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

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.

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).