Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

This is an interventional treatment trial for Functional Pancreatic Neuroendocrine Tumor Read More

Inclusion Criteria:

• Pathologically confirmed metastatic unresectable well differentiated (low grade and intermediate grade) neuroendocrine tumors (Ki-67 < 20% and mitotic rate < 2 per 10 high power field) that demonstrate progressive disease (by serial computed tomography [CT] or magnetic resonance imaging [MRI] scans) in past 12 months including

  • Carcinoid tumors originating anywhere in the body including the gastrointestinal (GI) tract or bronchial tree or thymus
  • Pancreatic neuroendocrine tumors (including functional and non-functional islet cell, insulinomas and glucagonomas)
  • Pheochromocytomas
  • Gastrinomas (Zollinger-Ellison syndrome)
  • Multiple endocrine neoplasia (MEN type I/II),
  • Adrenal carcinomas with NET markers by immunohistochemistry (IHC) or serum
  • Somatostatinoma
  • VIPoma (vasoactive intestinal peptide)
  • Merkel cell tumors
  • Medullary thyroid carcinoma
  • Neuroendocrine tumors of unknown primary site
• Patients must have progressed on octreotide therapy and/or radioactive isotopes linked to octreotide or its congeners if they had a positive octreotide scan; patients who have negative or mildly positive octreotide scans are exempt from this requirement
• Somatostatin analogs can be continued at their tolerated dose in patients with functional symptoms related to underlying disease such as in functional islet cell, insulinomas, glucagonomas etc
• Patients may have received prior chemotherapy for advanced disease including either capecitabine or temozolomide single agent as long as it did not include combination of capecitabine and temozolomide
• Patients must have completed prior (non-excluded) anti-cancer therapy (including surgery or chemotherapy or hepatic embolization/chemoembolization or radioactive isotopes i.e. yttrium 90) at least 4 weeks prior to day 1
• Patients with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease and have not had treatment with steroids within 1 week of study enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Anticipated life expectancy of greater than 3 months
• Patients must have measurable disease either primary and/or metastatic masses reproducibly measurable in one or two diameters by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 parameters by CT scan or MRI scan; positron emission tomography (PET) or octreotide scans are useful adjuncts but will not be used to measure response
• Granulocytes > 1,500/ml
• Platelets > 100,000/ml
• Hemoglobin >= 10 g/dl
• Creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
• Bilirubin < 1.5 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if liver metastases are present)
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of veliparib, capecitabine and temozolomide administration
• Ability to understand and the willingness to sign a written informed consent document
• Patients must be able to swallow pills

Exclusion Criteria:

• Prior chemotherapy with combination of capecitabine (or 5-flourouracil [5-FU]) "and" temozolomide (or dacarbazine [DTIC]) will be excluded; patients can have had prior therapies up to 3 prior chemotherapy regimens such as streptozocin, anthracyclines, irinotecan, etoposide, or a platinum agent including single agent capecitabine (or 5FU) or temozolomide (or DTIC).
• History of severe hypersensitivity reaction to capecitabine, 5-FU, temozolomide or DTIC will be excluded (i.e. anaphylaxis or anaphylactoid reactions)
• Patients who have active or uncontrolled infection or serious medical or psychiatric illness preventing informed consent or on intensive treatment
• Patients with brain metastases are excluded
• Patients with uncontrolled seizures or any neurological conditions resulting in increased risk for seizures are not eligible for study entry
• Patients with documented central nervous system (CNS) ischemia and/or infarction, whether symptomatic or discovered incidentally without clinical symptoms, will be excluded from study participation
• Patients with a history of the arterial or venous thromboembolism within =< 12 months of study entry are not eligible
• Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are excluded from the study
• Patients with another active malignancy within the past five years except for carcinoma in situ of cervix or in situ carcinoma of the bladder or non-melanomatous carcinoma of the skin
• Clinically significant and uncontrolled major medical conditions including but not limited to: active uncontrolled infection, psychiatric illness/ social situation that would limit compliance with study requirements; any medical condition, which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities
• Patients who are receiving any other investigational agents
• Major surgical procedure within 4 weeks of treatment

• Patients may not have any clinically significant cardiovascular disease including the following:

  • Myocardial infarction or ventricular tachyarrhythmia within 6 months
  • Prolonged QTc > 480 msec at baseline
  • Symptomatic congestive heart failure (CHF) of New York Heart Association (NYHA) functional class >= 3
  • Major conduction abnormality (unless a cardiac pacemaker is present)
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with capecitabine or temozolomide or veliparib