Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
This phase I trial studies the side effects and best dose of veliparib when given together
 with capecitabine and temozolomide in treating patients with neuroendocrine tumor that has
 spread to other places in the body and usually cannot be cured or controlled with treatment,
 has returned after a period of improvement, and cannot be removed by surgery. Veliparib may
 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs
 used in chemotherapy, such as capecitabine and temozolomide, work in different ways to stop
 the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading.
PRIMARY OBJECTIVES:

 I. To determine the maximum tolerated dose (MTD) of veliparib (ABT-888) in combination with
 capecitabine and temozolomide in patients with advanced well-differentiated neuroendocrine
 tumors.

 SECONDARY OBJECTIVES:

 2. To determine the safety profile of the combination of capecitabine, temozolomide and
 veliparib in patients with advanced well-differentiated neuroendocrine tumors (NET).

 3. To evaluate the antitumor activity of the combination of capecitabine, temozolomide and
 veliparib in advanced well-differentiated NET patients

 4. To determine progression-free survival (PFS) of the combination of capecitabine,
 temozolomide, and veliparib in advanced well-differentiated NET patients IV. To evaluate the
 association between pharmacodynamic biomarkers and response in patients with advanced
 well-differentiated NET patients.

 OUTLINE: This is a dose-escalation study of veliparib.

 Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14, temozolomide PO BID
 on days 10-14 and veliparib PO BID on days 10-14. Courses repeat every 28 days for up to 12
 courses in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 4 weeks.
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