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Clinical Cancer Research Vol. 8, 2116-2122, July 2002
© 2002 American Association for Cancer Research

Clinical Trials

Phase I and Pharmacokinetic Study of Once Daily Oral Administration of S-1 in Patients with Advanced Cancer1

Steven J. Cohen, Cynthia G. Leichman, Gwen Yeslow, Mary Beard, April Proefrock, Brian Roedig, Bharat Damle, Stephen P. Letrent, Arthur P. DeCillis and Neal J. Meropol2

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [S. J. C., G. Y., M. B., N. J. M.]; Division of Medical Oncology, Albany Medical College, Albany, New York 12208 [C. G. L.]; Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263 [A. P.]; and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660 [B. R., B. D., S. P. L., A. P. D.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To determine the maximum tolerated dose, dose-limiting toxicities(DLTs), and pharmacokinetics of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oxonic acid, administered once daily in patients with advanced cancer.

Experimental Design: Eighteen patients with refractory malignancies were treated with S-1 administered once daily for 21 consecutive days, followed by a 1-week break. Of 16 evaluable patients, 6 were treated at a dose of 50 mg/m2/day, and 10 were treated at 60 mg/m2/day.

Results: DLTs were observed in 1 of 6 evaluable patients treated with 50 mg/m2/day and in 4 of 10 evaluable patients treated with 60 mg/m2/day. DLTs included diarrhea, nausea/vomiting, fatigue, and hyperbilirubinemia. The maximum tolerated dose was 50 mg/m2/day. Pharmacokinetic data are consistent with potent modulation of 5-fluorouracil (5-FU) by CDHP, with prolonged half-life and 5-FU AUC at least 10-fold higher than reported in previous studies of equitoxic doses of tegafur modulated by uracil. Pharmacodynamic analysis demonstrated a correlation between diarrhea grade and both 5-FU Cmax (r = 0.57, P < 0.05) and 5-FU area under the curve (r = 0.74, P < 0.01).

Conclusions: The recommended Phase II dose of S-1 administered once daily for 21 consecutive days of 28 is 50 mg/m2. The pharmacokinetic data presented provide evidence of 5-FU modulation by CDHP. Pharmacodynamic analyses suggest that the utility of pharmacology-based dosing of S-1 should be explored in future trials. Evaluation of once-daily dosing of S-1 in malignancies for which fluoropyrimidines have known antitumor activity is warranted.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Since its introduction by Heidelberger et al. (1) in 1957, 5-FU3 has been used extensively in the treatment of solid tumors. Many methods of 5-FU administration have been explored in an effort to improve efficacy. In patients with colorectal cancer, protracted venous infusions of 5-FU result in higher response rates than bolus administration with a more favorable toxicity profile (2 , 3) . However, infusional 5-FU requires indwelling venous access and infusion pumps. Furthermore, 5-FU plasma concentrations are subject to considerable variability in patients receiving protracted 5-FU infusion (4) . DPD, the primary catabolic enzyme of 5-FU, is thought to contribute to this variability through interpatient differences and circadian variations in activity (5) . Elevated DPD levels have been associated with 5-FU resistance and account for the brief half-life of 5-FU when given by bolus administration (6 , 7) . Modulation of DPD may improve upon the therapeutic index of 5-FU through prolonged drug exposure in both plasma and tumor (8) . An attractive alternative method of delivering protracted 5-FU is through daily oral administration. However, there are great inter- and intrapatient differences in bioavailability (9) . The use of 5-FU prodrugs such as tegafur, with increased bioavailability, can facilitate chronic oral administration of fluoropyrimidines.

Tegafur is a 5-FU prodrug that is well absorbed after oral administration and gradually converted to 5-FU in the liver (8) . When tegafur is combined with uracil, a competitive inhibitor of DPD, to form the drug UFT, prolonged systemic 5-FU exposure is obtained (10) . UFT plus leucovorin has demonstrated similar efficacy when compared with bolus 5-FU plus leucovorin in recent Phase III trials in advanced colorectal cancer, with a favorable toxicity profile (11 , 12) .

S-1 is an oral fluorinated pyrimidine combination, developed in an effort to further enhance the therapeutic index of tegafur. S-1 is a fixed combination of tegafur, CDHP, and Oxo at a molar ratio of FT:CDHP:Oxo (1:0.4:1). CDHP is an inhibitor of DPD ~180-fold more potent than uracil in vitro (13 , 14) . When combined with tegafur, CDHP can potentially result in the prolonged maintenance of 5-FU concentrations in plasma and tumor (8) . Oxo has the potential to reduce 5-FU related gastrointestinal toxicity through its inhibition of orotate phosphoribosyl transferase and 5-FU phosphorylation (14 , 15) .

