Gemcitabine and S-1 for Locally Advanced Unresectable or Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Studying samples of tumor tissue and blood from patients with cancer in the laboratory may help doctors learn more about changes that may occur in DNA and identify biomarkers related to cancer. It may also help doctors predict a patient's response to treatment and help plan the best treatment. PURPOSE: This phase II trial is studying gene expression in predicting treatment response in patients receiving gemcitabine and S-1 for locally advanced unresectable or metastatic pancreatic cancer.

Detailed Description
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OBJECTIVES: Primary Correlate intratumoral expression level of ribonucleotide reductase subunit 1 (RRM1) with response to gemcitabine hydrochloride therapy in patients with locally advanced unresectable or metastatic adenocarcinoma of the pancreas. Secondary Correlate intratumoral expression levels of other genes (e.g., deoxycytidine kinase [dCK], equilibrative nucleoside transporter 1 [ENT1], and concentrative nucleoside transporters 1 and 3 [CNT1 and CNT3]) with response in these patients. Determine, preliminarily, the median survival of these patients, using a therapeutic strategy entailing sequential addition of agents and decision making based on early CA 19-9 biomarker response. Determine the safety of this approach. Determine the percentage of patients classified as potential biomarker responders. Determine the time to progression with each successive line of treatment. Determine the proportion of patients with ≥ 25% decline in CA 19-9 biomarker (i.e., biomarker response) with each successive line of treatment. Tertiary Identify other genes that may mediate sensitivity to gemcitabine hydrochloride, S-1, and other agents with activity in pancreatic cancer. Determine the frequency of host genetic polymorphisms in various nucleoside transporters. OUTLINE: This is a multicenter. Initial treatment (gemcitabine hydrochloride alone): Patients receive gemcitabine hydrochloride IV over 100 minutes on days 1, 8, and 15. CA 19-9 levels are assessed in weeks 1 and 3 of each course. Patients who are biomarker responders continue to receive treatment with gemcitabine hydrochloride alone. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who are no longer biomarker responders or show other evidence of disease progression proceed to therapy comprised of gemcitabine hydrochloride and S1. Gemcitabine hydrochloride and S-1 treatment: Patients receive gemcitabine hydrochloride IV over 100 minutes on days 1 and 15 and oral S-1 twice daily on days 1-7 and 15-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo core needle tumor biopsy and fine-needle aspiration at baseline. Tissue samples are analyzed for correlation between transcript and protein expression by immunohistochemistry and for expression of genes and gene products that may mediate sensitivity to gemcitabine hydrochloride (RRM1, ENT1, CNT1 and 3, dCK); S-1, thymidine phosphorylase [TP], TS, DPD, and ORPT; and other anticancer treatments (ERCC-1, epidermal growth factor receptor, GSK-3β) by reverse-transcriptase polymerase chain reaction. Tissue samples are also analyzed by microarray and comparative genomic hybridization to identify new genes that may predict chemotherapeutic response or mediate sensitivity to anticancer therapy. Mutational status of KRAS and p53 gene are also assessed. Blood samples are collected at baseline and are analyzed by genotyping assays to identify polymorphic variants of select genes. After completion of study treatment, patients are followed monthly. PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study.

Official Title
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Individualized Management of Pancreatic Cancer With Targeted Therapeutics (IMPACTT): A Phase II Clinical Trial

