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

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ClinicalTrials.gov Identifier: NCT01525082
Recruitment Status : Completed
First Posted : February 2, 2012
Results First Posted : December 30, 2020
Last Update Posted : May 4, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Shaheen Shagufta, 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:

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

  • Evaluate progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis.
  • Assess O6-methyl guanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) at baseline by central pathology (path) review.
  • Assess serum hormone marker levels.
  • Evaluate computed tomography (CT) Perfusion as a tool to predict early therapeutic response. (Optional)
  • Bank serum for future correlative analyses.

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30 to 90 minutes on days 1 and 15, capecitabine orally (PO) twice daily (BID) on days 1 to 14, and temozolomide PO once daily (QD) on days 10 to 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity, with assessment for treatment effect every 3 cycles.

After completion of study treatment, patients are followed up patients are followed long-term for survival.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors
Study Start Date : December 2012
Actual Primary Completion Date : January 2018
Actual Study Completion Date : December 31, 2019


Arm Intervention/treatment
Experimental: Bevacizumab + Capecitabine + Temozolomide
Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal.
Drug: Capecitabine
Capecitabine by mouth twice daily on Days 1 to 14
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda

Drug: Temozolomide
Temozolomide by mouth daily on Days 10 to 14
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ

Biological: Bevacizumab
Bevacizumab IV over 30 to 90 minutes on Days 1 & 15
Other Names:
  • Avastin
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • rhuMAb VEGF




Primary Outcome Measures :
  1. Radiographic Response (RR) [ Time Frame: 18 months ]

    Tumor response to treatment with the combination of capecitabine & temozolomide plus bevacizumab in patients with metastatic or unresectable pancreatic neuroendocrine tumors was assessed per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions. Response is defined as:

    • Complete Response (CR) = Disappearance of all target lesions
    • Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions
    • Overall Response (OR) = CR + PR
    • Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s)
    • Stable disease (SD) = Small changes that do not meet any of the above criteria

    The outcome is reported as the number of participants who between 3 and 18 months after treatment initiation achieve CR, PR, or clinical response (PR + CR), each a number without dispersion.



Secondary Outcome Measures :
  1. Treatment-related Toxicity [ Time Frame: 18 months ]
    Patients will be monitored for hematologic (blood and lymphatic), gastrointestinal (stomach and gut), renal (kidney), liver (metabolic), neurological, and systemic (constitutional) toxicities (treatment-related adverse events). Toxicity events occurring during treatment will be tabulated for each indicated organ system, and listed separated for serious and non-serious events, with the toxicity attribution indicated. The outcome is reported as the number of events, a number without dispersion.

  2. Progression-free Survival (PFS) [ Time Frame: 82 months ]
    Progression-free survival (PFS) means the length of time that participants survive without disease (tumor) progression, and was assessed using Kaplan-Meier analysis. The outcome is given as the mean in months with standard error of the mean.

  3. Overall Survival (OS) [ Time Frame: 82 mo ]

    Time from the date of enrollment to the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of data cutoff for the final analysis. The results will be reported as median in months

    The length of overall survival (OS) of participants was assessed by Kaplan-Meier analysis. The outcome is given as the median in months with full range.


  4. O6-methylguanine DNA Methyltransferase (MGMT) Status by Immunohistochemistry (IHC) [ Time Frame: 18 months ]

    O6-alkylguanine DNA alkyltransferase is a protein that in humans is encoded by the gene "O6-methylguanine DNA methyltransferase" (MGMT). Deficiency of the gene product, ie, the protein, is refereed to as "MGMT deficiency," and is thought to be predictive of response to temozolomide and is more often associated with pancreatic NETs.

    MGMT status in pre-treatment biopsy specimens was to be assessed by immuno-histochemistry (IHC), and associated to best clinical response. The outcome is reported by the the number of patients that were IHC-positive (MGMT detected) or IHC-negative (MGMT not detected), and by best clinical response [ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. The outcome is reported as a number without dispersion.


  5. O6-methylguanine DNA Methyltransferase (MGMT) by Promoter Methylation [ Time Frame: 18 months ]

    O6-alkylguanine DNA alkyltransferase is a protein that in humans is encoded by the gene "O6-methylguanine DNA methyltransferase" (MGMT). Deficiency of the gene product, ie, the protein, is refered to as "MGMT deficiency," and is thought to be predictive of response to temozolomide and is more often associated with pancreatic NETs.

    MGMT status in pre-treatment biopsy specimens was to be assessed by extent of genetic promoter methylation (an analysis of DNA), and correlated to subject survival.

    MGMT status in pre-treatment biopsy specimens was to be assessed by promoter methylation assessment (PM), and associated to best clinical response. The outcome is reported by the the number of patients that were PM-positive (MGMT detected) or PM-negative (MGMT not detected), and by best clinical response [ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. The outcome is reported as a number without dispersion.




