Oxaliplatin, Gemcitabine, Erlotinib, and Radiation Therapy in Treating Patients With Unresectable and/or Metastatic Pancreatic Cancer or Biliary Tract Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and gemcitabine, 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. Giving oxaliplatin together with gemcitabine, erlotinib, and radiation therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of oxaliplatin, gemcitabine, and erlotinib when given together with radiation therapy in treating patients with unresectable and/or metastatic pancreatic cancer or biliary tract cancer.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose (MTD) of oxaliplatin and gemcitabine hydrochloride when combined with radiotherapy in patients with unresectable and/or metastatic pancreatic or biliary tract adenocarcinoma. (Part 1) Determine the MTD of erlotinib hydrochloride and gemcitabine hydrochloride when combined with oxaliplatin at the MTD and radiotherapy in these patients. (Part 2) OUTLINE: This is a multicenter, nonrandomized, parallel group, uncontrolled, open-label, dose-escalation study of gemcitabine hydrochloride, oxaliplatin, and erlotinib hydrochloride. Part 1: Patients receive gemcitabine hydrochloride IV over 30-60 minutes and oxaliplatin IV on day 1. Patients also undergo external beam radiotherapy (EBRT) once daily on days 1-5. Treatment repeats every 7 days for up to 6 courses. Cohorts of 3-6 patients receive escalating doses of gemcitabine hydrochloride and oxaliplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT). Up to 10 patients are treated at the MTD. Part 2: Patients receive gemcitabine hydrochloride, oxaliplatin*, and EBRT as in part 1. Patients also receive oral erlotinib hydrochloride once daily on days 1-5. Treatment repeats every 7 days for up to 6 courses. Cohorts of 3-6 patients receive escalating doses of gemcitabine hydrochloride and erlotinib hydrochloride until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. Up to 10 patients are treated at the MTD. NOTE: *Patients receive oxaliplatin at the MTD determined in part 1. After completion of study treatment, patients are followed every 3 months.

Official Title
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A Two-Part Phase I Study of the Addition of Oxaliplatin to Gemcitabine, and Then Erlotinib Plus Oxaliplatin to Gemcitabine as Radiosensitizers for Pancreatic and Biliary Adenocarcinoma

Conditions
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Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Pancreatic Cancer

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: gemcitabine hydrochloride
* Drug: oxaliplatin
* Radiation: radiation therapy
* Drug: gemcitabine hydrochloride
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy confirmed diagnosis of any of the following: Pancreatic carcinoma Ampullary carcinoma Biliary tract (gallbladder or bile duct) carcinoma Unresectable and/or biopsy-proven metastatic disease Suitable for bimodality therapy, as determined by a medical oncologist and radiation oncologist PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 2 months ANC > 1,500/mm³ Platelet count > 100,000/mm³ Creatinine < 1.5 mg/dL Total bilirubin < 2 times upper limit of normal (ULN) AST < 3 times ULN (< 5 times ULN if liver metastases are present) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No known hypersensitivity to platinum agent or gemcitabine hydrochloride No serious medical or psychiatric illnesses that would preclude giving informed consent PRIOR CONCURRENT THERAPY: No prior radiotherapy to the upper abdomen More than 3 weeks since prior chemotherapy No prior erlotinib hydrochloride At least 5 days since prior and no concurrent CYP3A4 inducer/inhibitor

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: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I<br>Oxaliplatin + Gemcitabine + Radiation | Drug: gemcitabine hydrochloride<br>* Gemcitabine will be given at a dose of 100 mg/m2 for the first cohort and escalated to a fixed dose of 200 mg/m2 for the remaining 3 cohorts<br>Drug: oxaliplatin<br>* Oxaliplatin will be given at 30 mg/m2 weekly for the first two cohorts and then will be dose-escalated to 45 mg/m2 and 60 mg/m2 for the next 2 in cohorts<br>Radiation: radiation therapy<br>* 5040 cGy, every week, up to 6 weeks<br>|
| Experimental: Part II<br>Erlotinib + Oxaliplatin + Gemcitabine + Radiation | Drug: erlotinib hydrochloride<br>* Cohort (-1) = 50 mg daily Cohort 1 = 50mg daily Cohort 2= 75 mg daily Cohort 3 = 100mg daily Cohort 4 = 100mg daily Cohort 5 = 150mg daily<br>Radiation: radiation therapy<br>* 5040 cGy, every week, up to 6 weeks<br>Drug: gemcitabine hydrochloride<br>* Given weekly at a starting dose of 100mg/m2 in the first 3 cohorts and dose escalated to 200 mg/m2 for the remaining 2 cohorts<br>Drug: Oxaliplatin<br>* The Part II dose of oxaliplatin will be determined by Part I of the study. The dose for Part II will be one dose level increase from the MTD determined in Part I.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of oxaliplatin and gemcitabine hydrochloride (Part 1) | The MTC of Oxaliplatin and gemcitabine is defined as the combination for which the rate of toxicities that cause dose reductions plus twice the rate of dsoe limiting toxicity (DLT) is equal to 0.5 | 6 weeks | 
| Maximum Tolerated Dose (MTD) of erlotinib hydrochloride and gemcitabine hydrochloride (Part 2) | The highest dose for which the observed dose reduction rate plus twice the dose limiting toxicity (DLT) rate does not exceed 0.5 will be declared the MTD | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III pancreatic cancer, stage IV pancreatic cancer, unresectable extrahepatic bile duct cancer, unresectable gallbladder cancer, adenocarcinoma of the extrahepatic bile duct, adenocarcinoma of the gallbladder, adenocarcinoma of the pancreas, recurrent pancreatic cancer, recurrent extrahepatic bile duct cancer, recurrent gallbladder cancer