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: S-1
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Adenocarcinoma of the pancreas that is already or will be histologically or cytologically proven. Patients must have either locally advanced (unresectable) or metastatic disease. Radiographically measurable disease is not required. No prior therapy for advanced pancreatic cancer. Treatment given in the adjuvant setting (radiation and/or chemotherapy, given either concurrently or systemically) does not count as prior therapy as long as progressive disease occurs > 6 months following completion of treatment. Greater than or equal to 18 years of age. ECOG performance status of 0 or 1 (See Appendix D). Laboratory criteria: ANC > 1500/µL Platelet count > 100,000/µL Hemoglobin > 9 g/dL (may be transfused or receive epoetin alfa to maintain or exceed this level) INR < 1.5 (except those subjects who are receiving full-dose warfarin Total bilirubin < 2.0 mg/dL AST or ALT < 5 times upper limit of normal for subjects with documented liver metastases; < 2.5 times the upper limit of normal for subjects without evidence of liver metastases Serum creatinine < 2.0 mg/dL Serum CA19-9 > 2X upper limits of normal. All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. Women or men of reproductive potential must agree to use an effective contraceptive method during treatment and for 6 months afterwards. Exclusion criteria Inability to comply with study and/or follow-up procedures Disease determined to be not amenable to biopsy upon review of radiographs by the oncologist and/or interventional radiologist. Clearly resectable disease in a patient who is an appropriate operative candidate. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications Prior systemic therapy for advanced pancreatic cancer Pregnant (positive pregnancy test) or lactating Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not permitted while participating in this study. Use of concurrent investigational agents is not permitted. S-1 Specific Exclusion Criteria Is receiving a concomitant treatment with drugs interacting with S-1. The following drugs are prohibited because there may be an interaction with S-1: Sorivudine, brivudine, uracil, dipyridamole, cimetidine, and folinic acid (may enhance S-1 activity). Allopurinol (may diminish S-1 activity). Phenytoin (S-1 may enhance phenytoin activity). Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 and flucytosine activity). Pilocarpine (may inhibit cytochrome P-450 enzyme 2A6 activity).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Targeted therapy group<br>Gemcitabine monotherapy until disease progression, followed by gemcitabine + S-1 | Drug: S-1<br>* S-1 is given as follows: 25 mg/m2 bid on days 1-7 and 15-21 of the cycle (28 days)<br>* Other names: TS-ONE;Drug: gemcitabine hydrochloride<br>* Patients will receive gemcitabine at a dose of 1,000 mg/m2 i.v. at a fixed-dose rate (FDR) infusion of 10 mg/m2/minute (100 minutes), once a week for 3 consecutive weeks, followed by one week rest. Each 4 week period is referred to as a treatment cycle<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlate Intratumoral Expression Level of Ribonucleotide Reductase Subunit 1 (RRM1) With Response to Gemcitabine in Patients With Advanced Pancreatic Cancer. | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between RRM1 and response to gemcitabine. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of RRM1 and response to gemcitabine, a value of 0 indicating no association between RRM1 and response to gemcitabine, and a value of +1 indicating a positive linear association of RRM1 and response to gemcitabine. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlate Intratumoral Expression Levels of Other Genes, Including Deoxycytidine Kinase (dCK), Equilibrative Nucleoside Transporter 1 (ENT1) and Concentrative Nucleoside Transporters 1 and 3 (CNT1 and CNT3), With Response to Gemcitabine. | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between deoxycytidine kinase (dCK), equilibrative nucleoside transporter 1 (ENT1) and concentrative nucleoside transporters 1 and 3 (CNT1 and CNT3), with response to gemcitabine in a table format. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of intratumoral expression levels and response to gemcitabine, a value of 0 indicating no association between intratumoral expression levels and response to gemcitabine, and a value of +1 indicating a positive linear association of intratumoral expression levels and response to gemcitabine. | Up to 2 years | 
| Correlate Intratumoral Expression Levels of Thymidylate Synthase (TS), Thymidine Phosphorylase (TP), Dihydropyrimidine Dehydrogenase (DPD), Orotate Phosphoribosyltransferase (ORPT) With Response to the Combination of Gemcitabine/S-1. | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between intratumoral expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (ORPT) with response to the combination of gemcitabine/S-1 in a table format. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of intratumoral expression levels and the combination of gemcitabine/S-1, a value of 0 indicating no association between intratumoral expression levels and response to the combination of gemcitabine/S-1, and a value of +1 indicating a positive linear association of intratumoral expression levels and response to the combination of gemcitabine/S-1. | Up to 2 years | 
| Median Overall Survival | Overall survival will be defined from the date of receiving the first treatment until death | Up to 2 years | 
| Number of Patients With Dose Modifications | Treatment-related toxicities resulting in a dose modification be classified using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3 will be tabulated. | 8 weeks after 6th patient is enrolled | 
| Percentage of Patients Classified as Potential Biomarker Responders | Defined as the percentage of patients who will be categorized as potential biomarker responders if their CA19-9 has declined by > 10 % from peak value (peak value may have been at either week 1 or 3) during the initial gemcitabine monotherapy phase | Assessed after the first 5 weeks of treatment | 
| Median Time to Progression | Time to progression will be summarized according to the method of Kaplan and Meier | Up to 2 years | 
| Percentage of Patients With at Biomarker Response | A biomarker response for any given line of therapy is defined as patients with a baseline CA19-9 level > 75 units per cubic centimeter (U/cc) who demonstrate a > 25% decline in their peak CA19-9 level, sustainable for at least 2 consecutive measurements | Up to 2 years | 

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