Gemcitabine and S-1 for Locally Advanced Unresectable or Metastatic Pancreatic Cancer
- Registration Number
- NCT00429858
- Lead Sponsor
- Andrew Ko
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 21
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Targeted therapy group gemcitabine hydrochloride Gemcitabine monotherapy until disease progression, followed by gemcitabine + S-1 Targeted therapy group S-1 Gemcitabine monotherapy until disease progression, followed by gemcitabine + S-1
- Primary Outcome Measures
Name Time Method Correlate Intratumoral Expression Level of Ribonucleotide Reductase Subunit 1 (RRM1) With Response to Gemcitabine in Patients With Advanced Pancreatic Cancer. Up to 2 years 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.
- Secondary Outcome Measures
Name Time Method Percentage of Patients Classified as Potential Biomarker Responders Assessed after the first 5 weeks of treatment 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
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. Up to 2 years 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.
Median Overall Survival Up to 2 years Overall survival will be defined from the date of receiving the first treatment until death
Median Time to Progression Up to 2 years Time to progression will be summarized according to the method of Kaplan and Meier
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. Up to 2 years 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.
Number of Patients With Dose Modifications 8 weeks after 6th patient is enrolled 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.
Percentage of Patients With at Biomarker Response Up to 2 years 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
Trial Locations
- Locations (2)
University of California, San Francisco
🇺🇸San Francisco, California, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States