A Trial Evaluating the Activity and Safety of Combination Between Cabozantinib and Temozolomide in Lung and GEP-NENS Progressive After Everolimus, Sunitinib or PRRT (CABOTEM)

Inclusion Criteria: 1. 18 years and older patients. 2. Signed informed consent prior to initiation of any study-specific procedures or treatment, as confirmation of the patient's awareness and willingness to comply with the study requirements. 3. Documented histological or cytological diagnosis of well differentiated Lung and GEP-NENs (NET G1, NET G2, NET G3 in WHO 2017 classification) progressing after a first line of therapy with SSAs, sunitinib, everolimus, chemotherapy and/or PRRT or documented histological or cytological diagnosis of Large cells neuroendocrine carcinoma patients with Ki67\< 55% progressed after platinum-based first line chemotherapy. 4. Subjects must have evidence of progressed disease, radiologically documented in the 12 months previous study entry. 5. Subjects must have evidence of measurable disease as determined by the investigator. Target lesions must have shown evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria in the 12 months prior to study entry. Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) scan or magnetic resonance imaging (MRI). Gallium 68 PET Scan can be considered useful before and during the treatment. 6. Subject must have adequate swallowing capacity. 7. Subjects with functional (associated with a clinical hormone syndrome) and non functional tumors are eligible for the study. 8. The concurrent use of somatostatin analogues is allowed provided that the patient has been on a stable dose for at least two months. 9. At least 4 weeks of wash-out from previous targeted therapies. 10. At least 6 months of wash-out from previous PRRT treatment. 11. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. 12. Subjects must have adequate organ function, including the following: 13. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥1.5 x109/L; platelet count ≥ 100 x 109/L; haemoglobin ≥ 9 g/dL; 14. Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase \[AST/SGOT\] and alanine aminotransferase/serum glutamic pyruvic transaminase \[ALT/SGPT\]) ≤ 2.5 x ULN (\< 5 x ULN if liver metastases are present); 15. Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min (Cockroft-Gault formula); 16. Recovery from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. 17. Estimated life expectancy of ≥12 weeks 18. Sexually active fertile female subjects must agree to use effective contraceptive methods during the course of the study and for 4 months after the last dose of study treatment. While sexually active fertile male subjects must agree to use effective contraceptive methods during the course of the study and up to 6 months after the last dose of study treatment; 19. For women of child-bearing potential, negative serum pregnancy test within 14 days prior to the first study drug administration; 20. Ability to understand and willingness to sign informed consent form prior to initiation of any study procedures and willingness to comply with the study requirements. Exclusion Criteria: 1. Receipt of any type of anticancer therapy within 4 weeks before study entry. 2. Previous treatment with Temozolomide or cabozantinib 3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before recruitment. 4. Previous PRRT treatment: Systemic treatment with radionuclides within 6 months before study entry. 5. Subjects with clinically relevant ongoing complications from prior radiation therapy and/or surgery are not eligible. 6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before study entry 7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors. 8. Chronic hepatitis B infection (both active or not). 9. Chronic treatment with corticosteroids or other immuno-suppressive agents. 10. Serious illness other than cancer including, but not limited to, the following conditions: 1. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i.e. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before recruitment. Note: Complete healing of an intra-abdominal abscess must be confirmed prior to recruitment. 2. Cavitating pulmonary lesion(s) or endobronchial disease 3. Lesion invading a major blood vessel including, but not limited to: inferior vena cava, pulmonary artery, or aorta. Subjects with lesions invading the portal vasculature are eligible. 4. Clinically significant bleeding risk including the following within 3 months of recruitment: hematuria, hematemesis, hemoptysis of \>0.5 teaspoon (\>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors 5. Other clinically significant disorders such as: I. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness. II. Serious non-healing wound/ulcer/bone fracture III. Malabsorption syndrome IV. Uncompensated/symptomatic hypothyroidism V. Requirement for hemodialysis or peritoneal dialysis VI. History of solid organ transplantation 11. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to recruitment, preferably via gated equilibrium radionuclide ventriculography. The results from an earlier assessment (not exceeding 30 days prior to recruitment) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient's measured cardiac ejection fraction in these patients must be \>40% before recruitment. 12. QTcF \> 470 msec for females and QTcF \> 450 msec for males or congenital long QT syndrome. 13. Patients with rare hereditary problems of galattose intolerance, congenital lactase deficiency or glucose - galattose malabsorption. 14. Major surgery within 3 months before study entry. Complete wound healing from major surgery must have occurred 1 month before study entry and from minor surgery at least 10 days before study entry. 15. Pregnant or lactating females. 16. History of another malignancy within 2 years before study entry, except for superficial skin cancers. 17. Serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures. 18. Patients on chronic treatment with drugs that are contraindicated to with cabozantinib and temozolomide treatment according to the SmPC of each product.