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© 2000 American Society for Clinical Oncology Phase I Clinical and Pharmacokinetic Study of Oral S-1 in Patients With Advanced Solid TumorsFrom the University Hospital Vrije Universiteit, Netherlands Cancer Institute, and NDDO Oncology, Amsterdam, the Netherlands, and European Organization for Research and Treatment of Cancer, Early Clinical Studies Group, Brussels, Belgium. Address reprint requests to C.J. van Groeningen, MD, University Hospital Vrije Universiteit, Department of Medical Oncology, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; email dr.vangroeningen{at}azvu.nl
PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m2. The MTD was initially found at 45 mg/m2, with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m2, which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 µmol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m2 bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m2 bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.
FLUOROURACIL (5-FU) PLAYS an important role in the systemic treatment of various solid tumors, such as gastrointestinal cancer, breast cancer, and head and neck cancer.1 Extensive knowledge has been acquired on the metabolic pathways and mechanism of action of 5-FU.2 5-FU is not cytotoxic by itself and has to be metabolized in the cell to exert its antitumor effects. Ninety percent of the administered 5-FU is rapidly catabolized in the liver into inactive metabolites by the enzyme dihydropyrimidine dehydrogenase (DPD). The remainder is activated through several pathways, one of the most important of which is the formation of fluorodeoxyuridine monophosphate, a strong inhibitor of the enzyme thymidylate synthase. Also, fluorouridine triphosphate may be formed and incorporated into RNA as well as fluorodeoxyuridine triphosphate, which may be incorporated into DNA. Biochemical modulation of 5-FU metabolism offers attractive ways to increase activity, by selective reduction of the breakdown process, enhancement of the metabolic activation, or reduction of side effects. Biochemical modulation has been achieved with the use of a number of cytotoxic and noncytotoxic compounds.3,4 Among the latter is the most striking hallmark of biochemically modulated chemotherapy, ie, the combination of 5-FU with folinic acid.5 In metastatic colorectal cancer, this combination has resulted in a higher objective response rate than nonmodulated 5-FU. 5-FU is administered at different doses and schedules. Among all the administration schedules, continuous intravenous (IV) administration resulted in a significantly higher response rate in a randomized trial, as compared with IV bolus injections in patients with metastatic colorectal cancer.6 However, an important drawback of continuous administration of cytotoxic drugs is the need for implantable access devices and portable infusion pumps, which may lead to complications. Oral administration of fluoropyrimidines clearly would circumvent this problem. Orally administered prodrugs of 5-FU have been available for many years. Among them, the tegafur-uracil combination (UFT) is an active agent in metastatic gastrointestinal tumors and breast cancer.7 S-1 has recently been developed as an oral drug (Fig 1) consisting of the 5-FU prodrug tegafur combined with the two modulators of 5-FU activity, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, in a molar ratio of 1:0.4:1, which seemed to be optimal in preclinical models.8 After oral intake, tegafur is gradually converted to 5-FU. CDHP is a reversible inhibitor of DPD (200-fold more potent than uracil), while potassium oxonate inhibits the enzyme orotate phosphoribosyl transferase, the major enzyme responsible for 5-FU activation in colon cancer.9 Potassium oxonate preferentially localizes in the gut rather than in the tumor and has a potential biochemical effect on the enzyme orotate phosphoribosyl transferase, thereby selectively inhibiting there the formation of 5-FU nucleotides and theoretically reducing gastrointestinal side effects. S-1 in a bid schedule has been investigated in a phase I study in Japan. Although a formally determined maximum-tolerated dose (MTD) was not reported in the Japanese study, myelosuppression, skin rash, anorexia, nausea, vomiting, and fatigue were reported as major side effects.10 Adverse reactions other than myelosuppression, which caused discontinuation of the drug, were rash and vomiting. Diarrhea and stomatitis were mild and did not cause discontinuation of S-1 administration. Doses of S-1 in this study were fixed and not expressed in milligrams per square meter of body surface. In phase II studies, promising antitumor activity was observed in gastric cancer with response rates of 49%, and efficacy was also reported in head and neck, breast, and colorectal cancer patients.11
On the basis of these data, we initiated the first S-1 study outside Japan. The main objective of our phase I study was to determine the MTD of S-1 when administered orally, twice daily, for 28 consecutive days, every 5 weeks. Other objectives of this study were to investigate the pharmacokinetics of S-1 and to document any possible antitumor activity.
