Phase 2 Study of S-1 in Advanced or Metastatic Pancreatic Cancer

An Open-Label, Non-Randomized, Multicenter, Two-Stage, Phase 2 Study of S-1 in Chemotherapy-Naïve Patients With Locally Advanced or Metastatic Pancreatic Cancer

The purpose of this study is to determine whether S-1 is effective in slowing tumor activity in participants with locally advanced or metastatic pancreatic cancer who have not had chemotherapy. The study is also looking at the safety of S-1.

Locally advanced or metastatic pancreatic cancer is relatively unresponsive to chemotherapy. This is true for the nucleoside analogue gemcitabine, with a response rate of approximately 10%, as well as for 5-fluorouracil (5-FU). Even when gemcitabine is combined with other chemotherapeutic drugs or biological agents, the overall tumor response rate remains basically unchanged. S-1 is a new generation oral fluoropyrimidine that combines Tegafur (5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione [FT]), an oral prodrug of 5-FU, with two modulators, Gimeracil (5-chloro-2,4-dihydroxypyridine [CDHP]), which inhibits 5-FU degradation by dihydropyrimidine dehydrogenase (DPD) inhibition, and Oteracil potassium (Oxo), which inhibits 5-FU phosphorylation in the digestive tract. This combination of 3 compounds is designed to achieve enhanced antitumor activity while decreasing gastrointestinal toxicity.

Inclusion Criteria:

1. Has provided written informed consent.

2. Has histologically or cytologically confirmed locally advanced, unresectable or metastatic adenocarcinoma of the pancreas not amenable to curative radiotherapy or surgery.

3. Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ie, lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm using spiral computed tomography [CT] scan).

4. Is able to take medications orally.

5. Is 18 years of age or older.

6. Has a Karnofsky Performance Status (KPS) ≥ 70%.

7. Has a life expectancy of ≥ 12 weeks.

8. Has adequate organ function as defined by the following criteria:

   1. Transaminases AST (SGOT) and ALT (SGPT) ≤ 2.5 times the upper limit of normal (ULN). If liver function abnormalities are due to underlying liver metastasis, then AST (SGOT) and ALT (SGPT) may be ≤ 5 times ULN.
   2. Total serum bilirubin ≤ 3.0 times ULN (if due to underlying liver metastasis, then total bilirubin may be ≤ 5 times ULN).
   3. Absolute granulocyte count ≥ 1,500/mm3 (ie, ≥ 1.5 x 109/L by International Units [IU]).
   4. Platelet count ≥ 100,000/mm3 (IU: ≥ 100 x 109/L).
   5. Hemoglobin value ≥ 9.0 g/dL.
   6. Calculated creatinine clearance ≥ 60 mL/min (based on serum creatinine) (Cockcroft-Gault85 formula)

9. Is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Has had treatment with any of the following within the specified time frame prior to study drug administration:

   1. Any prior anticancer chemotherapy.
   2. Radiation therapy to a target lesion unless there was evidence of PD after radiotherapy (and this target lesion must not be the only site of measurable disease).
   3. Any radiotherapy within the previous 3 weeks.
   4. Any investigational agent received either concurrently or within the last 30 days.
   5. Current enrollment in another clinical study with an investigational agent. Patients participating in surveys or observational studies are eligible to participate in this study.

2. Major surgery within the previous 3 weeks.

3. Symptomatic brain metastasis not controlled by corticosteroids.

4. Leptomeningeal metastasis.

5. Previous or concurrent malignancy other than pancreatic cancer except adequately treated carcinoma in-situ of the cervix or non-melanoma skin cancer.

6. Uncontrolled ascites requiring drainage at least twice a week.

7. Other serious illness or medical condition(s) including, but not limited to, the following:

   1. Uncontrolled congestive heart failure (New York Heart Association [NYHA] Class III or IV), angina pectoris, arrhythmias, or hypertension.
   2. Active infection.
   3. Known (at time of entry) gastrointestinal disorder, including malabsorption, chronic nausea, vomiting, or diarrhea, present to the extent that it might interfere with oral intake and absorption of study medication.
   4. Poorly controlled diabetes mellitus.
   5. Psychiatric disorder that may interfere with consent and/or protocol compliance.
   6. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
   7. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.

8. 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:

   1. Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole (may enhance S-1 activity).
   2. Allopurinol (may diminish S-1 activity).
   3. Phenytoin (S-1 may enhance phenytoin activity).
   4. Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 and flucytosine activity).

9. Is a pregnant or lactating female.

10. Has known sensitivity to 5-FU.

11. Is a patient with reproductive potential who refuses to use an adequate means of contraception (including male patients).