Efficacy of Rechallenge With Sunitinib in Metastatic Pancreatic Neuroendocrine Tumor Previously Failed to Sunitinib

Inclusion criteria

• Subjects > 18 years old and able to give their informed consent.
• Patients diagnosed with Neuroendocrine Tumor of pancreatic origin and histologically confirmed, G1/2 according to the World Health Organization (WHO) classification (Ki67 <20% and/or mitotic count >20 mitoses x 10 HPF).
• Metastatic disease progression in the 12 months prior to baseline visit documented by CT, MRI or Octreoscan.
• Progression to prior treatment with sunitinib administered for metastatic disease and have received at least 1 line and no more than 2 lines of subsequent systemic treatment.
• Measurable disease according to the following criteria RECIST version 1.1
• No disease that can be treated with surgery, radiotherapy or combined treatment with curative intent.
• Eastern Cooperative Oncology Group (ECOG) 0-2.
• Pretreatment with somatostatin analogues, chemotherapy, anti-VEGF (vascular endothelial growth factor) and mTOR (mammalian target of rapamycin) inhibitors prior to participation in the study is allowed.
• Adequately controlled blood pressure (BP) <150/90 mmHg.
• Hematologic Function: - Absolute neutrophil count >1500 / microliter (uL) - Platelets >100,000 / uL - Hemoglobin >5.6 mmol / L (9 g / dL)
• Liver function: total bilirubin < 1.5 x upper limit of normal (ULN), unless unconjugated hyperbilirubinemia or Gilbert syndrome. - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN (< 5 times in case of liver metastases).
• Renal function: calculated creatinine clearance according to Cockcroft-Gault > 30 ml / min.
• Blood coagulation: prothrombin time (PT) or International Normalized Ratio (INR) < 1.2 x ULN.
• Proteinuria <2+ urine dipstick. If > 2+ proteinuria, urinary protein <1 g / 24 h.
• Life expectancy> 3 months.
• Patient able to swallow the study drug and comply with the monitoring requirements of the study. - Women of childbearing potential must present a negative pregnancy test. Women of childbearing potential must agree to use contraception.
• Men whose partners are women of childbearing potential must use effective contraception.

Exclusion criteria

• Neuroendocrine tumors of pancreatic origin G3 according to WHO classification.
• Patients who received 3 or more lines of systemic treatment.
• Major surgery or trauma within 4 weeks prior to the first dose of sunitinib.
• Radiation therapy or tumor embolization within 2 weeks prior to the first dose of sunitinib.
• Chemotherapy, immunotherapy, biologic therapy or investigational therapy within the previous 2 weeks or 5 half-lives of the drug last received before the start of the first dose of sunitinib treatment.
• Prior treatment with high-dose chemotherapy that required hematopoietic rescue.
• Immunosuppressive therapy or prolonged treatment with corticosteroids concomitantly administered in the previous 3 months.
• Resolution to grade <2 (CTCAE according V4.03) of all previous related toxicities except alopecia treatments.
• Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 (according CTCAE V4.03) and/or that is progressing in severity, except alopecia.
• Treatment with potent inhibitors or inducers of CYP3A4 or known to prolong the QT interval in the previous 7 days.
• Prior radiotherapy to more than 25% of the bone marrow - Presence of uncontrolled metastatic brain disease, spinal cord compression, meningeal carcinomatosis or leptomeningeal disease.
• Any gastrointestinal malabsorption disorder or any other condition that, at investigator's criteria, may affect the absorption of sunitinib or increase the risk of bleeding or perforation.
• Presence of any non-healing wound or ulcer.
• Grade III/IV diarrhea in the screening period.
• Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri.
• Clinically significant cardio/cerebrovascular disease in the 6 months prior to treatment.
• Cardiac arrhythmias (NCI CTCAE version 4.0 grade >2), atrial fibrillation of any grade that requires medical treatment.
• Corrected QT interval (QTcF) > 180 msec.
• Active hemoptysis in the past 6 weeks.
• Evidence of active bleeding or bleeding diathesis.
• Presence of endobronchial lesions and/or lesions that infiltrate large vessels.
• Current treatment with acenocoumarol at therapeutic doses.
• Known HIV infection.
• Presence of uncontrolled active infection.
• Pregnant or breastfeeding women.
• Previous allergic reaction to components structurally similar to sunitinib or any of the excipients.
• Inability to discontinue any prohibited concomitant medication.
• Any illness (medical or psychiatric) or reason, in the investigator's opinion, that interferes with the patient's ability to participate.