Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients
http://www.100md.com
《临床肿瘤学》
the Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands
the Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium
Aventis Pharma, Antony Cedex, France
present address: National Cancer Institute, Bethesda, MD (A.S.)
ABSTRACT
PATIENTS AND METHODS: Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days.
RESULTS: Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 x 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients.
CONCLUSION: The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 x 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.
INTRODUCTION
Capecitabine is an oral fluoropyrimidine carbamate that is preferentially converted into fluorouracil (FU) in tumors through a cascade of three enzymes—carboxylesterase, cytidine deaminase, and thimidine phosphorylase (dThdPase).8 After oral intake of capecitabine, the parent drug passes mainly unchanged from the gastrointestinal tract and is metabolized in the liver by carboxylesterases to 5'-deoxy-5-fluorocytidine (5'-DFCR), then by cytidine deaminase to 5'-deoxy-5-fluorouridine (5'-DFUR) in the liver and tumor tissues, and finally by dThdPase to FU in tumors. This minimizes the exposure of healthy tissues to systemic active FU.
In randomized phase III studies, capecitabine has demonstrated essentially equivalent survival with decreased toxicity compared with intravenous (IV) FU regimens,9 and currently, irinotecan administered IV is being investigated in combination with capecitabine.6,7,10 The development of oral irinotecan raises the possibility of using this agent with capecitabine in an all-oral regimen, possibly increasing the convenience of therapy, and therefore potentially improving patient quality of life.
Against this background, we performed a phase I study to evaluate the combination treatment of irinotecan capsules and capecitabine given concomitantly once daily for 5 consecutive days and twice daily for 14 consecutive days every 3 weeks, respectively, in patients with refractory solid tumors. The objectives of this trial were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this combination; (2) to characterize the pharmacokinetics of irinotecan, its metabolite SN-38, capecitabine, and its major metabolites in order to assess a potential interaction between the compounds; and (3) to document any evidence of antitumor activity.
PATIENTS AND METHODS
Treatment and Dose Escalation
Irinotecan was provided as semisolid matrix capsules, containing 5, 20, or 50 mg of the active drug substance, and was stored at room temperature. The capsules also contained lecithin and lauroyl macrogolglycerides as inactive ingredients, and a yellowish waxy mass. The drug was supplied by Aventis Pharma (Antony, France) in 30-mL bottles, containing 20 capsules of the 50-mg dosage form and 40 capsules of the 5-mg and 20-mg dosage forms.
Capecitabine was provided as film-coated, oblong tablets containing 150 and 500 mg of active substance. The tablets were already packed for the study in high-density polyethene bottles, whereby the 150-mg tablet was packed in bottles containing 28 tablets, and the 500-mg tablets, in bottles containing 56 tablets. Capecitabine was provided by Hoffmann-La Roche (Basel, Switzerland).
Irinotecan and capecitabine were concomitantly administered orally during the first 5 days of each cycle, and afterwards, treatment with capecitabine continued for 9 additional consecutive days. Irinotecan capsules were taken once daily in the morning, at the same time during the day, with approximately 180 mL of water, after an overnight fasting of at least 4 hours before the daily oral dose and 1 hour following dosing. Irinotecan was taken in fasting conditions because the effect of food on the pharmacokinetics of this drug was not yet known when this combination phase I study was initiated.
Capecitabine tablets were taken twice daily at the end of a meal (ie, breakfast and dinner), as recommended,11 in the morning, 2 hours after intake of irinotecan capsules and approximately 10 to 12 hours later, for 14 consecutive days, with a glass of water. Cycles were repeated every 3 weeks. Compliance with the scheduled treatment was assessed at the end of each cycle by counting the used and returned capsules and tablets. With the exception of days 5, 6, 14, and 15 of the first cycle, during which patients were hospitalized for pharmacokinetic sampling, patients were treated on an outpatient basis. Regarding oral irinotecan, taking this drug in fasting conditions is the usual recommendation when the effect of food on the pharmacokinetics of a drug is not yet known. In the first part of this phase I study, irinotecan was given as a single agent, in fasting or fed conditions, indeed to evaluate the effect of food on irinotecan pharmacokinetics in patients. The results of that study were not yet available when the combination phase I study was initiated.
Prophylactic antiemetics (either metoclopramide or a serotonin receptor antagonist) were allowed 1 hour before irinotecan dosing and as many as two additional times daily if necessary during all cycles of treatment.
