Pemetrexed, Gemcitabine, and Radiation Therapy in Treating Patients With Locally Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of pemetrexed when given together with radiation therapy in treating patients with locally advanced pancreatic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of pemetrexed disodium when given in combination with upper abdominal radiotherapy after induction therapy comprising gemcitabine hydrochloride and pemetrexed disodium followed by consolidation therapy with gemcitabine hydrochloride in patients with locally advanced pancreatic cancer. Determine the quantitative toxicity of this regimen in these patients. Secondary Determine the quantitative and qualitative dose-limiting toxicities of pemetrexed disodium in combination with upper abdominal radiation therapy. Evaluate patterns of failure, response, and survival of these patients at 1 year OUTLINE: This is an open-label, nonrandomized, dose-escalation study of pemetrexed disodium. Induction therapy: Patients receive pemetrexed disodium IV over 10 minutes and gemcitabine hydrochloride IV over 30 minutes on day 1. Treatment repeats every 14 days for 3 courses. Approximately 2 weeks later, patients without disease progression proceed to chemoradiotherapy. Chemoradiotherapy: Patients receive pemetrexed disodium IV over 10 minutes on days 1, 15, and 29 and undergo radiotherapy once daily 5 days a week for 5 ½ weeks. Approximately 2-3 weeks later, patients without disease progression proceed to consolidation therapy. Cohorts of 3-9 patients receive escalating doses of pemetrexed disodium during chemoradiotherapy until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which ≤ 20% or ≤ 2 of 9 patients experience dose-limiting toxicity. Consolidation therapy: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

Official Title
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A Phase I Dose-Escalating Study of Induction Gemcitabine/Pemetrexed Followed by Pemetrexed and Concurrent Upper Abdominal Radiation Therapy in Patients With Locally Advanced Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: pemetrexed disodium
* Device: Radiotherapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed carcinoma arising from the pancreas Stage II or III disease, meeting 1 of the following criteria: Nonresectable disease Potentially resectable disease Resectable disease Stage IV disease with symptomatic back pain requiring palliation allowed at the discretion of the principal investigator Measurable, evaluable, or nonmeasurable disease No neuroendocrine tumor of the pancreas No documented brain metastasis No clinically significant pleural or peritoneal effusions that cannot be drained PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 12 weeks Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL Serum bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 3 times ULN (5 times ULN if liver has tumor involvement) AST and ALT ≤ 3 times ULN (5 times ULN if liver has tumor involvement) Creatinine clearance ≥ 45 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment No active infection No serious systemic disorders that would preclude study treatment No significant cardiovascular disease in the form of abnormal electrocardiogram coupled with clinical features of recent or recurrent cardiac disease (including myocardial infarction, angina, or hypertension) PRIOR CONCURRENT THERAPY: More than 4 weeks since prior investigational agents No prior chemotherapy for pancreatic cancer Must be able to discontinue aspirin, dexamethasone, and other nonsteroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after pemetrexed disodium dose (5 days before for long-acting agents such as piroxicam) Must be able and willing to take folic acid and cyanocobalamin (vitamin B12) supplementation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pemetrexed in combination with concomitant radiotherapy<br>Patients will receive Pemetrexed plus Radiotherapy. | Drug: pemetrexed disodium<br>* 500 milligrams per meter squared day will be given during weeks 1, 3 and 5 of the radiation (3 total doses of Pemetrexed during the radiation therapy).<br>Device: Radiotherapy<br>* During the chemoradiation, the radiotherapy will be administered in 1.8 Gy/fractions after completion of the Pemetrexed infusion, and continue daily (Monday through Friday) for 5 1/2 weeks for a total delivered dose of 50.4 Gy (Total of 28 radiation treatments).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose of Pemetrexed When Administered With Concomitant Radiation Therapy |  | 42 days | 
| Quantitative Toxicity of Pemetrexed When Administered With Concomitant Radiation Therapy |  | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative Dose-limiting Toxicities of Pemetrexed in Combination With Radiation Therapy | Toxicity will be determined using the revised NCI Common Toxicity Criteria (CTC) version 3.0 for Toxicity and Adverse Event Reporting. Number of events with grade 1-5 will be reported. | 42 days | 
| Patterns of Failure |  | 1 year | 
| Patterns of Response |  | 1 year | 
| Number of Participants That Survived |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II pancreatic cancer, stage III pancreatic cancer, stage IV pancreatic cancer