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

NCT ID: NCT00429858

Last Updated: 2020-09-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-22
• Study Completion Date: 2010-01-20

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.

Conditions

Pancreatic Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Targeted therapy group

Gemcitabine monotherapy until disease progression, followed by gemcitabine + S-1

Group Type: EXPERIMENTAL

S-1

Intervention Type: DRUG

S-1 is given as follows: 25 mg/m2 bid on days 1-7 and 15-21 of the cycle (28 days)

gemcitabine hydrochloride

Intervention Type: DRUG

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

Interventions

S-1

S-1 is given as follows: 25 mg/m2 bid on days 1-7 and 15-21 of the cycle (28 days)

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

tegafur-gimeracil-oteracil potassium; TS-1; TS-ONE; Gemzar

Eligibility Criteria

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.

• 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Taiho Pharmaceutical Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

Andrew Ko

OTHER

Sponsor Role: lead

Responsible Party

Andrew Ko

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Andrew Ko, MD

Role: STUDY_CHAIR

University of California, San Francisco

Locations

University of California, San Francisco

San Francisco, California, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

Other Identifiers

NCI-2011-01215

Identifier Type: REGISTRY

Identifier Source: secondary_id

UCSF-H12191-29556-01

Identifier Type: OTHER

Identifier Source: secondary_id

06456

Identifier Type: -

Identifier Source: org_study_id