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Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01525082
Recruitment Status : Active, not recruiting
First Posted : February 2, 2012
Last Update Posted : April 18, 2018
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Stanford University

Brief Summary:
The purpose of this research is to evaluate the effectiveness and safety of a combination of capecitabine, temozolomide and bevacizumab in the treatment of advanced pancreatic neuroendocrine tumors.

Condition or disease Intervention/treatment Phase
Gastrinoma Glucagonoma Insulinoma Pancreatic Polypeptide Tumor Recurrent Islet Cell Carcinoma Recurrent Pancreatic Cancer Somatostatinoma Stage III Pancreatic Cancer Stage IV Pancreatic Cancer Drug: capecitabine Drug: temozolomide Biological: bevacizumab Phase 2

Detailed Description:


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 analysis.

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 year.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors
Study Start Date : December 2012
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : July 2019

Arm Intervention/treatment
Experimental: monoclonal antibody therapy, chemotherapy
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, capecitabine PO BID on days 1-14, and temozolomide PO QD on days 10-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: capecitabine
Given PO
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda

Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ

Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

Primary Outcome Measures :
  1. RR % determined by RECIST v1.1 [ Time Frame: 18 months ]
    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.

  2. Toxicities according to CTCAE v4.0 [ Time Frame: 18 months ]
    Patients will be monitored for systemic, renal, gastrointestinal, hematologic, neurological and liver toxicities. Adverse events will be tabulated by organ system and severity. Proportions will be estimated along with 95% exact confidence intervals.

Secondary Outcome Measures :
  1. PFS (median in months) [ Time Frame: 18 months ]
  2. OS (median in months) [ Time Frame: 18 months ]
  3. MGMT by central pathology review [ Time Frame: Baseline ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 treatment.
  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 dihydropyrimidine 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01525082

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United States, California
University of California San Francisco
San Francisco, California, United States, 94143
Stanford University
Stanford, California, United States, 94305
United States, Florida
Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
Stanford University
National Cancer Institute (NCI)
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Principal Investigator: Pamela Kunz Stanford University

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Responsible Party: Stanford University Identifier: NCT01525082     History of Changes
Other Study ID Numbers: NET0012
NCI-2011-03497 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
SU-10282011-8571 ( Other Identifier: Stanford University )
END0012 ( Other Identifier: Old OnCore Number )
First Posted: February 2, 2012    Key Record Dates
Last Update Posted: April 18, 2018
Last Verified: April 2018
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neuroendocrine Tumors
Carcinoma, Islet Cell
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Adenoma, Islet Cell
Neoplasms, Glandular and Epithelial
Carcinoma, Neuroendocrine
Antineoplastic Agents, Immunological