To be eligible, patients had to have a solid tumor at a stage not amenable to established forms of therapy. They had to be  18 years of age, have a World Health Organization performance status of 2 or better, and have a life expectancy of at least 3 months. In the 4 weeks before entry onto the study, the patients should not have received any chemotherapy, immunotherapy, or radiotherapy. Eligibility criteria for bone marrow function included a WBC count of 4 x 109/L and a platelet count of 100 x 109/L. A serum creatinine level of less than 120 µmol/L or a creatinine clearance rate of 60 mL/min was required. Serum bilirubin levels had to be below 25 µmol/L. The liver enzyme levels had to be within two times the upper limit of normal, unless they were elevated due to liver metastasis or to bone metastasis in the case of alkaline phosphatase. No concomitant use of drugs that could possibly interact with S-1 was allowed (eg, sorivudine, uracil, dipyramidole, allopurinol, or phenytoin). Patients with clinical signs of brain metastasis or leptomeningeal metastasis were not eligible. Written informed consent was required from all patients. The study was approved by the scientific and ethical review committees of the two participating institutions.
Treatment The selected starting dose of S-1 was 25 mg/m2, based on earlier studies.10 The projected second dose level was 45 mg/m2. At least three patients were entered at each dose level; in case of severe toxicity, additional patients were to be included at that dose level. The MTD was the dose at which at least two of six patients experienced grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity. Before the start of treatment, a medical history was taken and patients underwent a complete physical examination, including assessments of height, weight, blood pressure, temperature, and performance status. The pretreatment evaluation also included a full blood cell count, a biochemical screening profile, urinalysis, creatinine clearance, carcinoembryonic antigen or other tumor marker determination if appropriate, ECG, and chest x-ray. Tumor deposits were evaluated using adequate imaging techniques. On a weekly basis during the study, toxicity (according to common toxicity criteria), weight, and performance status were assessed and full blood cell counts, biochemical screening profiles, and urinalyses were performed. Before each treatment course, an interval history, a physical examination, a creatinine clearance assessment, an ECG, a chest x-ray, and a tumor parameter assessment were conducted.
Pharmacokinetics 5-FU plasma concentrations were measured using gas chromatography coupled with mass spectrometry, as described previously12,13 with a slight modification.14 The following were added to 100 µL of plasma: 50 µL of 1 µmol/L 5-FU–15N2, 1 mL of Milli-Q water (Millipore, Bedford, MA), and 100 µL of 2 mol/L Tris (pH 6). A calibration line of 5-FU was included in each set of measurements. The solution was extracted twice with 4 mL of diethylether/2-propanol (80/20, vol/vol). The organic fraction was blown to dryness under N2 at 60°C. The residue was reconstituted in 80 µL of acetonitrile and 10 µL of triethylamine, and 10 µL of pentafluorobenzylbromide was added. The mixture was left at room temperature for 15 minutes, at which time the derivatization had reached a plateau. After the addition of 400 µL of 0.1 mol/L HCl, the solution was extracted once with 1 mL of hexane. The organic layer was blown to dryness under N2 at 45°C, and the residue was dissolved in 50 µL of hexane/propanon (3/1, vol/vol). From this sample, 1 µL was injected, with an injector temperature of 320°C, into the gas chromatography/mass spectrometry system (VG30-250; Fisons, Weesp, the Netherlands). Chromatographic separation was carried out on a CPSil19CB column (internal diameter, 25 m x 0.25 mm; film thickness, 0.25 µm) (Chrompack, Middelburg, the Netherlands) with an oven temperature gradient starting at 200°C for 1 minute and increasing by 20°C/min to a temperature of 320°C, which was maintained for 2 minutes. The ions for 5-FU and 5-FU–15N2 (m/z -309 and m/z -311, respectively) were recorded with negative ionization detection and methane as the moderating gas.
