Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors

Study Overview
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Brief Summary
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This randomized phase II trial studies how well giving temozolomide with or without capecitabine works in treating patients with advanced pancreatic neuroendocrine tumors. Drugs used in chemotherapy, such as temozolomide and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether temozolomide is more effective with or without capecitabine in treating patients with advanced pancreatic neuroendocrine tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate progression-free survival (PFS) associated with temozolomide alone or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors. SECONDARY OBJECTIVES: I. To evaluate response rates (RR) associated with temozolomide alone or temozolomide and capecitabine treatment in patients with advanced pancreatic neuroendocrine tumors. II. To evaluate overall survival (OS) associated with temozolomide alone or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors. III. To evaluate the toxicity associated with temozolomide alone or temozolomide and capecitabine treatment in patients with advanced pancreatic neuroendocrine tumors. IV. To evaluate the usefulness of methyl guanine methyltransferase (MGMT) status (by immunohistochemistry [IHC] and promoter methylation) for predicting response in pancreatic neuroendocrine tumor patients treated with either temozolomide or temozolomide and capecitabine. V. To bank radiology images for evaluation of quality, reproducibility, and compliance with computed tomography (CT) methodology. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive capecitabine PO twice daily (BID) on days 1-14 and temozolomide PO QD on days 10-14. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.

Official Title
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A Randomized Phase II Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors

Conditions
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Gastrinoma, Glucagonoma, Insulinoma, Islet Cell Carcinoma, Pancreatic Polypeptide Tumor, Recurrent Islet Cell Carcinoma, Somatostatinoma

Intervention / Treatment
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* Drug: temozolomide
* Drug: capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically or pathologically confirmed locally unresectable or metastatic low or intermediate grade pancreatic neuroendocrine tumor Patient must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; baseline measurements and evaluations of all sites of disease must be obtained <= 4 weeks prior to randomization and must be acquired by multiphasic CT or contrast magnetic resonance imaging (MRI) Date of last documented disease progression must be within 12 months from date of randomization Prior everolimus and/or sunitinib therapy is allowed, so long as it was discontinued >= 4 weeks prior to randomization Concurrent somatostatin analogues are allowed provided that patients Have been on a stable dose for 8 weeks and Have documented disease progression on that dose Chemoembolization is allowed if ≥ 4 weeks from study entry. There are 2 possible scenarios: If patient has hepatic disease only: they need to have progressed in the liver since chemoembolization and have measurable disease by RECIST 1.1 in order to be eligible. If patient has hepatic and extrahepatic disease: they will need to have progressed inside OR outside the liver and have measureable disease by RECIST 1.1 in order to be eligible. Leukocytes >= 3,000/mm^3 Absolute neutrophil count >= 1,500/mm^3 Hemoglobin >= 9 g/dL Platelets >= 100,000/mm^3 Total bilirubin <= institutional upper limit of normal (ULN) or <= 1.5 X institutional ULN (if the patient has liver metastases) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) <= 3 X institutional ULN or (<= 5 X institutional ULN if the patient has liver metastases) Serum creatinine <= 1.5 X institutional ULN Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Patient must have life expectancy >= 12 weeks all females of childbearing potential must have a blood test or urine study within =< 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately Patient must be able to swallow pills Patient must be able to tolerate CT or magnetic resonance (MR) imaging including contrast agents as required for their treatment and the protocol Exclusion Criteria: Small cell carcinoma Prior temozolomide, dacarbazine (DTIC), or capecitabine, or 5-FU (fluorouracil) therapy Receiving any other investigational agents while on study treatment Receiving Coumadin while on treatment; other anticoagulants are allowed Patients with either clinically apparent central nervous system metastases or carcinomatous meningitis are ineligible Active or uncontrolled infection or serious medical or psychiatric illness History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or capecitabine Absorption issues that would limit the ability to absorb study agents Patients with a history of the following within 12 months of study entry: Arterial thromboembolic events Unstable angina Myocardial Infarction Symptomatic peripheral vascular disease Patients with previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions: Non-melanoma skin cancer, in situ cervical cancer, or breast cancer in situ OR Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years OR Prior malignancy cured by non-surgical modalities and patient has been continuously disease free for > 5 years Pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (temozolomide)<br>Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. | Drug: temozolomide<br>* Given PO<br>* Other names: Temodar;|
| Experimental: Arm B (temozolomide and capecitabine)<br>Patients receive capecitabine PO BID on days 1-14 and temozolomide PO QD on days 10-14. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. | Drug: temozolomide<br>* Given PO<br>* Other names: Temodar;Drug: capecitabine<br>* Given PO<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival (PFS) is defined as the time from randomization to progression or death without evidence of progression. Progression was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Kaplan-Meier method was used to estimate PFS. | Assessed every 3 months for 3 years and then every 6 months for years 3-5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Response | Response was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Assessed every 3 months for 3 years and then every 6 months for years 3-5 | 
| Overall Survival | Overall survival is defined as time from randomization to death or date last known alive. | Assessed every 3 months for 3 years and then every 6 months for years 3-5 | 
| Association Between Methyl Guanine Methyltransferase (MGMT) Status by Immunohistochemistry (IHC) and Response | Response was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. MGMT status was determined by IHC using paraffin-embedded sections of 4µm. A score (H-score) was generated based on the findings and scoring was performed by two pathologists. This H-score ranges from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor). The highest score was used if there was disagreement. H-scores were grouped into 3 standard categories for MGMT status: Category 1 - <=50 Category 2 - 51-100 Category 3 - >100 | Assessed every 3 months for 3 years and then every 6 months for years 3-5 | 
| Association Between Methyl Guanine Methyltransferase (MGMT) Status by Promoter Methylation and Response | Response was evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and defined as either complete response (CR) or partial response (PR). CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. MGMT status is determined by promoter methylation, a clinically validated methylation-specific polymerase chain reaction (PCR) analysis. A tumor sample is considered positive for MGMT promoter methylation if an 80bp band is detected in the methylated PCR reaction. It would be considered MGMT negative if an 80bp band is not detected in the methylated PCR reaction. | Assessed every 3 months for 3 years and then every 6 months for years 3-5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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temozolomide, capecitabine, pancreatic neuroendocrine tumor