Gemcitabine, Cisplatin, Epirubicin, and Capecitabine in Treating Patients With Stage I-II Resectable Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride, cisplatin, epirubicin hydrochloride, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gemcitabine hydrochloride, with or without cisplatin, epirubicin hydrochloride, and capecitabine before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these drugs after surgery may kill any tumor cells that remain after surgery. PURPOSE: This randomized phase II/III trial is studying how well gemcitabine hydrochloride, with or without cisplatin, epirubicin hydrochloride, and capecitabine, works when given before and/or after surgery in treating patients with stage I or stage II pancreatic cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To assess the proportion of patients who are event-free (defined as disease progression, local recurrence, distant metastasis, new tumor, or death) at 1 year after neoadjuvant therapy comprising gemcitabine hydrochloride with cisplatin, epirubicin hydrochloride, and capecitabine (PEXG), and adjuvant chemotherapy comprising gemcitabine hydrochloride or PEXG regimen in patients with resectable stage I or II adenocarcinoma of the pancreas. (phase II) To assess whether the best experimental regimen, which will be selected on the basis of the phase II part of the trial, is able to improve overall survival when compared to standard adjuvant gemcitabine in these patients. (phase III) Secondary To assess radiological, biochemical, and pathological response rate (neoadjuvant arm only) in these patients. To assess surgical resection rate, surgical mortality and morbidity, and proportion of patients with negative surgical margins. To assess lymph node status in these patients. To determine tolerability of these regimens in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to center. Patients are randomized to 1 of 3 treatment arms. Arm I (adjuvant gemcitabine hydrochloride) : Patients receive gemcitabine hydrochloride IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity. Arm II (adjuvant cisplatin, epirubicin hydrochloride, gemcitabine hydrochloride, and capecitabine [PEXG regimen]): Patients receive cisplatin IV over 1 hour on days 1-5, epirubicin hydrochloride IV on days 1 and 8, gemcitabine hydrochloride IV over 1 hour on days 1 and 8, and oral capecitabine on days 1-14. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. Arm III (neoadjuvant and adjuvant PEXG regimen): Patients receive neoadjuvant cisplatin IV over 1 hour on days 1-5, epirubicin hydrochloride IV on days 1 and 8, gemcitabine hydrochloride IV over 1 hour on days 1 and 8, and oral capecitabine on days 1-14. Treatment repeats every 14 days for up to 3 months. Patients then undergo surgery for pancreatic cancer followed by adjuvant (within 2 months of surgery) PEXG given as in neoadjuvant therapy. Treatment with adjuvant PEXG repeats every 14 days for 3 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

Official Title
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Randomized Phase II-III Trial of Peri- or Post-Operative Chemotherapy in Resectable Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: cisplatin
* Drug: epirubicin
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically* confirmed adenocarcinoma of pancreas Stage I-II disease Resectable disease No superior mesenteric vein or artery, portal vein, celiac trunk, or hepatic artery infiltration No symptomatic duodenal stenosis NOTE: Patients without histological or cytological results may be allowed provided ≥ 1 attempt has been made by needle aspiration with negative imaging and clinical signs suggestive of adenocarcinoma. PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% WBC ≥ 3,500/mm³ ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10 g/dL Creatinine ≤ 1.5 mg/dL ALT and AST ≤ 3 times upper limit of normal Bilirubin ≤ 3 mg/dL No prior or concurrent malignancy within the past 5 years except for surgically cured carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin Not pregnant or nursing No psychological, familial, sociological, or geographical condition that would potentially hinder study compliance or follow-up schedule PRIOR CONCURRENT THERAPY: No prior chemotherapy or radiotherapy for pancreatic adenocarcinoma No other concurrent experimental drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: adjuvant PEXG<br>cisplatin and epirubicin at 30 mg/mq, gemcitabine at 800 mg/mq and capecitabine at 1250 mg/mq/day per os for 14 days every 14 days for 6 months | Drug: capecitabine<br>* 1250 mg/mq/day per os for 14 days every 14 days for 6 months<br>* Other names: XELODA;Drug: cisplatin<br>* 30 mg/mq every 14 days for 6 months<br>* Other names: cisplatino TEVA;Drug: epirubicin<br>* 30 mg/mq every 14 days for 6 months<br>* Other names: farmorubicina;Drug: gemcitabine<br>* ARM A: 1000 mg/mq for 3 weekly infusions every 4 weeks for 6 months ARM B and C: 800 mg/mq every 14 days for 6 months<br>* Other names: GEMZAR;|
| Experimental: perioperative PEXG<br>cisplatin and epirubicin at 30 mg/mq, gemcitabine at 800 mg/mq and capecitabine at 1250 mg/mq/day per os for 14 days every 14 days for 3 months before surgery and 3 months after surgery | Drug: capecitabine<br>* 1250 mg/mq/day per os for 14 days every 14 days for 6 months<br>* Other names: XELODA;Drug: cisplatin<br>* 30 mg/mq every 14 days for 6 months<br>* Other names: cisplatino TEVA;Drug: epirubicin<br>* 30 mg/mq every 14 days for 6 months<br>* Other names: farmorubicina;Drug: gemcitabine<br>* ARM A: 1000 mg/mq for 3 weekly infusions every 4 weeks for 6 months ARM B and C: 800 mg/mq every 14 days for 6 months<br>* Other names: GEMZAR;|
| Active Comparator: Adjuvant Gemcitabine<br>Adjuvant Gemcitabine at 1000 mg/mq for 3 weeks every 4 weeks for 6 months | Drug: gemcitabine<br>* ARM A: 1000 mg/mq for 3 weekly infusions every 4 weeks for 6 months ARM B and C: 800 mg/mq every 14 days for 6 months<br>* Other names: GEMZAR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival at 1 year (phase II) | CT scan | every 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological, biochemical, and pathological response rate (neoadjuvant arm only) | CT scan, CA19.9 serology; pathology report | after 3 months of induction therapy | 
| Surgical resection rate | surgeon report | immediately after surgery | 
| Surgical mortality and morbidity | surgeon report | immediately after surgery | 
| Tolerability | outpatient visit; laboratory report | every 2 weeks during therapy | 
| Proportion of patients with negative surgical margins | pathology report | immediately after surgery | 
| Lymph node status | pathology report | immediately after surgery | 

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