For irinotecan-induced delayed-type diarrhea, high-dose loperamide therapy was administered orally and consisted of a starting dose of 4 mg at the first episode of diarrhea followed by 2 mg every 2 hours for at least 12 hours. The patient was allowed to stop loperamide only after a 12-hour diarrhea-free interval. If the diarrhea persisted for more than 48 hours despite the recommended loperamide treatment, a 7-day prophylactic oral antibiotic therapy (ciprofloxacine 500 mg bid) was added during subsequent cycles.
In case of severe acute cholinergic symptoms, patients were treated curatively and as secondary prevention with either orally or subcutaneously administered atropine.
The starting doses for irinotecan and capecitabine were 50 mg/m2/d given once daily and 800 mg/m2 given twice daily. The starting dose of irinotecan was based on results of a previous phase I study with single-agent oral irinotecan, and was 20 mg/m2/d lower than the single-agent MTD.12
Further dose escalations were based on the prior dose level toxicity. If no DLT was observed during the first cycle at a given dose level, then the dose was escalated to the next higher dose level, with 10-mg/m2/d increments for irinotecan. After the determination of the MTD for oral irinotecan with 2 x 800 mg/m2/d of capecitabine, the dose of capecitabine was increased to 1,000 mg/m2 given twice daily for 14 consecutive days, and the dose of irinotecan tapered to the next previous dose in combination with capecitabine 800 mg/m2 twice daily.
At least three patients were entered at each dose level. If one of three patients experienced DLT at the first cycle, three additional patients were entered at that dose level. The MTD was defined as one dose level below the dose that induced DLTs in two of six patients during the first cycle. DLTs were defined as National Cancer Institute Common Toxicity Criteria version 2.0 (NCI-CTC) grade 3 neutropenia before day 7, or grade 4 neutropenia during the treatment cycle, or grade 4 neutropenia lasting ≥ 5 days; neutropenic fever (defined as grade 4 neutropenia with fever ≥ 38.5°C); neutropenic infection (defined as grade 3-4 neutropenia with ≥ grade 3 infection or documented infection); thrombocytopenia less than 25 x 109/L; diarrhea ≥ grade 3, despite maximal intensive loperamide support; nausea or vomiting ≥ grade 2, despite maximal oral antiemetic therapy, or vomiting leading to discontinuation of the study drugs intake ≥ 3 days; other nonhematological toxicities ≥ grade 3 (eg, grade 3 stomatitis, grade 3 palmar-plantar erythrodysesthesia [hand-foot syndrome]); and treatment delay due to toxicities attributed to the study drugs laster longer than 2 weeks.13 Intrapatient dose escalation was not allowed. The treatment was resumed when the neutrophil count had recovered to ≥ 1.5 x 109/L, the platelet count to ≥ 100 x 109/L, when diarrhea was absent, and when any other treatment-related toxicities were ≤ grade 1. The need to interrupt the study treatment due to toxicity, as well as the need for any kind of supportive care, led to the investigator's evaluation of the clinical situation. At the time the study protocol was drafted, the stopping rules for capecitabine, especially in the case of even moderate diarrhea, were not yet established. Hence, the interruption of the cycle was recommended in case of diarrhea grade 3 or 4, with a dose reduction of both drugs for further cycles.
Treatment Assessment
Before initiating therapy, a complete medical history was taken, and a physical examination was performed. A CBC, including hemoglobin, white cells with differential count, platelets, and serum biochemistry, was performed, as were ECG and chest x-ray. Weekly evaluations included history, physical examination, CBC, and toxicity assessment according to the NCI-CTC. CBC was done twice weekly throughout cycle 1 and weekly thereafter, and serum biochemistry was performed on days 8 and 15 of cycle 1 and weekly thereafter until recovery, and then every 3 weeks at every subsequent cycle. Tumor evaluation was performed after every two cycles, and response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST).14 Patients were treated for at least two cycles of therapy unless disease progression or unacceptable toxicity was encountered.
Sample Collection and Drug Analysis
For pharmacokinetic analysis, a total of 34 blood samples (total volume of approximately 170 mL; corresponding to 11 samples for irinotecan and 23 samples for capecitabine) were obtained from an indwelling IV canula and were collected into heparin-coated tubes for irinotecan and into EDTA-containing tubes for capecitabine on days 5 (irinotecan and capecitabine) and 14 (capecitabine only) of the first cycle. The samples were taken immediately before intake of irinotecan and at 0.5, 1, 1.5, 2, 2.25, 2.50, 3, 4, 5, 6, 7, 8, 10, 12, 18, and 24 hours after administration on day 5 at cycle 1. Samples were also taken immediately before intake of capecitabine, and at 0.25, 0.50, 1, 2, 3, 4, 5, 6, 8, and 10 hours after the morning intake of capectabine on day 14 of cycle 1. After sampling, all blood specimens were immediately put in an ice-water bath (4°C) until centrifugation at 2,000 rpm for 15 minutes at 4°C. Plasma samples were stored frozen at a temperature below –20°C, until analysis.
Concentrations of irinotecan and its active metabolite SN-38 were quantified as total drug (ie, the total of lactone and carboxylate forms) with a validated high-performance liquid chromatographic (HPLC) assay with fluorescence detection following solid-phase extraction of 50-μL samples. The lower limit of quantitation was 1 ng/mL. The accuracy of the assay was defined as the present difference between the nominal and the mean measured concentrations of quality controls, and ranged from –2.1% to 5.4% for irinotecan, and from –0.11% to 1.2% for SN-38 in plasma during the analysis period. The precision of the assay, established by the coefficients of variation (CVs) of the quality controls, was lower than 6.5% for both compounds. Concentrations of capecitabine and its metabolites 5'-DFCR, 5'-DFUR, FU, and {alpha}-fluoro--alanine (FBAL) were determined by HPLC with tandem mass-spectrometric detection. The lower limits of quantitation were 50 ng/mL for 5'-DFUR, 11.3 ng/mL for FBAL, 10 ng/mL for capecitabine and 5'-DFCR, and 2 ng/mL for FU. The accuracy of the assay ranged from –4.3% to 3.3% for FU, and from –5.8% to 4.0% for FBAL. The precision of the assay was lower than 8%, 13%, 6.2%, 11%, and 16% for capecitabine, 5'-DFCR, 5'-DFUR, FU, and FBAL, respectively.
Pharmacokinetic Data Analysis
Pharmacokinetic parameters were calculated by standard noncompartmental methods using WINNonlin (Scientific Consultant, Apex, NC) software version 3.3 (Pharsight Corp, Mountain View, CA). The following parameters were determined for irinotecan, capecitabine, and their metabolites in the dosing interval ({tau}): peak concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), half-life of the terminal phase (T1/2), and the metabolic ratio of AUCs of SN-38 and irinotecan.
Statistical Analysis
The effect of capecitabine on irinotecan pharmacokinetics was assessed by comparing Cmax and AUC on day 5 of this study (concomitant combination step) with day 5 of monotherapy with oral irinotecan (single-agent step12). The comparison was made with 25 patients treated at 70 mg/m2/d or 80 mg/m2/d for 5 days with the single agent. The statistical analysis was carried out on dose-normalized Cmax and AUC(0-24 hours) of irinotecan and SN-38 and after log transformation. The Proc-Mixed procedure of SAS (SAS Institute, Cary, NC) software version 8.2 was used with treatment (concomitant intake of irinotecan and capecitabine v oral irinotecan monotherapy) taken as fixed effect. For comparison of the metabolic ratios, the t test was used.
To assess a possible influence of irinotecan and SN-38 on the pharmacokinetics of capecitabine, a Proc-Mixed procedure was applied on log-transformed Cmax and AUC(0-10 hours) of capecitabine and its metabolites at day 5 (concomitant intake of irinotecan with capecitabine) versus day 14 (intake of capecitabine only) taken as fixed effect and patient as random effect. Of note, 10 hours corresponds to the time between the first and second daily intake of capecitabine. All tests results with a P < .05 were considered statistically significant. The effect of body-surface area (BSA) on the pharmacokinetic parameters of irinotecan and capecitabine was evaluated as described previously.15 In brief, the apparent oral clearance for irinotecan and capecitabine, as well as the apparent metabolic clearance of the metabolites SN-38 and FU was expressed either as liters per hour (L/h) or as L/h normalized to BSA in meters squared (L/h/m2). Interpatient variation in this parameter was calculated by dividing the standard deviation by the mean and was expressed as a percentage (ie, the CV). The previously described, arbitrarily defined criterion relative reduction in variability (RIV) was used to determine if BSA-based dosing was statistically significantly associated with a reduction in interpatient variation in clearance. The RIV was calculated according to the following formula
and was considered to reach statistical significance when ≥ 15%.
