E2. Patients in whom imatinib had been already reintroduced after sunitinib as second line; E3. Known D842V mutation in Exon 18 of PDGFRA; E4. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4 , anti-TIGIT, anti PD-1,and anti PD-L1 therapeutic antibodies; E5. Any approved anticancer therapy (chemotherapy, hormonal therapy or radiotherapy) or treatment with any investigational product within 2 weeks or within 5 elimination half-lives (whichever is longer) prior to study treatments start; E6. Residual adverse events from prior anticancer therapy that has not resolved to grade ≤1, except for alopecia and lab values (provided that inclusion criteria described in section 6.1 are met); E7. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met: * Measurable disease, per RECIST v1.1, must be present outside the CNS. * The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. * The patient has not undergone stereotactic radiotherapy within 7 days prior to randomization, whole-brain radiotherapy within 14 days prior to randomization, or neurosurgical resection within 28 days prior to randomization. * The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable dose is permitted. * Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord). * There is no evidence of interim progression between completion of CNS-directed therapy and randomization. * Spinal cord compression not definitively treated with surgery and/or radiation, and/or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for 2 weeks prior to screening. * History of leptomeningeal disease. E8. Patients using or require to use while on the study of any prohibited concomitant and/or concurrent medications (see section "Prohibited concomitant/concurrent treatments) : * Live, attenuated vaccines within 28 days prior to enrolment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed during the study active period. * Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to C1D1, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: * Patients who receive acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor confirmation. * Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroid. * Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to C1D1. * Traditional herbal medicines since the ingredients of many herbal medicines are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound assessment of toxicity, E9. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 4 for a more comprehensive list of pre-existing autoimmune diseases and immune deficiencies), with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: * Rash must cover less than 10% of body surface area * Disease is well controlled at baseline and requires only low-potency topical corticosteroids * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months E10. History of severe allergic / anaphylactic reaction or other hypersensitivity reactions to: * chimeric or humanized antibodies or fusion proteins, * biopharmaceuticals produced in Chinese hamster ovary cells, any active substance or to any of the chemical excipients of atezolizumab (refer to its IB) or imatinib (refer to its respective SmPC) E11. Patients with active infectious disease: * severe infections within 4 weeks prior to randomisation including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia, * active infection requiring or have required treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection) are eligible for the study. * active B or C hepatitis infection, Note: Patients with past Hepatitis B Virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti-HBc\] antibody test) are eligible. Patients positive for Hepatitis C Virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. * active tuberculosis * HIV infection E12. Active or prior history of primary immunodeficiency; E13. Major surgical procedure within 28 days prior to study treatments start, or need for a major surgery during the course of the study; E14. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within : * 6 months after the final dose of study treatment for patients included in the standard arm (imatinib alone) * 11 months after the final dose of study treatment for patients included in the experimental arm (imatinib + atezolizumab) Women of childbearing potential must have a negative pregnancy test result within 72 hours prior to treatment start (any urine positive pregnancy test must be confirmed by a serum pregnancy test prior to treatment start); E15. Patient that impairs their ability to swallow and retain imatinib or with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of imatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) E16. Clinically significant unrelated systemic illness (e.g., significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results. E17. Patients under tutorship or curatorship.