Summary

This phase II trial studies the effect of capecitabine and temozolomide after surgery in treating patients with high-risk well-differentiated pancreatic neuroendocrine tumors. Chemotherapy drugs, 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. Giving capecitabine and temozolomide after surgery could prevent or delay the return of cancer in patients with high-risk well-differentiated pancreatic neuroendocrine tumors.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate recurrence-free survival (RFS) in participants with resected pancreatic neuroendocrine tumors (pNETs) randomized to treatment with capecitabine + temozolomide (CAPTEM) compared to observation only.

SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS) in participants randomized to treatment with CAPTEM compared to observation only.
II. To evaluate the safety and tolerability of CAPTEM compared to observation only.

BANKING OBJECTIVE:
I. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14 and temozolomide PO once daily (QD) on days 10-14. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo surveillance with no active treatment.

Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) and may undergo blood sample collection while on study.

After completion of study treatment, patients are followed up every 6 months for 3 years and then annually until 5 years from randomization.

Eligibility

1. Participants must have a histologic diagnosis of well-differentiated pancreatic neuroendocrine tumor (pNET) that was resected between 14 and 120 days prior to registration. Participants must have a scan within 90 days prior to registration without evidence of metastatic disease, unless liver oligo-metastatic disease was deemed to be resected/ablated at time of surgery. If longer than 90 days, updated scans are recommended for grade 3 tumors or metastatic tumors. Acceptable scans are multiphase CT abdomen, MRI with intravenous (IV) contrast of the abdomen; Multiphasic CT of the abdomen should include arterial-phase imaging of the liver in addition to the portal venous phase. The most recent scan should be submitted
2. Resection must have been an R0 or R1 per treating investigator’s assessment and/or pathology report
3. Participants may have received resection/ablation of liver oligo-metastatic disease (up to 5 liver metastases) at the time of well-differentiated pNET resection
4. Participants must have Ki-67 testing performed from the surgical specimen collection between 14 and 120 days prior to registration. The Ki-67 result must be >= 3% and =< 55%. NOTE: The Ki-67 testing, is considered standard of care in the pathology report. Treating investigators are encouraged to contact the S2104 Study Chairs and/or the study pathology chair with questions. If more than one Ki-67 is reported (e.g., primary tumor versus lymph node or metastatic site), the highest one should be considered for the study eligibility criteria
5. Participants with localized resected pNETS must have a Zaidi score of >= 3 derived by the following factors and points: * 1 point; prior symptomatic tumor defined as at least one of the following: ** Gastrointestinal bleed ** Jaundice ** Gastrointestinal obstruction ** Pain from primary tumor prior to surgical resection ** Pancreatitis * 2 points; primary pancreas tumor size > 2 cm * 1 point; Ki-67 3% to 20% * 1 point; lymph node positivity = 1 * 6 points; Ki-67 21% to 55% The Zaidi score should be calculated after resection and prior to registration. The Zaidi score does not apply to the subset of participants with liver only metastatic disease; for the purpose of stratification, these participants will be assigned a score of 6.
6. Participants must not have unresected or unablated metastatic disease
7. Participants must not have clinically apparent central nervous system metastases or carcinomatous meningitis
8. Participants must have recovered from effects of surgery as determined by the treating investigator
9. Participants must not have received prior neoadjuvant therapy for treatment of pancreatic neuroendocrine tumor. Use of somatostatin analogs prior to surgery is permitted
10. Participants must not have received somatostatin analogs after surgery for tumor control. The use of a limited course of somatostatin analogs post-surgery for prevention or control of complications from surgery (e.g. prevention of postoperative pancreatic fistula development) is allowed as long as somatostatin analogs are discontinued by the time of patient registration
11. Participants must be >= 18 years old
12. Participants must have Zubrod performance status of 0-2
13. Participants must have a complete medical history and physical exam within 28 days prior to registration
14. Participants must have adequate organ and marrow function as defined below within 28 days prior to registration:
15. Leukocytes >= 3 x 10^3/uL (within 28 days prior to registration)
16. Absolute neutrophil count >= 1.5 x 10^3/uL (within 28 days prior to registration)
17. Platelets >= 100 x 10^3/uL (within 28 days prior to registration)
18. Total bilirubin =< institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration)
19. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to registration)
20. Serum creatinine =< 1.5 x institutional ULN (within 28 days prior to registration)
21. Calculated creatinine clearance >= 50 ml/min (within 28 days prior to registration)
22. Participants must be able to swallow pills
23. Participants must be able to tolerate CT or MRI including contrast agents as required for their treatment and the protocol
24. Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
25. Participants must not be planning to receive warfarin while on protocol treatment. Other anticoagulants are allowed
26. Participants must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or capecitabine
27. Participants must not have known absorption issues that would limit the ability to absorb study agents
28. Participants must not have had an arterial thromboembolic event, unstable angina, or myocardial infarction within 90 days prior to registration. Pulmonary embolism is not considered an arterial event
29. Participants must not have active or uncontrolled infection
30. Participants must not have serious medical or psychiatric illness that could affect study participation in the judgement of the treating investigator
31. Participants must not be pregnant due to the possibility of harm to the fetus. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
32. Participants registered by sites located in the United States only must agree to have a hematoxylin and eosin (H&E) slide and a KI-67 immunohistochemistry (IHC) slide of the tumor submitted for central confirmatory quality review
33. Participants registered by sites located in the United States only must be offered the opportunity to participate in the optional specimen banking. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System
34. Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

Treatment Sites in Georgia