Gemcitabine With or Without Capecitabine and/or Radiation Therapy or Gemcitabine With or Without Erlotinib in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known which regimen of chemotherapy with or without erlotinib and/or radiation therapy is most effective in treating pancreatic cancer. PURPOSE: This randomized phase III trial is studying giving gemcitabine together with or without capecitabine and/or radiation therapy to see how well it works compared with giving gemcitabine together with or without erlotinib in treating patients with locally advanced pancreatic cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To assess whether administrating chemoradiotherapy in patients whose tumor is controlled after 4 months of induction chemotherapy (CT) increases survival compared with continuation of the same CT in patients with unresectable, locally advanced adenocarcinoma of the pancreas. Secondary To assess whether erlotinib hydrochloride combined with gemcitabine hydrochloride and administered as maintenance treatment increases progression-free survival compared with gemcitabine hydrochloride alone and without maintenance treatment. To evaluate the response rate in the CT and chemoradiotherapy (CRT) arms. To evaluate tolerance to erlotinib hydrochloride as maintenance treatment after the end of CT or CRT. To study the predictive molecular factors (i.e., survivin, K-ras, EGFR, PTEN, or AKT) of survival. OUTLINE: This is a multicenter study. Patients in the first randomization are stratified according to center and ECOG performance status (0-1 vs 2). Patients in the second randomization are stratified according to center and initial treatment arm (I vs II). First randomization: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. Following the first evaluation, patients continue to receive gemcitabine hydrochloride on days 57, 64, 71, 85, 92, and 99 for a total of 4 months. Arm II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. Following the first evaluation, patients continue to receive gemcitabine hydrochloride on days 57, 64, 71, 85, 92, and 99. Patients also receive oral erlotinib hydrochloride once daily for 4 months. After completion of treatment in the first randomization proceed to the second randomization. Second randomization: Patients are randomized to 1 of 4 treatment arms. Arm I: Patients continue gemcitabine hydrochloride as in arm I in the first randomization on days 113, 120, and 127 and on days 141, 148, and 155 for 2 months in the absence of disease progression. Arm II: Patients continue gemcitabine hydrochloride as in arm II in the first randomization on days 113, 120, and 127 and on days 141, 148, and 155 and oral erlotinib hydrochloride daily for 2 months followed by erlotinib hydrochloride alone as maintenance therapy in the absence of disease progression. Arm III: Patients receive oral capecitabine twice daily and undergo radiotherapy beginning on day 127, 5 days a week, for 6 weeks, in the absence of disease progression. Arm IV: Patients receive oral capecitabine twice daily and undergo radiotherapy beginning on day 127, 5 days a week, for 6 weeks. Beginning 15 days after completion of CRT, patients receive a reintroduction of oral erlotinib hydrochloride alone once daily in the absence of disease progression or unacceptable toxicity. Tumor tissue will be analyzed for the relationship between biological markers and resistance to treatment. After completion of study treatment, patients are followed every 2 months.

Official Title
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Randomized Multicenter Phase III Study in Patients With Locally Advanced Adenocarcinoma of the Pancreas: Gemcitabine With or Without Chemoradiotherapy and With or Without Erlotinib. Intergroup Study

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: erlotinib hydrochloride
* Drug: gemcitabine hydrochloride
* Other: laboratory biomarker analysis
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the pancreas meeting the following criteria: De novo locally advanced disease Unresectable disease Stage III according to the UICC classification No distant metastases No localized stage IA-IIB or metastatic stage IV disease according to UICC classification Not considered for curative resection after pluridisciplinary discussion PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status 0-2 Life expectancy ≥ 12 weeks Polynuclear neutrophils ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) For patients who have had a recent biliary drain and whose bilirubin is descending, a value of ≤ 3 times ULN is acceptable Creatinine ≤ 2 mg/dL AST and ALT ≤ 2.5 times ULN Alkaline phosphatase ≤ 5 times ULN Albumin ≥ 25 g/L Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of therapy Exclusion criteria: Diarrhea ≥ grade 2 and/or uncontrolled diarrhea Affiliated with a social security regime Unable to follow instructions for psychological, familial, or geographical reasons Allergic to one of the ingredients in erlotinib hydrochloride Cancer within the past 5 years, except for in situ cancer of the neck of the uterus or basal cell skin cancer Severe infection Ophthalmic disease (i.e., inflammation, keratopathy, or infection) Symptomatic coronary or cardiac insufficiency, myocardial infarction, or stroke within the last 6 months Unable to take oral treatments Gastrointestinal disorders that could be associated with absorption disorders Untreated gastric or duodenal ulcer PRIOR CONCURRENT THERAPY: No prior radiotherapy (including abdominal radiotherapy) or chemotherapy for any reason No prior anti-epidermal growth factor-receptor therapy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 (A1) - Gemcitabine<br>Gemcitabine 2 months, then stop until progression | Drug: gemcitabine hydrochloride<br> <br> Other: laboratory biomarker analysis<br> <br> |
| Experimental: Arm 2 (B1) Gemcitabine + Erlotinib<br>B1 Gemcitabine + Erlotinib (100mg/d) 2 months, then erlotinib maintenance (150 mg/d)until progression | Drug: erlotinib hydrochloride<br> <br> Drug: gemcitabine hydrochloride<br> <br> Other: laboratory biomarker analysis<br> <br> |
| Experimental: Arm 3 (A2) CRT<br>A2 CRT then stop until progression | Drug: capecitabine<br> <br> Other: laboratory biomarker analysis<br> <br> Radiation: radiation therapy<br> <br> |
| Experimental: Arm 4 (B2) CRT then erlotinib<br>B2 CRT then erlotinib maintenance (150mg/d) until progression | Drug: capecitabine<br> <br> Drug: erlotinib hydrochloride<br> <br> Other: laboratory biomarker analysis<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | an interim analysis is planned when 196 deaths will be observed | from the date of the first randomization to the date of patient death,due to any cause, or to the last date the patient was known to be alive, assessed up to 8 years after the beginning of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | time from the date of the first randomization to the date of progressive disease or death, assessed up to 8 years after the beginning of the study. | 
| Relationship between biological markers and survival | 1 biopsy/patient of the pancreas before treatment | From baseline to death, assessed up to 8 years after the beginning of the study | 
| tolerance to erlotinib | To evaluate tolerance to erlotinib as maintenance treatment after the end of CT or CRT. During each visit, any adverse events will be noted and graded according to version 3 of the NCI-CTCAE. Any adverse events that persist at the end of the CTI will be followed up until they disappear. | from start of treatment until the event has resolved or stabilized or until death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the pancreas, stage III pancreatic cancer