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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: S-1; Drug: gemcitabine hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Targeted therapy group; Gemcitabine monotherapy until disease progression, followed by gemcitabine + S-1

Drug: S-1; S-1 is given as follows: 25 mg/m2 bid on days 1-7 and 15-21 of the cycle (28 days); Other Names: TS-1; tegafur-gimeracil-oteracil potassium; TS-ONE; Drug: gemcitabine hydrochloride; 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; Other Names: Gemzar

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Andrew Ko
• Collaborators: Eli Lilly and Company; Taiho Pharmaceutical Co., Ltd.
• Investigators: Study Chair: Andrew Ko, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2007
• Primary Completion (Actual): January 20, 2010
• Study Completion (Actual): January 20, 2010

Study Registration Dates

• First Submitted: January 30, 2007
• First Submitted That Met QC Criteria: January 30, 2007
• First Posted (Estimate): February 1, 2007

Study Record Updates

• Last Update Posted (Actual): September 18, 2020
• Last Update Submitted That Met QC Criteria: August 28, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: recurrent pancreatic cancer; adenocarcinoma of the pancreas; stage IV pancreatic cancer; stage III pancreatic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine; Tegafur
• Other Study ID Numbers: 06456; NCI-2011-01215 (Registry Identifier: NCI Clinical Trials Reporting Program (CTRP)); UCSF-H12191-29556-01 (Other Identifier: UCSF California CHR Approval #)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No