Phase II Study of Ibrutinib in Advanced Carcinoid and Pancreatic Neuroendocrine Tumors
Condition: Carcinoid Tumors; Pancreatic NET
MeSH terms: Neuroendocrine Tumors; Carcinoid Tumor
Intervention: Ibrutinib
Intervention description: Ibrutinib will be administered orally once daily and each cycle will be defined as 4 weeks duration. Study treatment should begin within 14 days following enrollment into the study and continue until disease progression, unacceptable toxicity, or withdrawal of consent.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: neuroendocrine tumors (NETs); gastroenteropancreatic NETs; pancreatic NETs; gastrointestinal (GI) tract NET; advanced carcinoid tumors

Summary:

      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).
    

Eligibility criteria:

        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