Statistical Evaluation
Twenty-eight patients were enrolled onto this phase I study between June 1996 and May 1997 at two institutions. Patient characteristics are described in Table 1. At the time of this analysis (May 1999), all patients were off-study. One patient with a locally advanced squamous cell carcinoma of the auditory canal was ineligible because the tumor had infiltrated the brain. This patient received only 2 weeks of S-1 treatment (at the 35-mg/m2 dose level) and died shortly thereafter as a result of progressive tumor growth; this patient was not included in the analysis of the study results. More than 50% of the patients had advanced or metastatic tumors of the gastrointestinal tract.
Patients were treated at four different dose levels, and the number of patients entered at each dose level is listed in Table 2. Because we selected doses in the vicinity of those used by Japanese investigators,10 we decided to enroll more patients per dose level than is usually required in a phase I study, in order to assess more carefully the safety profile of this drug. At the second dose level (45 mg/m2), dose-limiting toxicity was encountered; therefore, the dose was decreased to 35 mg/m2 in the next cohort of patients. At the fourth dose level (40 mg/m2), a difference in side effects was noted between patients heavily pretreated with chemotherapy and those with no or only minimal prior exposure to antineoplastic agents. This observation was made in the first six patients entered at this dose level. Therefore, another five patients, who had received no or minimal prior chemotherapy, were included at the 40-mg/m2 dose level The total number of cycles of S-1 administered was 129. The median number of cycles per patient was two (range, one to 22 cycles).
Toxicity When observed, dose-limiting toxicities were always observed in the first cycle, and there was no indication of cumulative toxicity. The dose-limiting toxicity was diarrhea, which occurred at the second dose level (45 mg/m2). Four of the five patients at this dose level developed diarrhea, which was severe in three of them. The major nonhematologic toxicities reported for all cycles are summarized in Table 3. The 45-mg/m2 dose was therefore considered the MTD. No patient received more than one course at the 45-mg/m2 dose level. At this level, two patients discontinued S-1 administration on day 15 and day 18, due to diarrhea and leukopenia, respectively. Four patients at this dose level continued S-1 treatment at the reduced dose of 25 mg/m2. On the next selected dose level of 35 mg/m2, diarrhea was not severe. At the fourth dose level of 40 mg/m2, severe dose-limiting diarrhea was observed in three of the first six patients entered at this level. This side effect seemed to be related to the extent of prior chemotherapy; in fact, two of the three patients who developed severe diarrhea had breast cancer and ovarian cancer that had previously been exposed to extensive chemotherapy. Therefore, this cohort was extended with five additional patients who had not received prior heavy chemotherapy. Grade 3 diarrhea was observed in only one of these patients. The dose of 40 mg/m2 was then defined as the MTD in patients heavily exposed to prior chemotherapy.
Other types of gastrointestinal side effects (stomatitis, nausea, vomiting) were usually not severe (Table 3). Grade 4 vomiting occurred in only two patients; both were treated at the two highest dose levels and were among the patients who also experienced severe diarrhea. Besides severe diarrhea and vomiting, one patient treated at the highest dose level developed a paralytic ileus that was successfully managed by conservative treatment. Hematologic toxicity was mild (Table 4). Grade 3 leukopenia and grade 3 neutropenia occurred in only one patient at the dose of 45 mg/m2. In three patients who had a normal pretreatment hemoglobin level, grade 1 anemia was observed. In addition, eight patients showed worsening of pre-existing anemia. Other toxicities were usually also mild. Grade 1/2 and grade 3 fatigue were reported in six patients and one patient, respectively. Nine patients experienced an increase in fatigue that was already present before the start of S-1 treatment. Grade 1/2 and grade 3 anorexia were seen in five patients and one patient, respectively, and an additional five patients reported further loss of appetite during S-1 administration. One patient experienced an alteration in taste, and the sensation of tearing and burning eyes was reported by four patients. Minimal hair loss (grade 1) was recorded in two patients. At the highest dose level of 45 mg/m2, two patients developed grade 2 skin toxicity consisting of an erythematous rash with itching and pain. One patient developed grade 2 periocular erythema during cycle 14 at a reduced dose of 30 mg/m2. Four patients had minor skin toxicity (grade 1) at the doses of 40 and 45 mg/m2.