The optimal molar concentrations of the three components of S-1 were defined in initial preclinical models using sarcoma-bearing rats (8) . Subsequent animal studies demonstrated antitumor activity for S-1 in tumor-bearing rodents at lower administered doses than UFT, FT, or 5-FU (14 , 16) . S-1 therapy in athymic nude mice was associated with retention of higher and more prolonged concentration of 5-FU in plasma and tumor tissue when compared with UFT (17) . An early Phase I study identified 45 and 40 mg/m2 as the MTDs for S-1 when administered twice daily for 28 days, followed by a 1-week rest in minimally or heavily pretreated patients, respectively (18) . Diarrhea was the predominant DLT. A second Phase I study of S-1 using a similar schedule identified 30 mg/m2 twice daily as the MTD with diarrhea as the primary DLT (19) . Phase II trials have demonstrated antitumor activity of S-1 in patients with advanced gastric and colorectal cancer, with grade 3/4 toxicities predominantly hematological and including diarrhea and mucositis (20 , 21) .

Given the Phase II activity of S-1 and its convenient oral route of administration, this current Phase I study was undertaken as the initial step in developing a once-daily treatment schedule to improve convenience while maintaining efficacy. We hypothesized that prolonged inhibition of DPD by CDHP, with resultant prolonged 5-FU half-life, might render a single daily dosing schedule feasible. The primary objective of this study was to determine the MTD and DLTs of S-1 administered once daily for 21 consecutive days, followed by a 1-week break. Secondary objectives included describing the pharmacokinetics of S-1 and its metabolites when administered on this schedule, exploring pharmacodynamic relationships, and evaluating preliminary evidence of antitumor activity.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility.
Patients enrolled into this study had to be at least 18 years of age and have a histologically or cytologically confirmed diagnosis of advanced or metastatic solid tumor that was refractory to conventional therapy or for which no standard therapy existed. Additional inclusion criteria were as follows: measurable or evaluable disease, at least 4 weeks elapsed since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C), 8-week interval since prior therapy with a DPD inhibitor (e.g., ethynyluracil), complete recovery from toxicities resulting from previous therapy (excluding alopecia), Eastern Cooperative Oncology Group performance status <=2 (ambulatory at least 50% of waking hours), adequate hematological function (WBC >=3,000/mm3, absolute granulocyte count >=1,500/mm3, platelet count >=100,000/mm3, hemoglobin >=9.0 g/dl), adequate hepatic function (aspartate aminotransferase and alanine aminotransferase <=1.5 times the upper limit of normal, total bilirubin <=1.5 times the upper limit of normal), adequate renal function (serum creatinine <=1.5 times the upper limit of normal), ability to swallow capsules, and expected survival of at least 12 weeks. Exclusion criteria included primary brain tumors or evidence of central nervous system metastasis, concurrent chemotherapy, radiotherapy, immunotherapy, or investigational drugs, concomitant treatment with drugs with potential interactions with S-1 (flucytosine, sorivudine, and ethynyluracil), psychiatric disorders prohibiting full compliance, and pregnancy or lactation or fertile men or women not using adequate method of contraception. Patients provided written informed consent as per institutional and federal requirements, and the protocol was approved by the review boards of the two participating institutions.

Definition of DLT.
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria v. 2.0.4 DLT was defined as >=grade 3 nonhematological toxicity (excluding nausea/vomiting), >=grade 3 nausea/vomiting uncontrolled by antiemetics, inability of the patient to take >=75% of the planned chemotherapy dose during a treatment cycle, grade 4 neutropenia lasting >=3 days, febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia requiring transfusion, or any toxicity that required a greater than 14-day delay in treatment.

Treatment Plan and Definition of MTD.
This was a Phase I, open label, two-center, single-arm, dose-escalation study. S-1 was supplied by Bristol-Myers Squibb as 20- and 25-mg capsules (as the amount of tegafur) in two different color combinations. The study drug was administered p.o. once a day for 21 consecutive days, followed by 1 week of rest. This 28-day cycle was repeated until evidence of unacceptable toxicity or disease progression. At least 3 patients were to be enrolled at each dose level. The planned cohort size was 3–6 patients. Dose escalation would proceed if none of the initial 3 patients experienced DLT in the first cycle of therapy. If 1 of 3 encountered DLT, 3 additional patients were added to that dose level. The MTD was defined as the highest dose level that did not cause DLT in >=2 of 3 or >=2 of 6 (i.e., >33%) patients treated at that level during their first cycle of therapy.

