Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors
Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors
This randomized phase II trial studies how well giving temozolomide with or without
 capecitabine works in treating patients with advanced pancreatic neuroendocrine tumors. Drugs
 used in chemotherapy, such as temozolomide and capecitabine, 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. It is not yet known whether temozolomide is more effective with
 or without capecitabine in treating patients with advanced pancreatic neuroendocrine tumors.
PRIMARY OBJECTIVES:

 I. To evaluate progression-free survival (PFS) associated with temozolomide alone or
 temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors.

 SECONDARY OBJECTIVES:

 I. To evaluate response rates (RR) associated with temozolomide alone or temozolomide and
 capecitabine treatment in patients with advanced pancreatic neuroendocrine tumors.

 II. To evaluate overall survival (OS) associated with temozolomide alone or temozolomide and
 capecitabine in patients with advanced pancreatic neuroendocrine tumors.

 III. To evaluate the toxicity associated with temozolomide alone or temozolomide and
 capecitabine treatment in patients with advanced pancreatic neuroendocrine tumors.

 IV. To evaluate the usefulness of methyl guanine methyltransferase (MGMT) status (by
 immunohistochemistry [IHC] and promoter methylation) for predicting response in pancreatic
 neuroendocrine tumor patients treated with either temozolomide or temozolomide and
 capecitabine.

 V. To bank radiology images for evaluation of quality, reproducibility, and compliance with
 computed tomography (CT) methodology.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 ARM A: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5. Treatment
 repeats every 28 days for up to 13 courses in the absence of disease progression or
 unacceptable toxicity.

 ARM B: Patients receive capecitabine PO twice daily (BID) on days 1-14 and temozolomide PO QD
 on days 10-14. Treatment repeats every 28 days for up to 13 courses in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months for 2 years, and
 then every 6 months for 3 years.
Inclusion Criteria:

 -  Patient must have histologically or pathologically confirmed locally unresectable or
 metastatic low or intermediate grade pancreatic neuroendocrine tumor, excluding small
 cell carcinoma

 -  Patient must have measurable disease by Response Evaluation Criteria in Solid Tumors
 (RECIST) 1.1 criteria; baseline measurements and evaluations of all sites of disease
 must be obtained =< 4 weeks prior to randomization and must be acquired by multiphasic
 CT or contrast magnetic resonance imaging (MRI)

 -  Date of last documented disease progression must be =< 12 months from date of
 randomization

 -  Patient must not have received prior temozolomide, dacarbazine (DTIC), or
 capecitabine, or 5-FU (fluorouracil) therapy

 -  Prior everolimus and/or sunitinib therapy is allowed, so long as it was discontinued
 >= 4 weeks prior to randomization

 -  Concurrent somatostatin analogues are allowed provided that patients

 -  Have been on stable doses for 8 weeks and

 -  Have documented disease progression on that dose

 -  Patients may not be receiving any other investigational agents while on study
 treatment

 -  Patients may not be receiving Coumadin while on treatment; other anticoagulants are
 allowed

 -  Leukocytes >= 3,000/mm^3

 -  Absolute neutrophil count >= 1,500/mm^3

 -  Hemoglobin >= 9 g/dL

 -  Platelets >= 100,000/mm^3

 -  Total bilirubin =< institutional upper limit of normal (ULN) or =< 1.5 X institutional
 ULN (if the patient has liver metastases)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 3 X institutional ULN or (=< 5 X institutional ULN if the patient has liver
 metastases)

 -  Serum creatinine =< 1.5 X institutional ULN

 -  Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

 -  Patient must have life expectancy >= 12 weeks

 -  Patients with either clinically apparent central nervous system metastases or
 carcinomatous meningitis are ineligible

 -  Patients must NOT have active or uncontrolled infection or serious medical or
 psychiatric illness

 -  Patients must NOT have history of allergic reactions attributed to compounds of
 similar chemical or biologic composition to temozolomide or capecitabine

 -  Patient must NOT have absorption issues that would limit the ability to absorb study
 agents

 -  Patients with a history of the following within =< 12 months of study entry are not
 eligible:

 -  Arterial thromboembolic events

 -  Unstable angina

 -  Myocardial Infarction

 -  Patients with symptomatic peripheral vascular disease are not eligible

 -  Patients must NOT have previous or concurrent malignancy; exceptions are made for
 patients who meet any of the following conditions:

 -  Non-melanoma skin cancer, in situ cervical cancer, or breast cancer in situ OR

 -  Prior malignancy completely excised or removed and patient has been continuously
 disease free for > 5 years OR

 -  Prior malignancy cured by non-surgical modalities and patient has been
 continuously disease free for > 5 years

 -  Women must not be pregnant or breast-feeding; all females of childbearing potential
 must have a blood test or urine study within =< 2 weeks prior to randomization to rule
 out pregnancy; a female of childbearing potential is any woman, regardless of sexual
 orientation or whether they have undergone tubal ligation, who meets the following
 criteria:

 -  Has not undergone a hysterectomy or bilateral oophorectomy; or

 -  Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
 has had menses at any time in the preceding 24 consecutive months)

 -  Women of childbearing potential and sexually active males must be strongly advised to
 use an accepted and effective method of contraception or to abstain from sexual
 intercourse for the duration of their participation in the study; should a woman
 become pregnant while participating in this study, she should inform her treating
 physician immediately; if a man impregnates a woman while participating in this study,
 he should inform his treating physician immediately

 -  Patient must be able to swallow pills

 -  Patient must be able to tolerate CT or magnetic resonance (MR) imaging including
 contrast agents as required for their treatment and the protocol