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 pathologyreport), meeting one of the following (according to WHO 2010 classification):

6. Cohort 1: Well-differentiated neuroendocrine tumours of the lung and thymus (WHO grade 1 and 2, typical and atypical carcinoids) after progression tosomatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

7. Cohort 2: Anaplastic thyroid cancer in first-line or after progression tochemotherapy or investigational drugs. Primary tumour can be resected or notbut risk of aerodigestive compression or bleeding should be ruled out.

8. Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/ormitotane.

9. Cohort 4: Pheochromocytoma and paraganglioma after progression to peptidereceptor radionuclide therapy (PRRT) if indicated. Prior chemotherapy andbiological therapy, such as somatostatin analogs, are allowed.

10. Cohort 5: Well-differentiated neuroendocrine tumours of digestive system (WHOgrade 1 and 2) after progression to somatostatin analogs, targeted agents,PRRT, and/or chemotherapy.

11. Cohort 6: Grade 3 neuroendocrine neoplasm (WHO grade 3, includingneuroendocrine (NET) and neuroendocrine carcinomas (NEC) G3) of any origin,excluding small cell lung cancer, after progression to chemotherapy or targetedagents/PRRT.

12. Recovery from toxicity related to any prior treatments to ≤ Grade 1, unless theadverse events (AEs) are clinically non-significant and/or stable on supportivetherapy.

13. Ability to swallow tablets.

14. Adequate normal organ and marrow function as defined below:

15. Haemoglobin ≥ 9.0 g/dL.

16. Absolute neutrophil count (ANC) > 1500 per mm.

17. Platelet count ≥ 100,000 per mm.

18. Serum bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless livermetastases are present, in which case it must be ≤ 2X ULN. This will not applyto patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence ofhaemolysis or hepatic pathology); however, they will be allowed only inconsultation with their physician.

19. 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.

20. Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 40mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hoururine collection for the determination of creatinine clearance.

21. Female subjects of childbearing potential (not surgically sterile or at least 2years postmenopausal) must provide a negative urine pregnancy test at Screening, anduse a medically accepted double barrier method of contraception (i.e condom withspermicide + IUD or cervical caps). In addition, they must agree to continue the useof this double barrier method for the duration of the study and for 4 months afterparticipation in the study.

22. Males should agree to abstain from sexual intercourse with a female partner or agreeto use a double barrier method of contraception (i.e.condom with spermicide, inaddition 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 4months after participation in the study.

23. Willingness and ability of patients to comply with the protocol for the duration ofthe study including undergoing treatment as well as availability for scheduledvisits 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 investigationalkinase 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) orsystemic chemotherapy within 2 weeks before starting treatment.

4. Current or prior use of immunosuppressive medication within 2 weeks before the firstdose of cabozantinib and atezolizumab, with the exceptions of intranasal and inhaledcorticosteroids or systemic corticosteroids at physiological doses, which are not toexceed 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 systemictreatment (within the past 2 years) are not excluded.

6. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease andulcerative colitis).

7. History of allogeneic organ transplant.

8. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroidtherapy or any other form of immunosuppressive therapy within 28 days prior to thefirst dose of trial treatment.

9. Receipt of radiation therapy for bone metastasis within 2 weeks or any otherradiation therapy within 4 weeks before inclusion. Subjects with clinically relevantongoing complications from prior radiation therapy that have not completely resolvedare not eligible (e.g, radiation esophagitis or other inflammation of the viscera).

10. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksbefore inclusion. Eligible subjects must be neurologically asymptomatic and withoutcorticosteroid treatment at the time of study treatment.

11. Concomitant anticoagulation with oral anticoagulants (e.g, warfarin, direct thrombinand factor Xa inhibitors) or platelet inhibitors (e.g, clopidogrel), except for thefollowing allowed anticoagulants:

• Low-dose aspirin for cardioprotection (per local applicable guidelines) andlow-dose low molecular weight heparins (LMWH).

• Anticoagulation with therapeutic doses of LMWH in subjects without known brainmetastases and who are on a stable dose of LMWH for at least 6 weeks beforeinclusion and who have had no clinically significant hemorrhagic complicationsfrom 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 bythe New York Heart Association, unstable angina pectoris, and serious cardiacarrhythmias. ii. Uncontrolled hypertension defined as sustained blood press > 150 mm hg systolicor > 100 mm hg diastolic despite optimal antihypertensive treatment. iii. Stroke, including transient ischemic attack (TIA), myocardial infarction, otherischemic event, or thromboembolic event, e.g, deep venous thrombosis (DVT) andpulmonary embolism) within 6 months before inclusion. Subjects with a more recentdiagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for atleast 6 weeks before study treatment. b. Gastrointestinal disorders (e.g, malabsorption syndrome or gastric outletobstruction) including those associated with a high risk of perforation or fistulaformulation: 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 ofthe pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominalfistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6months before inclusion. Note: complete healing of an intra-abdominal abscess mustbe confirmed prior to start of the treatment. c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 ml) ofred 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 significantdisorders such as: i. Active infection requiring systemic treatment, infection withhuman 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 hepaticimpairment (child-pugh B or C). iv. Requirement for hemodialysis or peritonealdialysis. v. Uncontrolled diabetes mellitus. vi. History of solid organtransplantation.

13. Major surgery (e.g, GI surgery and removal or biopsy of brain metastasis) within 8weeks before inclusion. Complete wound healing from major surgery must have occurred 4 weeks before study treatment and from minor surgery (e.g, simple excision, toothextraction) at least 10 days before study treatment. Subjects with clinicallyrelevant ongoing complications from prior surgery are not eligible.

14. Corrected QT interval calculated by the Fridericia formula (QTcf) > 500 ms within 28days before study treatment. Note: if a single ECG shows a QTCf with an absolute value > 500 ms, two additionalECGs at intervals of approximately 3 min must be performed within 30 min after theinitial ECG, and the average of these 3 consecutive results for qtcf will be used todetermine eligibility.

15. Pregnant or lactating females.

16. Inability to swallow tablets.

17. Previously identified allergy or hypersensitivity to components of the studytreatment formulations.

18. Diagnosis of another malignancy within 3 years before study treatment, except forsuperficial skin cancers, or localized, low grade tumors deemed cured and nottreated with systemic therapy.