A Phase 1, Open-Label, Randomized, Cross-Over, Pharmacokinetic Study Evaluating the Effect of the Dihydropyrimidine Dehydrogenase (Dpd) Inhibitory Action of 5-Chloro-2,4-Dihydroxypyridine (Cdhp) as an S-1 Component
A patient must meet all of the following inclusion criteria to be eligible for enrollment
in this study:
1. Has histologically or cytologically proven advanced solid tumors for which no
standard therapy exists.
2. Has provided written informed consent.
3. Is 18 years of age or older.
4. Is able to take medications orally.
5. Has Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 (Appendix A,
6. Has adequate organ function as defined by the following criteria:
- Has transaminases AST (SGOT) and ALT (SGPT) ≤ 2.5 times the upper limit of
normal (ULN). If liver function abnormalities are due to underlying malignancy,
then AST (SGOT) and ALT (SGPT) may be ≤ 5 times ULN.
- Has a total serum bilirubin ≤ 1.5 times ULN.
- Has an absolute granulocyte count ≥ 1,500/mm3 (ie, ≥ 1.5 x 109/L by
International Units [IU]).
- Has a platelet count ≥ 100,000/mm3 (IU: ≥ 100 x 109/L).
- Has a hemoglobin value of ≥ 9.0 g/dL.
- Has a calculated creatinine clearance > 60 mL/min (by Cockcroft-Gault formula.76
See Appendix E).
7. Is willing and able to comply with scheduled visits, treatment plan, laboratory
tests, and other study procedures.
Exclude a patient from this study if he/she does not fulfill the inclusion criteria, or if
any of the following conditions are observed:
1. Has had treatment with any of the following within the specified time frame prior to
study drug administration:
- An investigational agent received either concurrently or within the last 30
- Previous therapy for malignancy within 21 days, including any chemotherapy,
immunotherapy, biologic or hormonal therapy (6 weeks for nitrosureas or
- Previous radiotherapy within 14 days.
- 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. Has a serious illness or medical condition(s) including, but not limited to, the
- Myocardial infarction within the last 6 months, severe/unstable angina,
congestive heart failure (New York Heart Association [NYHA] Class III or IV, see
- Known (at the 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 the study medication.
- 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.
- Known brain metastasis.
- Known leptomeningeal metastasis.
- Manifest ascites.
- Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
3. Is receiving a concomitant treatment with drugs interacting with S-1 or FT. The
following drugs are prohibited because there may be an interaction with S-1 or FT:
- Sorivudine, uracil, dipyridamole, cimetidine and folinic acid (may enhance S-1
or FT activity).
- Allopurinol (may diminish S-1 or FT activity).
- Phenytoin (S-1 or FT may enhance phenytoin activity).
- Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 or FT,
and flucytosine activity).
- Pilocarpine (may inhibit CYP2A6 activity).
4. Has sensitivity to 5-FU.
5. Is a pregnant or lactating female.
6. Is a patient with reproductive potential who refuses to use an adequate means of
contraception (including male patients). 3.3.3 Discontinuation Criteria Clearly
document the reason for the patient's discontinuation in the patient's source
documents and on the CRF. Discontinue the patient from study if any of the following
- Patient withdraws consent.
- Patient has toxicities that, in the opinion of the Investigator, require the
- Patient has an intercurrent illness that in the opinion of the Investigator
requires the patient's discontinuation.
- The Investigator concludes that it is in the patient's best interest to
- Patient is willingly or inadvertently noncompliant in the opinion of the
Investigator and requires the patient to be discontinued.
- During optional Extension Phase, the patient has objective PD (defined by
imaging studies or clinical evaluation). g. During optional Extension Phase, the
patient requires a recovery period of > 4 weeks (ie, more than 3 weeks from the
scheduled start date of the next cycle; see Section 188.8.131.52.1).
- The patient completes the Cross-Over Pharmacokinetic Phase but does not choose
to enter the optional S-1 Extension Phase.