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

Inclusion Criteria

• Male or female subjects ≥ 18 years old.
• Willingness to participate in the study by signing informed consent form (ICF) approved by the trial Central Ethic Committee (CEIm).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Measurable disease per RECIST 1.1 as determined by the investigator.
• Patients with an histopathologically confirmed disease (as per local pathology report), meeting one of the following (according to WHO 2010 classification):
• 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.
• 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.
• Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane.
• 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.
• 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.
• 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.
• 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.
• Ability to swallow tablets.
• Adequate normal organ and marrow function as defined below:
• Haemoglobin ≥ 9.0 g/dL.
• Absolute neutrophil count (ANC) > 1500 per mm.
• Platelet count ≥ 100,000 per mm.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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

• Prior treatment with cabozantinib or any immune checkpoint