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GastrinomaPhase 2NCT01525082

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

A Phase 2 study testing Capecitabine, Temozolomide and Bevacizumab in people with Gastrinoma and Glucagonoma, run by Shaheen Shagufta at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Gastrinoma, Glucagonoma, Insulinoma
What is being tested?
Capecitabine, Temozolomide and Bevacizumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteUnited States
Study dates
Dec 2012to 31 Dec 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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)].

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Stanford University Medical Center

    Stanford, California, 94305

Other trials in United States

About this study

Official title: A Phase 2 Study of Capecitabine, Temozolomide, and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

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.

Read the 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.

Medical subject headings
Gastrinoma, Glucagonoma, Insulinoma, Carcinoma, Islet Cell, Pancreatic Neoplasms, Somatostatinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CapecitabineDrug

    Also called CAPE, Ro 09-1978/000, Xeloda

    Capecitabine by mouth twice daily on Days 1 to 14

  • TemozolomideDrug

    Also called SCH 52365, Temodal, Temodar, TMZ

    Temozolomide by mouth daily on Days 10 to 14

  • BevacizumabBiological

    Also called Avastin, anti-VEGF humanized monoclonal antibody, anti-VEGF monoclonal antibody, rhuMAb VEGF

    Bevacizumab IV over 30 to 90 minutes on Days 1 \& 15

Study groups in NCT01525082
Study groupRoleWhat they receive
Bevacizumab + Capecitabine + TemozolomideExperimentalCycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal.
Receives: Drug: Capecitabine; Drug: Temozolomide; Biological: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Radiographic Response (RR)

    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.

    Measured: 18 months

Secondary outcomes (5)

  1. Treatment-related Toxicity

    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.

    Measured: 18 months

  2. Progression-free Survival (PFS)

    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.

    Measured: 82 months

  3. Overall Survival (OS)

    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.

    Measured: 82 mo

  4. O6-methylguanine DNA Methyltransferase (MGMT) Status by Immunohistochemistry (IHC)

    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.

    Measured: 18 months

  5. O6-methylguanine DNA Methyltransferase (MGMT) by Promoter Methylation

    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.

    Measured: 18 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Feb 2012 (estimated)
  2. Study startDec 2012
  3. Primary completionJan 2018
  4. Study completion31 Dec 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01525082
Sponsor's protocol ID
IRB-22412
Other IDs
NCI-2011-03497, SU-10282011-8571, NET0012, END0012, 4593
Status last verified
Jan 2024
First submitted
10 Jan 2012
Last updated
6 Feb 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Capecitabine, Temozolomide and Bevacizumab in people with Gastrinoma and Glucagonoma, run by Shaheen Shagufta at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Radiographic Response (RR) (time frame: 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01525082.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2024.

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