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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Stanford University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Stanford University
ClinicalTrials.gov Identifier:
NCT01525082
First received: January 10, 2012
Last updated: August 5, 2014
Last verified: August 2014
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • RR % determined by RECIST v1.1 [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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.

  • Toxicities according to CTCAE v4.0 [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
    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:
  • PFS (median in months) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • OS (median in months) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • MGMT by central pathology review [ Time Frame: Baseline ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: December 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

OUTLINE:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01525082

Locations
United States, California
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94143
Contact: Iche Siah    415-353-7792    isiah@medicine.ucsf.edu   
Principal Investigator: Iche Siah         
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Pamela A. Kunz    650-498-7061    pkunz@stanford.edu   
Principal Investigator: Pamela Kunz         
Sub-Investigator: George Fisher         
Sub-Investigator: James Ford         
Sub-Investigator: Aya Kamaya         
United States, Florida
Moffitt Cancer Center and Research Institute Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Helen M. Jump    813-745-4834    helen.jump@moffitt.org   
Principal Investigator: Helen M. Jump         
Sponsors and Collaborators
Stanford University
Investigators
Principal Investigator: Pamela Kunz Stanford University
  More Information

No publications provided

Responsible Party: Stanford University
ClinicalTrials.gov Identifier: NCT01525082     History of Changes
Other Study ID Numbers: NET0012, NCI-2011-03497, SU-10282011-8571, END0012
Study First Received: January 10, 2012
Last Updated: August 5, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Carcinoma, Islet Cell
Pancreatic Neoplasms
Neuroendocrine Tumors
Glucagonoma
Gastrinoma
Somatostatinoma
Adenoma, Islet Cell
Insulinoma
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
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
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Carcinoma, Neuroendocrine
Adenoma
Bevacizumab
Capecitabine
Temozolomide
Fluorouracil
Dacarbazine
Antibodies

ClinicalTrials.gov processed this record on October 19, 2014