Over all the dose levels studied, grades 1 and 2 transient proteinuria was observed in five and six patients, respectively (one patient had pre-existing grade 1 proteinuria). In only one case, proteinuria could not be ruled out as being caused by S-1. Proteinuria was not quantitated in these patients. However, one patient who started course 1 at the dose of 45 mg/m2, and who was subsequently treated with 10 courses at a reduced dose, developed a severe nephrotic syndrome with a loss of up to 6 g of protein per 24-hour urine collection, along with severe hypoalbuminemia. Before study entry, this patient did not have proteinuria. The proteinuria could also have been caused by the chronic use of diclofenac, but S-1 could not be definitively excluded as the cause of this adverse event. No other related abnormalities were noted. One patient had a transient grade 3 increase in serum bilirubin. A relationship with S-1 could not be ruled out with certainty, although this patient had lymph node metastases of gastric cancer in the upper abdomen that may have contributed to this side effect.
Antitumor Activity
Pharmacokinetics
Pharmacodynamics A statistically significant relationship was observed between the occurrence of dose-limiting (grades 3 and 4) diarrhea and the AUC (Fig 4), and the 5-FU plasma concentration at 8 and 24 hours after administration, as determined after the single pharmacokinetic dose of 5-FU (P = .004, .006, and .019, respectively, and rho = 0.542, 0.515, and 0.450, respectively). With respect to the 5-FU plasma concentrations measured during the 28 days of oral intake, only the level just before drug intake in week 2 was significantly related to grade 3 or 4 diarrhea (P = .002). Response to treatment was not correlated with any of the pharmacokinetic parameters.
The development of effective oral drugs in the treatment of cancer would be appealing and convenient. Oral administration of 5-FU is associated with erratic intestinal absorption, unpredictable 5-FU plasma concentrations and toxicities, and uncertain antitumor activity.15 Several prodrugs of 5-FU have shown more promising results by oral administration, including tegafur,16 UFT (tegafur plus uracil),7 and capecitabine.17 Also, combinations of low doses of oral 5-FU with inhibitors of DPD activity, such as 5-ethynyluracil,18 have resulted in consistent plasma 5-FU concentrations after oral administration. The dose-limiting toxicity of S-1 in our study was diarrhea, despite the presence of potassium oxonate. The optimal molar ratios of the constituents of S-1, and in particular the amount of potassium oxonate used in the formulation of S-1 for this phase I trial, provided the best prevention against gastrointestinal side effects in preclinical experiments; when the molar ratio of potassium oxonate was increased, however, impairment of the antitumor activity was observed.8 Although the number of patients at the different dose levels was limited, the extent of prior chemotherapy seemed to influence the development of diarrhea, as chemotherapy-naive patients and patients with limited pretreatment tolerated the drug better, although there is no explanation for this observation. Interestingly, diarrhea is also the major dose-limiting toxicty of UFT,7 and it has yet to be proven that the inclusion of CDHP and potassium oxonate leads to a better pharmacologic profile of the drug as well as a better therapeutic index. Although the development of orally administered anticancer drugs has been hampered by the variable intestinal absorption and patient compliance,19 for a number a drugs, convincing evidence has recently been provided that absorption has been reliable and that predictable plasma drug concentrations have been achieved.20,21 When prolonged exposure is desirable, oral administration is certainly the most appealing route of administration. Moreover, patients have a clear preference for oral chemotherapy in the palliative setting, at least when efficacy is not sacrificed.22 In this study, in the presence of the