Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study

Inclusion Criteria: 1. Male or female subjects ≥ 18 years old. 2. Willingness to participate in the study by signing informed consent form (ICF) approved by the trial Central Ethic Committee (CEIm). 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Measurable disease per RECIST 1.1 as determined by the investigator. 5. Patients with an histopathologically confirmed disease (as per local pathology report), meeting one of the following (according to WHO 2010 classification): 1. Cohort 1: Well-differentiated neuroendocrine tumours of the lung and thymus (WHO grade 1 and 2, typical and atypical carcinoids) after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy. 2. Cohort 2: Anaplastic thyroid cancer in first-line or after progression to chemotherapy or investigational drugs. Primary tumour can be resected or not but risk of aerodigestive compression or bleeding should be ruled out. 3. Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane. 4. Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide receptor radionuclide therapy (PRRT) if indicated. Prior chemotherapy and biological therapy, such as somatostatin analogs, are allowed. 5. Cohort 5: Well-differentiated neuroendocrine tumours of digestive system (WHO grade 1 and 2) after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy. 6. Cohort 6: Grade 3 neuroendocrine neoplasm (WHO grade 3, including neuroendocrine (NET) and neuroendocrine carcinomas (NEC) G3) of any origin, excluding small cell lung cancer, after progression to chemotherapy or targeted agents/PRRT. 6. Recovery from toxicity related to any prior treatments to ≤ Grade 1, unless the adverse events (AEs) are clinically non-significant and/or stable on supportive therapy. 7. Ability to swallow tablets. 8. Adequate normal organ and marrow function as defined below: 1. Haemoglobin ≥ 9.0 g/dL. 2. Absolute neutrophil count (ANC) \> 1500 per mm. 3. Platelet count ≥ 100,000 per mm. 4. Serum bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician. 5. Aspartate Transaminase (AST) (SGOT)/Alanine aminotransferase (ALT) (SGPT) ≤ 2.5x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3x ULN. 6. Measured creatinine clearance (CL) \> 40 mL/min or Calculated creatinine CL \> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance. 9. Female subjects of childbearing potential (not surgically sterile or at least 2 years postmenopausal) must provide a negative urine pregnancy test at Screening, and use a medically accepted double barrier method of contraception (i.e condom with spermicide + IUD or cervical caps). In addition, they must agree to continue the use of this double barrier method for the duration of the study and for 4 months after participation in the study. 10. Males should agree to abstain from sexual intercourse with a female partner or agree to use a double barrier method of contraception (i.e.condom with spermicide, in addition to having their female partner use some contraceptive measures such as, intrauterine device (IUD) or cervical caps), for the duration of the study and for 4 months after participation in the study. 11. Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up. Exclusion Criteria: 1. Prior treatment with cabozantinib or any immune checkpoint inhibitor therapy (e.g, CTLA4, PD-1, or PD-L1 targeting agent). 2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer. Patients should have been out of mitotane for at least 4 weeks. 3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 2 weeks before starting treatment. 4. Current or prior use of immunosuppressive medication within 2 weeks before the first dose of cabozantinib and atezolizumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 5. Active or prior documented autoimmune disease within the past 2 years. Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. 6. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis). 7. History of allogeneic organ transplant. 8. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment. 9. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before inclusion. Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved are not eligible (e.g, radiation esophagitis or other inflammation of the viscera). 10. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before inclusion. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of study treatment. 11. Concomitant anticoagulation with oral anticoagulants (e.g, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (e.g, clopidogrel), except for the following allowed anticoagulants: * Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). * Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases and who are on a stable dose of LMWH for at least 6 weeks before inclusion and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumour. 12. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: a. Cardiovascular disorders: i. Class 3 or 4 congestive heart failure as defined by the New York Heart Association, unstable angina pectoris, and serious cardiac arrhythmias. ii. Uncontrolled hypertension defined as sustained blood press \> 150 mm hg systolic or \> 100 mm hg diastolic despite optimal antihypertensive treatment. iii. Stroke, including transient ischemic attack (TIA), myocardial infarction, other ischemic event, or thromboembolic event, e.g, deep venous thrombosis (DVT) and pulmonary embolism) within 6 months before inclusion. Subjects with a more recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks before study treatment. b. Gastrointestinal disorders (e.g, malabsorption syndrome or gastric outlet obstruction) including those associated with a high risk of perforation or fistula formulation: i. Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before inclusion. Note: complete healing of an intra-abdominal abscess must be confirmed prior to start of the treatment. c. Clinically significant hematemesis or hemoptysis of \> 0.5 teaspoon (\> 2.5 ml) of red blood or history of other significant bleeding within 3 months before treatment. d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. e. Lesions invading major pulmonary blood vessels. f. Other clinically significant disorders such as: i. Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection. ii. Serious non-healing wound/ulcer/bone fracture. iii. Moderate to severe hepatic impairment (child-pugh B or C). iv. Requirement for hemodialysis or peritoneal dialysis. v. Uncontrolled diabetes mellitus. vi. History of solid organ transplantation. 13. Major surgery (e.g, GI surgery and removal or biopsy of brain metastasis) within 8 weeks before inclusion. Complete wound healing from major surgery must have occurred 4 weeks before study treatment and from minor surgery (e.g, simple excision, tooth extraction) at least 10 days before study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. 14. Corrected QT interval calculated by the Fridericia formula (QTcf) \> 500 ms within 28 days before study treatment. Note: if a single ECG shows a QTCf with an absolute value \> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these 3 consecutive results for qtcf will be used to determine eligibility. 15. Pregnant or lactating females. 16. Inability to swallow tablets. 17. Previously identified allergy or hypersensitivity to components of the study treatment formulations. 18. Diagnosis of another malignancy within 3 years before study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.