History and physical, baseline complete blood count, chemistries, and liver function were obtained within 14 days of the initiation of therapy. Computed tomographic scans of areas of measurable disease, chest X-ray, and electrocardiogram were performed within 30 days. All women of childbearing potential had serum or urine pregnancy tests before the start of study medication. Complete blood counts and chemistries were obtained weekly on study.

The starting dose of S-1 was 50 mg/m2 administered p.o. once daily. Calculated doses were rounded down to the nearest 5 mg. Patients were instructed to take the daily dose between 7–10 a.m. and, because of the potential instability of Oxo in acidic conditions, to take capsules within 1 h after a meal. In the absence of DLT, dose escalation in additional cohorts continued at a dose increase of 10 mg/m2/dose. If a dose level exceeded MTD, enrollment would continue with a dose decrease of 10 mg/m2/dose. Patients receiving at least two cycles of therapy or progressing before the completion of two cycles were evaluable for response. Tumor assessment with computed tomographic scans was performed every two cycles, and tumor response was evaluated by WHO criteria (22) .

Pharmacokinetic/Pharmacodynamic Assessment.
Six-ml blood samples were collected on days 1 and 21 of the first course of treatment for analysis of concentrations of FT, 5-FU, CDHP, and Oxo at the following time intervals (expressed as h:min after dosing): predose, 0:15, 0:30. 1:00, 1:30, 2:00, 3:00, 5:00, 8:00, and 24:00. Tegafur was analyzed using a high performance liquid chromatography/UV assay with a standard curve range of 10–4000 ng/ml (23) . 5-FU, CDHP, and Oxo were analyzed using gas chromatography with mass spectrometric detection with standard curve range 1–400, 2–800, and 1–200 ng/ml, respectively (23) . The plasma concentration-time data were analyzed by a noncompartmental method (24) . The peak plasma concentration (Cmax) and the time to peak plasma concentration (Tmax) were obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-squares linear regression of at least three data points, which yielded a minimum mean square error. The elimination half-life (t1/2) was calculated as 0.693/K, where K is the absolute value of the slope of the terminal log-linear phase. The AUC from zero to infinity (AUC0-{infty}) was determined by summing the areas from time zero to the time of last measured concentration, calculated by using the linear trapezoidal method (until Cmax) and the log-trapezoidal method (until the last measurable concentration), and the extrapolated area. The extrapolated area was determined by dividing the final measured concentration by the slope of the terminal log-linear phase. AUC over the dosing interval, AUC(TAU), AUC from time 0 to the last measurable plasma concentration, was determined using linear trapezoidal and log-trapezoidal method. AUC(inf) was the AUC to infinity. The relationships between tegafur and 5-FU AUC and Cmax and maximum grade of diarrhea were determined using Spearman’s test for correlation (STATA Corp., College Station, TX).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographics.
Eighteen patients were enrolled into this study. Sixteen patients received a total of 41 cycles of treatment (median, 2; range, 1–6). Patient characteristics are listed in Table 1Citation . Twelve of 18 patients had colorectal cancer. All colorectal cancer patients previously received systemic therapy, 11 with 5-FU and 1 with raltitrexed. All enrolled patients had received at least two prior chemotherapy regimens, with 78% having received prior 5-FU. One patient was treated previously with the DPD inhibitor ethynyluracil. The median difference between calculated dose based on body surface area and actual prescribed dose was 1 mg (range, 0–5 mg).


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  		Table 1 Patient characteristics (n = 18)

 
Toxicity.
One patient developed grade 2 nausea and discontinued treatment after 3 days. Another patient developed progressive disease on the sixth day of therapy and was removed from study. These two patients were considered inevaluable. One of 3 initial patients treated with S-1 at 50 mg/m2/day, a 71-year-old male with colorectal cancer, experienced grade 2 hyperbilirubinemia, which did not resolve within 14 days. Three additional patients treated at this dose level did not experience DLT. Dose escalation thus proceeded to 60 mg/m2/day. One of the 3 initial patients at this level, a 67-year-old female with colorectal cancer developed grade 3 diarrhea and grade 3 fatigue. Three additional patients were enrolled at this dose level, with a 31-year-old female with colorectal cancer having grade 3 vomiting. Because there was no clear pattern of toxicity, it was decided to expand the cohort further. Expansion of the 60 mg/m2 dose level to better characterize toxicity in 10 total patients resulted in two additional DLTs (1 73-year-old female with cancer of the parotid gland experiencing grade 3 fatigue and an 80-year-old female with gallbladder cancer developing grade 3 diarrhea, grade 3 nausea/vomiting, grade 4 ileus, and grade 3 rectal bleeding). Because >=33% of subjects had a DLT, 60 mg/m2/day exceeded the MTD, and an S-1 dose of 50 mg/m2/day was considered MTD. Other toxicities are listed in Table 2Citation . Grade 1 and 2 toxicities were primarily gastrointestinal (diarrhea, nausea/vomiting, and anorexia) and fatigue. Thirteen patients were evaluable for response. No objective responses were seen.