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
Criteria

INCLUSION CRITERIA

  • Histologically-confirmed pancreatic neuroendocrine tumors that are moderately- or well-differentiated
  • Metastatic or unresectable disease
  • If prior surgical resection > 5 years before the development of metastatic disease, a separate (recent) histological or cytological confirmation of metastatic disease is required
  • If there is substantial clinical ambiguity regarding the nature or source of apparent metastases, clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease
  • The site of previous radiotherapy, if the only site of disease, has evidence of progressive disease
  • If prior sunitinib and everolimus has been administered, a 2-week wash-out period is required prior to 1st dose on this study
  • If prior liver-directed therapies (ie, chemoembolization, radioembolization), target lesions in the liver have demonstrated growth since the liver-directed treatment
  • If prior peptide receptor radionuclide therapy (PRRT), target lesions in the liver have demonstrated growth since the liver-directed treatment
  • Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial thromboembolic disease.
  • Primary or metastatic tumor lesion measurable in at least 1 dimension, within 4 weeks prior to entry of study.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  • ≥ 18 years of age.
  • Laboratory values as follows, ≤ 2 weeks prior to randomization:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L (≥ 1500/mm³)
  • Platelets (PLT) ≥ 100 x 10e9/L (≥ 100,000/mm³)
  • Hemoglobin (Hgb) ≥ 9 g/dL
  • Serum creatinine ≤ 1.5 x upper limit of normal (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: endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous stenting may be used to normalize the liver function tests
  • Urine dipstick or urinalysis for protein, value must be 0, trace, or 1+ protein to enroll. EXCEPTION: if ≥ 2+ must check 24-hour urine protein and must be < 1 g
  • Life expectancy ≥ 12 weeks
  • Ability to give written informed consent according to local guidelines
  • If any prior therapy-related toxicities, must have recovered from all

EXCLUSION CRITERIA Disease-Specific Exclusions

  • Prior bevacizumab; fluoropyrimidines (eg, capecitabine or 5-fluorouracil, 5FU); or temozolomide
  • Poorly-differentiated or high-grade pancreatic neuroendocrine tumors
  • Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to enrollment
  • Diagnosis of another malignancy, unless > 3 years earlier and has been disease-free for > 6 months following the completion of curative intent therapy, specific eligibility exceptions as follows:
  • Curatively-resected non-melanomatous skin cancer
  • Curatively-treated cervical carcinoma in situ
  • Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values, 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 > 3 years
  • Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment
  • Known hypersensitivity to capecitabine, temozolomide, or any component of the formulation
  • Known deficiency of dihydropyrimidine dehydrogenase Bevacizumab-specific Exclusions
  • Inadequately-controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure
  • History of myocardial infarction or unstable angina within 6 months prior to Day 1
  • History of stroke or transient ischemic attack within 6 months prior to Day 1
  • Known central nervous system (CNS) metastases
  • Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
  • History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 month prior to Day 1
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • 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
  • Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
  • History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
  • Serious, non-healing wound, active ulcer, or untreated bone fracture
  • Known hypersensitivity to any component of bevacizumab General Medical Exclusions
  • Inability to comply with study and/or follow-up procedures
  • Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study
  • Pregnant or lactating/breast feeding
  • Lack of effective contraception men or women of child-bearing potential
  • 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)
  • Known history of HIV, HBV, or HCV
  • Current, ongoing treatment with full-dose warfarin. However, patients may be on stable doses of a low-molecular weight heparin are allowed [eg, (enoxaparin (Lovenox)].

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 ClinicalTrials.gov identifier (NCT number): NCT01525082


Locations
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United States, California
Stanford University Medical Center
Stanford, California, United States, 94305
Sponsors and Collaborators
Shaheen Shagufta
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Shaheen Shagufta, MD Stanford University
  Study Documents (Full-Text)

Documents provided by Shaheen Shagufta, Stanford University:
Informed Consent Form  [PDF] March 24, 2020

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Responsible Party: Shaheen Shagufta, Clinical Assistant Professor, Stanford University
ClinicalTrials.gov Identifier: NCT01525082    
Other Study ID Numbers: IRB-22412
NCI-2011-03497 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
SU-10282011-8571 ( Other Identifier: Stanford University )
NET0012 ( Other Identifier: OnCore )
END0012 ( Other Identifier: superceded OnCore )
4593 ( Other Identifier: superceded IRB number )
First Posted: February 2, 2012    Key Record Dates
Results First Posted: December 30, 2020
Last Update Posted: May 4, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neuroendocrine Tumors
Insulinoma
Carcinoma, Islet Cell
Gastrinoma
Glucagonoma
Somatostatinoma
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
Adenoma, Islet Cell
Adenoma
Neoplasms, Glandular and Epithelial
Adenocarcinoma
Carcinoma
Carcinoma, Neuroendocrine
Bevacizumab
Antineoplastic Agents, Immunological
Capecitabine
Temozolomide
Antibodies
Immunoglobulins