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I1. Male or female ≥ 18 years at the day of consenting to the study |
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I2. Patients must have histologically confirmed diagnosis of GIST (within the French |
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Reference Network in Pathology of Sarcomas - RRePS network); archival tumor sample must be |
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made available for translational research program (in case there is no sufficient archival |
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tumor material available, a biopsy must be performed prior to treatment start); Nota Bene |
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mutational status and level of expression of PD1/PD-L1 will not be considered as selection |
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criteria but will be studied as endpoints for translational objectives |
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I3. Locally advanced or metastatic disease confirmed as measurable according to the RECIST |
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V1.1 (Appendix 1) |
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I4. Patients who previously failed to at least imatinib, sunitinib and then regorafenib |
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Failure is defined for Imatinib as progressive disease, and for sunitinib and regorafenib |
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as progressive disease and/or intolerance |
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I5. Performance Status of the ECOG of 0 or 1 |
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I6. Adequate bone marrow and organ function defined by the following laboratory results |
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a. Bone marrow: i. Hemoglobin ≥ 9.0 g/dl, ii. Absolute Neutrophils Count (ANC) ≥ 1.5 G/l |
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iii. Lymphocytes count ≥ 0.5 G/l, iv. Platelets ≥ 100 G/l |
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b. Coagulation: i. Prothrombin time ≤ 1.5 x Upper Limit of the Normal (ULN) for patients |
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without therapeutic anticoagulation |
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Patients with therapeutic anticoagulation must have stable dose of treatment |
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c. Hepatic function: i. Total serum bilirubin ≤ 1.5 x ULN (except patients with Gilbert's |
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syndrome who must have total serum bilirubin ≤ 3.0 x ULN), ii. Transaminases (ASAT/ALAT) ≤ |
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5 x ULN (or ≤ 5.0 x ULN in case of documented liver metastases) iii. Alkaline |
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Phosphatases ≤ 2.5 x ULN (or ≤ 5.0 x ULN in case of documented bone metastases) |
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d. Renal function: i. Serum creatinine ≤ 1.5 x ULN or Cr. Cl. ≥ 40ml/min/1.73m² (MDRD or |
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CKD-EPI formula) |
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I7. Willingness and ability to comply with the study requirements |
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I8. Signed and dated informed consent indicating that the patient has been informed of all |
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the aspects of the trial prior to enrolment |
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I9. Women of childbearing potential are required to have a negative serum pregnancy test |
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within 72 hours prior to study treatment start. A positive urine test must be confirmed by |
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a serum pregnancy test |
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I10. Women of childbearing potential and male patients must agree to use adequate highly |
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effective contraception for the duration of study participation (Appendix 3) |
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I11. Patient must be covered by a medical insurance |
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E1. Prior malignancy within the last 3 years except for locally curable disease with no
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sign of relapse
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E2. Patients in whom imatinib had been already reintroduced after sunitinib as second line
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E3. Known D842V mutation in Exon 18 of PDGFRA
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E4. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
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anti-cytotoxic T lymphocyte-associated protein 4 , anti-TIGIT, anti PD-1,and anti PD-L1
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therapeutic antibodies
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E5. Any approved anticancer therapy (chemotherapy, hormonal therapy or radiotherapy) or
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treatment with any investigational product within 2 weeks or within 5 elimination
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half-lives (whichever is longer) prior to study treatments start
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E6. Residual adverse events from prior anticancer therapy that has not resolved to grade
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≤1, except for alopecia and lab values (provided that inclusion criteria described in
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section 6.1 are met)
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E7. Symptomatic, untreated, or actively progressing central nervous system (CNS)
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metastases
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Asymptomatic patients with treated CNS lesions are eligible, provided that all of the
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following criteria are met
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Measurable disease, per RECIST v1.1, must be present outside the CNS
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The patient has no history of intracranial hemorrhage or spinal cord hemorrhage
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The patient has not undergone stereotactic radiotherapy within 7 days prior to
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randomization, whole-brain radiotherapy within 14 days prior to randomization, or
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neurosurgical resection within 28 days prior to randomization
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The patient has no ongoing requirement for corticosteroids as therapy for CNS disease
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Anticonvulsant therapy at a stable dose is permitted
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Metastases are limited to the cerebellum or the supratentorial region (i.e., no
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metastases to the midbrain, pons, medulla, or spinal cord)
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There is no evidence of interim progression between completion of CNS-directed therapy
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and randomization
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Spinal cord compression not definitively treated with surgery and/or radiation, and/or
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previously diagnosed and treated spinal cord compression without evidence that disease
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has been clinically stable for 2 weeks prior to screening
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History of leptomeningeal disease
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E8. Patients using or require to use while on the study of any prohibited concomitant
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and/or concurrent medications (see section "Prohibited concomitant/concurrent treatments)
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Live, attenuated vaccines within 28 days prior to enrolment. Examples of live vaccines
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include, but are not limited to, the following: measles, mumps, rubella, chicken pox
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yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for
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injection are generally killed virus vaccines and are allowed; however intranasal
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influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed