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  		Table 2 Adverse events (n = 16)

Values represent number of patients experiencing each adverse event as maximum Common Toxicity Criteria grade. One additional patient with grade 2 nausea discontinued treatment after 3 days. The patient with grade 4 ileus also had grade 3 rectal bleeding in association with ischemic bowel.

 
Pharmacokinetics and Pharmacodynamics.
Pharmacokinetic parameters on days 1 and 21 for tegafur, 5-FU, CDHP, and Oxo at the two dose levels are summarized in Table 3Citation . Tegafur was rapidly absorbed and quickly achieved Cmax at ~1 h. All other components were rapidly absorbed with median Tmax of all analytes 3 h or less. 5-FU was formed relatively quickly from tegafur with sustained plasma levels. Its mean half-life was greater than 2 h with AUC exceeding 1200 h·ng/ml. Mean 5-FU plasma levels remained >100 ng/ml until 8 h after dose. On the basis of the ratio of AUC(TAU) on day 21 versus day 1, none of the compounds had significant accumulation at day 21. However, the large variability in tegafur on day 21 AUC precludes definitive assessment.


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  		Table 3 Mean (SD) pharmacokinetic parameters for S-1

 
Fig. 1Citation shows day 1 plasma concentration versus time profiles at both S-1 dose levels for tegafur, 5-FU, CDHP, and Oxo. Pharmacodynamic analysis revealed a significant correlation between 5-FU AUC and maximum grade of diarrhea (r = 0.74, P < 0.01) and a lesser correlation between 5-FU Cmax and maximum grade of diarrhea (r = 0.57, P < 0.05; Fig. 2Citation ). Similar pharmacodynamic relationships were not found for tegafur, and there was no relationship between fluoropyrimidine levels and hematological toxicity (data not shown).



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  		Fig. 1. Mean plasma concentrations of S-1 components and 5-FU. A–D, mean plasma concentrations of tegafur, 5-FU, CDHP, and Oxo during a 24-h period after day 1 administration at two dose levels. Bars, SD.

 


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  		Fig. 2. Correlations between 5-FU pharmacokinetics and diarrhea. A, 5-FU AUC versus diarrhea (r = 0.74, P < 0.01). B, 5-FU Cmax versus diarrhea (r = 0.57, P < 0.05).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This Phase I trial determined the maximum tolerated dose of S-1 to be 50 mg/m2/day when administered to advanced cancer patients once daily for 21 days, followed by a 1-week break. DLTs included fatigue, nausea, vomiting, ileus, diarrhea, and hyperbilirubinemia. Myelosuppression was not a significant toxicity in our study, although it has been predominant in several previous studies (20 , 21) . Pharmacokinetic analysis revealed rapid oral absorption of S-1 components. The 5-FU AUC derived from S-1 observed at both dose levels (50 and 60 mg/m2 of tegafur) is >10 times higher than we reported previously with administration of a single UFT dose of 100 mg/m2 (1225 and 1887 h·ng/ml versus 103 h·ng/ml; Ref. 25 ). Our 5-FU half-life of 2.6 h compares favorably with that of 5-FU bolus administration (8–14 min) and approximates that seen with UFT (7 , 26) .

Toxicity in our study did not differ significantly from that seen in two other Phase I studies that evaluated S-1 on a twice-daily schedule for 28 days, followed by a 1-week rest. Hoff et al. (19) determined the MTD of S-1 on this schedule to be 30 mg/m2 twice daily and diarrhea to be the primary DLT, with nausea/vomiting, hyperbilirubinemia, and granulocytopenia also dose limiting. Using a similar schedule, van Groeningen et al. (18) reported the MTDs of S-1 to be 45 and 40 mg/m2 administered twice daily to untreated and treated patients, with diarrhea as the primary DLT. In a preliminary report of a longer, once-daily schedule of S-1 (28 days of treatment), Ochoa et al. (27) projected 50 mg/m2 to be the MTD, with diarrhea as the principal DLT.

