This is a prospective phase II open-label trial, stratifying patients equally into two cohorts consisting of carcinoid tumors and pancreatic neuroendocrine tumors (pNETs). The purpose of this study is to test any good and bad effects of the study drug called Ibrutinib.

The study population will consist of adult patients with histologically confirmed low to intermediate grade NETs of the GI tract, lungs and unknown primary (carcinoid tumors) or pNETs. All patients must be confirmed to have advanced disease. The study will enroll up to 51 patients in two cohorts (30 carcinoid and 21 pNET patients).

Inclusion Criteria:

• Locally unresectable or metastatic carcinoid or pancreatic neuroendocrine tumors (pNETs)
• Measureable disease by Response Evaluation Criteria in Solid Tumors (RECIST)
• 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: a) Surgery (major surgery at least more than four weeks prior to baseline assessment); b) 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; c) 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.
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Life expectancy 12 weeks or more
• Adequate bone marrow function as shown by: absolute neutrophil count ≥ 1,000/mm^3, Platelets ≥ 100,000/mm^3, Hb > 10 g/dl
• Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN, and serum transaminases activity ≤ 2.5 x ULN, with the exception of serum transaminases (< 3 x ULN) if the patient has liver metastases
• Adequate renal function as shown by 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
• Prior antitumor therapy within 2 weeks of enrollment (with the exception of somatostatin analogs)
• No other active malignancy within 3 years of enrolment 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

3 years, 5 months

SAEs are reported that occurred after first dose of study drug through 30 days after discontinuation of study drug.