DPD inhibitor CDHP, the half-life of 5-FU was markedly prolonged in comparison with the half-life of 5-FU after IV administration. The half-life of 5-FU after an IV bolus injection amounts to 10 to 20 minutes,23-25 whereas that of 5-FU using S-1 was several hours. This indicates that CDHP effectively inhibits DPD in vivo, although reversibly. Regarding the correlation between the pharmacokinetics of S-1 and diarrhea, it seemed that the long-term retention of 5-FU (concentration of 5-FU at 8 and 24 hours after administration) predicted the occurrence of this side effect. In the future, this correlation may be used for adequate dosing of S-1. In considering the pharmacokinetic data, the important question arises as to whether the selected schedule of twice-daily dosing of S-1 can be improved. Mean 5-FU plasma concentrations during a 2-week IV infusion of the drug at a dose of 300 mg/m2/d have been reported to be approximately 0.7 µmol/L on day 7 and 2.8 µmol/L on day 14,25 although others have found somewhat lower 5-FU levels using the same dose.26 S-1 used in the present dose schedule provides 5-FU plasma levels of this magnitude only within 6 hours after each S-1 administration. Thus, during the rest of the day the plasma concentration of 5-FU will be below the level that is believed to be the minimal effective cytotoxic concentration.27 More frequent dosing during the day is likely to lead to a more stable steady-state 5-FU plasma concentration. However, whether 5-FU concentrations need to be above these levels continuously is unknown. Because the retention of 5-FU in tissues has been demonstrated to be longer than that in plasma,12 tissue concentrations may be more than 1 µmol/L despite plasma 5-FU concentrations progressively decreasing below 1 µmol/L. A more complete insight into other pharmacokinetic and pharmacodynamic parameters (including the kinetics of CDHP, oxonic acid, and uracil; DPD inhibition in WBCs; and the urinary excretion of 5-FU, 5-fluoro-beta-alanine and beta-alanine, in preparation) might be helpful in suggesting changes in the S-1 administration schedule. Japanese investigators have also reported on the pharmacokinetics of S-1.28 In 12 patients with gastric, colorectal, or breast cancer who had received an average single S-1 dose of 35.9 mg/m2, the Cmax of 5-FU amounted to 0.98 ± 0.32 µmol/L, whereas the 5-FU AUC was 331.6 ± 124.9 µmol/L·min. In a comparison with our values at the 35-mg/m2 S-1 dose, we found the 5-FU Cmax to be approximately 40% higher and the AUC to be approximately 50% higher. Thus, the exposure to 5-FU in our patients seems to be substantially higher at similar doses of S-1, which may explain the differences seen in toxicity between Japanese and Dutch patients. A possible explanation for this observation may be the polymorphism of cytochrome P450, with differences in activity among patients with different ethnic backgrounds.29 Cytochrome P450 seems to be involved in the conversion of tegafur into 5-FU,30 resulting in higher 5-FU levels in Dutch patients. Given these findings and the Japanese results, further investigation of S-1 in phase II trials has been started in the Early Clinical Studies Group of the European Organization for the Research and Treatment of Cancer, in previously untreated metastatic colorectal cancer and in advanced gastric cancer. The dose of S-1 selected in these studies, based on the results of our phase I study, is 40 mg/m2 bid, on 28 consecutive days, every 5 weeks. Based on the results of our study, the recommended dose for patients with extensive prior chemotherapy should be 35 mg/m2 bid. In conclusion, S-1, and possibly other agents with similar properties, may in the future substantially replace the use of IV 5-FU, by providing similar activity in conjunction with better safety and improved convenience and quality of life.
Supported in part by Taiho Pharmaceutical Co, Ltd, Tokyo, Japan. We thank D.A. Voorn and U. Holwerda for expert technical assistance.
Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