In contrast to the results described above, studies conducted in Japan have yielded primarily hematological toxicity. Hirata et al. (28) reported that 3 of 12 patients receiving fixed twice-daily doses of S-1 experienced grade 3 or 4 hematological toxicity. Phase II trials of S-1 have also been reported. Sakata et al. (20) reported a 49% response rate in advanced gastric cancer patients treated with 40 mg/m2 twice daily. Hematological toxicities were predominant. Sugimachi et al. (29) demonstrated a 54% response rate in patients with advanced gastric cancer using a fixed S-1 dose of 50–75 mg twice daily. Grade 3/4 anemia and leukopenia occurred in 10.7% of patients, with diarrhea occurring in 7.1%. Koizumi et al. (30) reported a 44% response rate in 43 patients with advanced gastric cancer treated with 40–60 mg twice daily of S-1. Only 5 patients experienced grade 3–4 toxicity, with diarrhea and hematological toxicity dose limiting. S-1 has also shown activity against colorectal cancer, with 35% of patients dosed between 40 and 60 mg twice daily achieving a response (21) . Neutropenia was the predominant grade 3–4 toxicity, occurring in 12.9% of patients.

It is not clear why our toxicity profile in this Phase I study differs from studies reported in Japanese populations. Our study had no dose-limiting myelosuppression, but we were unable to dose escalate near cumulative doses of S-1 used in other Phase I/II studies secondary to significant gastrointestinal toxicity. Although oxonic acid decreased diarrhea in fluoropyrimidine-treated rats (15) , its gastrointestinal protective effects have not been clearly validated in humans. Our patient population was heavily pretreated, with all having received >=2 prior chemotherapy regimens. Our day 21 values for 5-FU Cmax and AUC are greater than corresponding day 28 values reported for twice-daily fixed dosing of 40–60 mg by Hirata et al. (Ref. 28 ); 237 ng/ml versus 113 ng/ml and 1225 h·ng/ml versus 609 h·ng/ml, respectively). When compared with a study reported by Hoff et al. (19) using 30–40 mg/m2 of S-1 twice-daily, our values for 5-FU Cmax (237 ng/ml versus 176 ng/ml) and 5-FU AUC (1225 h·ng/ml versus 1004 h·ng/ml) are similar, with a more convergent toxicity profile. Furthermore, the pharmacodynamic data suggest a possible correlation between 5-FU exposure and grade of diarrhea, not hematological toxicity as associated previously with high peak 5-FU levels (3) . Potential pharmacogenetic differences leading to differing exposure or susceptibility of intestinal mucosal cells to fluoropyrimidines may contribute to the variability in toxicity profiles (31) . Alternatively, capture of clinical symptoms may have differed between the studies. In addition, the female predominance in our sample may have resulted in greater nonhematological toxicity, as has been described previously with fluoropyrimidines (3) . Finally, our study is of relatively small size, and it is possible that the toxicity seen may not be representative of potential toxicity seen in a broader population.

We conducted exploratory analyses correlating 5-FU pharmacokinetic parameters with diarrhea. These observations should be interpreted with caution given the few patients enrolled in our study. However, they suggest the possibility of individualized dosing of S-1 based upon pharmacological considerations. This hypothesis requires confirmation in a larger study.

The treatment of cancer by an oral route of administration remains potentially attractive for patient convenience (32) . This study is the first step in development of a once-daily oral fluoropyrimidine regimen. The pharmacokinetic data presented show 5-FU plasma levels that exceed those obtained by protracted infusion 5-FU for at least 8 h (33) . Whether these plasma concentrations are accurate surrogates for intratumoral drug accumulation is uncertain. Likewise, determination of relative clinical efficacy of once-daily versus multiple daily doses of S-1 will require comparative clinical trials. The MTD and recommended Phase II dose for once-daily dosing of S-1 is 50 mg/m2/day. Evaluation of this once-daily regimen in malignancies for which fluoropyrimidines have demonstrated efficacy is warranted.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by a grant from Bristol-Myers Squibb. Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, May 12–15, 2001, San Francisco, California. Back

2 To whom requests for reprints should be addressed, at Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728-2450; Fax: (215) 728-3639. Back

3 The abbreviations used are: 5-FU, 5-fluorouracil; DPD, dihydropyrimidine dehydrogenase; tegafur, 1-[2-tetrahydrofuranyl]-5-FU; UFT, uracil and tegafur; CDHP, 5-chloro-2,4-dihydroxypyridine; Oxo, potassium oxonate (oxonic acid); MTD, maximum tolerated dose; DLT, dose-limiting toxicity; AUC, area under the plasma concentration time curve. Back

4 Internet address: http://ctep.info.nih.gov/CTC3/ctc.htm. Back

Received 10/15/01; revised 3/22/02; accepted 3/28/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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