Study of Ibrutinib in Advanced Carcinoid and Pancreatic Neuroendocrine Tumors

Inclusion Criteria

• Locally unresectable or metastatic carcinoid or pNET
• Measureable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
• Tumors must be histologically or cytologically proven and considered low or intermediate grade; patients with high grade neuroendocrine carcinomas or small cell carcinomas are excluded from the study
• Evidence of progressive disease within 12 months of study entry
• Allowed prior therapies include: * Surgery (major surgery at least more than four weeks prior to baseline assessment) * Locoregional therapy such as: chemoembolization, radio-embolization, radiofrequency ablation, radiotherapy as long as there is progressive measurable disease outside the area of locoregional therapy or there is progression in the previously treated areas * Any number of previous lines of systemic therapy; last treatment before enrollment must have occurred more than 4 weeks for chemotherapy, 6 weeks for antibodies or more than 5 half-lives of prior tyrosine kinase inhibitors (TKIs) or small molecules
• Prior or concurrent therapy with somatostatin analogs is permitted for patients with secretory NET
• All patients with gastroenteropancreatic NETs must have progressed on (or are intolerant of) prior somatostatin analog
• Patients with pancreatic NETs must have progressed on (or are intolerant of) either everolimus or sunitinib
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Life expectancy 12 weeks or more
• Absolute neutrophil count >= 1,000/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin (Hb) > 10 g/dl
• Serum bilirubin =< 1.5 x ULN
• Serum transaminases activity =< 2.5 x ULN, with the exception of serum transaminases (< 3 x ULN) if the patient has liver metastases
• Serum creatinine =< 2 mg/dl
• Women of childbearing potential must have a negative serum pregnancy test within 7 days of the administration of the first study treatment; women must not be lactating; both men and women of childbearing potential must be advised of the importance of using effective birth control measures during the course of the study
• Signed informed consent to participate in the study must be obtained from patients after they have been fully informed of the nature and potential risks by the investigator (or his/her designee) with the aid of written information

Exclusion Criteria

• High grade NET or small cell neuroendocrine carcinoma
• Clinically apparent central nervous system metastases or carcinomatous meningitis
• Known positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class III or IV cardiac disease as defined by the New York Heart Association (NYHA) functional classification
• Requirement for anticoagulation with warfarin or similar vitamin K antagonists
• Requirement for treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
• Prior antitumor therapy within 2 weeks of enrollment (with the exception of somatostatin analogs)
• No other active malignancy within 3 years of enrollment except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least three years
• Any medical condition or organ system dysfunction which, in the investigator’s opinion, could compromise the patient’s safety, interfere with the absorption or metabolism of ibrutinib
• Known hypersensitivity to ibrutinib or any component of the ibrutinib formulation
• History of noncompliance to medical regimens or unwillingness to comply with the protocol
• Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification