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A Phase II Study of Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

Phase 2
18 Years
Open (Enrolling)
Gastrinoma, Glucagonoma, Insulinoma, Pancreatic Polypeptide Tumor, Recurrent Islet Cell Carcinoma, Recurrent Pancreatic Cancer, Somatostatinoma, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

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Trial Information

A Phase II Study of Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors


I. To estimate if the combination of capecitabine and temozolomide with bevacizumab for
metastatic or unresectable neuroendocrine tumors will improve response rate (RR) by 62% over
historical controls (null RR of 40% to true RR 65%).

II. Assess the toxicities using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.


I. To evaluate progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier

II. To assess O6-methyl guanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) by
central pathology (path) review.

III. To assess serum hormone marker levels. IV. To evaluate computed tomography (CT)
Perfusion as a tool to predict early therapeutic response. (Optional) V. To bank serum for
future correlative analyses.


Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15,
capecitabine orally (PO) twice daily (BID) on days 1-14, and temozolomide PO once daily (QD)
on days 10-14. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up patients are followed up for 1

Inclusion Criteria:

1. Patients must have histologically confirmed pancreatic neuroendocrine tumors that are
considered well- or moderately- differentiated

2. Patients must have metastatic or unresectable disease

3. Patients with prior surgical resection who develop radiological or clinical evidence
of metastatic cancer do not require separate histological or cytological confirmation
of metastatic disease unless an interval of > 5 years has elapsed between the primary
surgery and the development of metastatic disease. Clinicians should consider biopsy
of lesions to establish diagnosis of metastatic disease if there is substantial
clinical ambiguity regarding the nature or source of apparent metastases.

4. Prior sunitinib and everolimus will be permitted. A wash-out period of 2 weeks is
required prior to first dose on this study.

5. Prior liver directed therapies will be permitted (ie. chemoembolization,
radioembolization) as long as target lesions in the liver have demonstrated growth
since the liver directed treatment.

6. Prior peptide receptor radionuclide therapy (PRRT) will be permitted as long as
target lesions in the liver have demonstrated growth since the liver directed

7. Low-dose aspirin (<= 325 mg/d) may be continued in subjects at higher risk for
arterial thromboembolic disease.

8. Patients must have a primary or metastatic lesion measurable in at least one
dimension by Modified RECIST criteria v1.1 (see Section 4.2) within 4 weeks prior to
entry of study.

9. Patients must have ECOG performance status of 0-2

10. Patients must be >= 18 years of age.

11. Laboratory values <= 2 weeks prior to randomization:

- Absolute Neutrophil Count (ANC) >= 1.5 x 109/L (>= 1500/mm3)

- Platelets (PLT) >= 100 x 10^9/L (=> 100,000/mm^3)

- Hemoglobin (Hgb) >= 9 g/dL

- Serum creatinine <= 1.5 x ULN

- Serum bilirubin <= 1.5 x ULN

- Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) <=
3.0 x ULN (<= 5.0 x ULN if liver metastases present). Note: ERCP or
percutaneous stenting may be used to normalize the liver function tests.

12. Life expectancy >= 12 weeks.

13. Ability to give written informed consent according to local guidelines.

Exclusion Criteria:

Disease-Specific Exclusions

1. Prior bevacizumab, fluoropyrimidines (capecitabine or 5FU) or temozolomide.

2. Poorly differentiated or high grade pancreatic neuroendocrine tumors

3. Prior full field radiotherapy <= 4 weeks or limited field radiotherapy <= 2 weeks
prior to enrollment. Patients must have recovered from all therapy-related
toxicities. The site of previous radiotherapy should have evidence of progressive
disease if this is the only site of disease.

4. Diagnosis of another malignancy, unless the patient was diagnosed at least 3 years
earlier and has been disease-free for at least 6 months following the completion of
curative intent therapy, specifics as follows:

- Curatively resected non-melanomatous skin cancer

- Curatively treated cervical carcinoma in situ

- Patients with organ-confined prostate cancer with no evidence of recurrent or
progressive disease based on prostate-specific antigen (PSA) values are also
eligible for this study if hormonal therapy has been initiated or a radical
prostatectomy has been performed.

- Other primary solid tumor curatively treated with no known active disease
present and no treatment administered for the last 3 years.

5. Concurrent use of other investigational agents and patients who have received
investigational drugs <= 4 weeks prior to enrollment.

6. Known hypersensitivity to capecitabine, temozolomide, or any component of the
formulation and or a known deficiency of dihyropyrimidine dehydrogenase.

General Medical Exclusions

Subjects meeting any of the following criteria are ineligible for study entry:

7. Inability to comply with study and/or follow-up procedures.

8. Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study .

9. Pregnancy (positive pregnancy test) or lactation- breast feeding Lack of of effective
means of contraception (men and women) in subjects of child-bearing potential.

10. Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment).

11. Known history of HIV, HBV, or HCV

12. Current, ongoing treatment with full-dose warfarin. However patients may be on
stable doses of a low molecular weight heparin are allowed (ie. Lovenox).

Bevacizumab-Specific Exclusions

13. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
and/or diastolic blood pressure > 100 mmHg).

14. Prior history of hypertensive crisis or hypertensive encephalopathy.

15. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see
Appendix E).

16. History of myocardial infarction or unstable angina within 6 months prior to Day 1.

17. History of stroke or transient ischemic attack within 6 months prior to Day 1.

18. Known CNS metastases

19. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1.

20. History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1.

21. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation).

22. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1 or anticipation of need for major surgical procedure during the course
of the study.

23. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1.

24. History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1.

25. Serious, non-healing wound, active ulcer, or untreated bone fracture.

26. Proteinuria: Patients are allowed to have 0, trace, or 1+ protein by urine dipstick
or urinalysis to enroll, if >= 2+ must check 24h urine protein and must be < 1g to
start study.

27. Known hypersensitivity to any component of bevacizumab.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

RR % determined by RECIST v1.1

Outcome Description:

RR is defined as the proportion of patients with complete response + partial response (CR + PR] based on a patient's best response. The proportion of RR (CR+PR) will be estimated along with a one-sided lower 95% exact confidence bound to allow an informal assessment of the null hypothesis (RR=40%) based on binomial probabilities.

Outcome Time Frame:

18 months

Safety Issue:


Principal Investigator

Pamela Kunz

Investigator Role:

Principal Investigator

Investigator Affiliation:

Stanford University


United States: Institutional Review Board

Study ID:




Start Date:

December 2012

Completion Date:

December 2014

Related Keywords:

  • Gastrinoma
  • Glucagonoma
  • Insulinoma
  • Pancreatic Polypeptide Tumor
  • Recurrent Islet Cell Carcinoma
  • Recurrent Pancreatic Cancer
  • Somatostatinoma
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Carcinoma
  • Gastrinoma
  • Zollinger-Ellison Syndrome
  • Glucagonoma
  • Insulinoma
  • Pancreatic Neoplasms
  • Somatostatinoma
  • Neuroendocrine Tumors
  • Adenoma, Islet Cell
  • Carcinoma, Islet Cell



Stanford University Stanford, California  94305
University of California San Francisco San Francisco, California  941104206
Moffitt Cancer Center and Research Institute Tampa, Florida  33612