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during the study active period
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Treatment with systemic immunosuppressive medication (including, but not limited to
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corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
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anti-TNF-alpha agents) within 2 weeks prior to C1D1, or anticipation of need for
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systemic immunosuppressive medication during study treatment, with the following
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exceptions
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Patients who receive acute, low-dose systemic immunosuppressant medication or a
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one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
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corticosteroids for a contrast allergy) are eligible for the study after Medical
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Monitor confirmation
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Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for
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chronic obstructive pulmonary disease or asthma, or low-dose corticosteroid
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Systemic immunostimulatory agents (including, but not limited to, interferons and
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IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is
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longer) prior to C1D1
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Traditional herbal medicines since the ingredients of many herbal medicines are not
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fully studied and their use may result in unanticipated drug-drug interactions that
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may cause or confound assessment of toxicity
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E9. Active or history of autoimmune disease or immune deficiency, including, but not
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limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
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erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody
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syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple
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sclerosis (see Appendix 4 for a more comprehensive list of pre-existing autoimmune diseases
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and immune deficiencies), with the following exceptions
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Patients with a history of autoimmune-related hypothyroidism who are on
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thyroid-replacement hormone are eligible for the study
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Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are
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eligible for the study
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Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
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dermatologic manifestations only (e.g., patients with psoriatic arthritis are
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excluded) are eligible for the study provided all of following conditions are met
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Rash must cover less than 10% of body surface area
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Disease is well controlled at baseline and requires only low-potency topical
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corticosteroids
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No occurrence of acute exacerbations of the underlying condition requiring psoralen
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plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
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calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12
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months
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E10. History of severe allergic / anaphylactic reaction or other hypersensitivity reactions
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to
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chimeric or humanized antibodies or fusion proteins
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biopharmaceuticals produced in Chinese hamster ovary cells, any active substance or to
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any of the chemical excipients of atezolizumab (refer to its IB) or imatinib (refer to
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its respective SmPC)
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E11. Patients with active infectious disease
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severe infections within 4 weeks prior to randomisation including but not limited to
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hospitalization for complications of infection, bacteraemia, or severe pneumonia
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active infection requiring or have required treatment with therapeutic oral or IV
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antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving
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prophylactic antibiotics (e.g., to prevent a urinary tract infection) are eligible for
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the study
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active B or C hepatitis infection, Note: Patients with past Hepatitis B Virus (HBV)
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infection or resolved HBV infection (defined as having a negative HBsAg test and a
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positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible
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Patients positive for Hepatitis C Virus (HCV) antibody are eligible only if polymerase
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chain reaction (PCR) is negative for HCV RNA
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active tuberculosis
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HIV infection
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E12. Active or prior history of primary immunodeficiency
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E13. Major surgical procedure within 28 days prior to study treatments start, or need for a
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major surgery during the course of the study
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E14. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
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or within
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months after the final dose of study treatment for patients included in the standard
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arm (imatinib alone)
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months after the final dose of study treatment for patients included in the
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experimental arm (imatinib + atezolizumab) Women of childbearing potential must have a
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negative pregnancy test result within 72 hours prior to treatment start (any urine
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positive pregnancy test must be confirmed by a serum pregnancy test prior to treatment
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start)
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E15. Patient that impairs their ability to swallow and retain imatinib or with impairment
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of gastrointestinal (GI) function or GI disease that may significantly alter the absorption
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of imatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea
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malabsorption syndrome, or small bowel resection)
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E16. Clinically significant unrelated systemic illness (e.g., significant cardiac
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pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability
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to tolerate study treatment or would likely interfere with study procedures or results
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E17. Patients under tutorship or curatorship
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