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

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CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and progressive tumors from endocrine system. Hypothesis: The main hypothesis is that the administration of cabozantinib plus atezolizumab will improve the probability of expected objective response rate in advance...

CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and progressive tumors from endocrine system. Hypothesis: The main hypothesis is that the administration of cabozantinib plus atezolizumab will improve the probability of expected objective response rate in advanced and refractory tumors of the endocrine system. Objectives: The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) evaluated following RECIST v1.1 criteria in advanced endocrine tumors. Secondary objectives include: To evaluate the safety profile of cabozantinib and atezolizumab combination, according to NCI-CTCAE V5.0. Duration of response (DoR) as per RECIST V1.1. Progression-free survival (PFS): median PFS as per RECIST V1.1. Overall Survival (OS): median OS as per RECIST V1.1. Tumor biomarkers: translational sub-study (optional). Treatment: All the subjects will be treated with the combination until disease progression, unacceptable toxicity, or patient consent withdrawal (whichever occurs first): Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously. Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle). Rationale: Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal gland and paraganglia) are characterized by being remarkably vascular and expressing several growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF), and transforming growth factor (TGF)-? and -?. The (over) expression of some of these factors has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the resistance to prior antiangiogenic drugs. Patients allocation: The trial will include patients with advanced and refractory tumors of endocrine system and patients would be allocated to six different cohorts according to the following tumor types: Cohort 1: Well-differentiated neuroendocrine tumors of the lung and thymus (grades 1 and 2) 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. 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 tumors of digestive system after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy. Cohort 6: Grade 3 neuroendocrine neoplasm of any origin, excluding small cell lung cancer, after progression to chemotherapy or targeted agents/PRRT.

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