RESULTS
Dose-Limiting Toxicity
Grade 3 colitis associated with grade 3 anorexia, and grade 3 delayed diarrhea with grade 2 nausea, despite maximal antiemetic support with a serotonin antagonist, were the DLTs in the first cycle at the second dose level irinotecan 60 mg/m2/d and capecitabine 800 mg/m2 twice daily, in two of six patients (Table 2). Three additional patients were entered at the next lower dose level (ie, the study starting dose level [irinotecan 50 mg/m2/d and capecitabine 2 x 800 mg/m2/d]). No DLTs were observed in the first cycle in these patients. Subsequently, the dose level irinotecan 50 mg/m2/d and capecitabine 1,000 mg/m2 twice daily was explored. No DLTs were observed in the first six patients at this dose level. Since capecitabine 1,000 mg/m2 twice daily is the most commonly used combination dose, it was unlikely that a higher dose in combination with irinotecan would be feasible; therefore, the dose of capecitabine was not further escalated. Hence, the recommended dose for phase II trials of the oral irinotecan and capecitabine combination was set at 50 mg/m2/d for 5 consecutive days (ie, total dose of 250 mg/m2) and 1,000 mg/m2 twice daily for 14 consecutive days every 3 weeks, respectively. Thirteen additional patients were treated at this dose level to confirm its feasibility. Ultimately, two of 16 patients experienced DLTs in the first cycle, viz grade 3 delayed diarrhea, grade 2 nausea despite maximal antiemetic supportive treatment, and grade 3 fatigue, thereby confirming the recommended dose level. These 16 patients received a total of 92 cycles (median, 6 cycles; range, 1 to 11 cycles). Among them, 43.8% (seven of 16, including four for toxicity and three for reasons other than toxicity) required a treatment delay during least one cycle, and 12.5% (two of 16, both for nonhematologic toxicity) required at least one dose reduction (in both cases, dose reduction of capecitabine only, each time at cycle 2).
Hematologic Toxicity
Worst-grade hematologic toxicities per patient are listed in Table 3. Overall, hematologic toxicity was mild to moderate across all dose levels, with no grade 4 observed. Although grade 3 leukocytopenia and grade 3 neutropenia were observed in four patients at irinotecan doses of 50 mg/m2/d and capecitabine 1,000 mg/m2/d x 2, this was not considered a DLT because the adverse event occurred after the first cycle, and the grade 3 myelosuppression occurred after day 7 of the cycle. Grade 3 anemia was seen in two patients at the feasibility dose level of irinotecan 50 mg/m2/d and capecitabine 1,000 mg/m2/d x 2, and was considered a DLT at subsequent cycles.
Nonhematologic Toxicity
Other nonhematologic toxicities were mild to moderate, with no grade 4 toxicity observed, as summarized in Table 4. Overall, gastrointestinal toxicity (ie, diarrhea, nausea and vomiting) was the most common adverse event. Most patients (82%) experienced grade 1 to 2 nausea (mean durations of grade 1 and 2 nausea, 8.0 days and 10.6 days, respectively), and 17 (61%) of 28 patients experienced grade 1 to 2 vomiting (mean durations of grade 1 and 2 vomiting, 3.4 days and 5.5 days, respectively). Prophylactic antiemetics, either metoclopramide or serotonin antagonists, were used to manage nausea and vomiting. Grade 3 delayed diarrhea was observed in five patients (18%) across all dose levels, including one patient at the first dose level (irinotecan 50 mg/m2/d and capecitabine 2 x 800 mg/m2), considered a DLT at subsequent cycle, and two patients at the second dose level (irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2), not considered DLTs because of inappropriate supportive treatment with loperamide. Grade 1 and 2 diarrhea was noted in 19 patients (70%), and was manageable with supportive treatment with loperamide. The mean durations of grade 1, 2, and 3 diarrhea were 6.1 days, 4.2 days, and 8.2 days, respectively. Grade 2 anorexia was observed in 9 patients (32%), and one patient had grade 3 anorexia, considered a DLT at the second dose level (mean durations of grade 1 and ≥ 2 anorexia, 16.3 days and 15.8 days, respectively). In addition, grade 1 and 2 asthenia was seen in nine patients (32%), and one patient experienced dose-limiting (grade 3) asthenia in the first cycle at dose levels of irinotecan 50 mg/m2/d and capecitabine 1,000 mg/m2/d x 2 after 5 days of the treatment. Mild alopecia (grade 1) was seen in eight patients, and moderate alopecia (grade 2) was encountered in four patients. Across all dose levels, mild to moderate abdominal pain was noted in eight (29%) and two (7%) patients, respectively. Hand-foot syndrome (palmar-plantar erythrodysesthesia), a well-known adverse event of capecitabine, was seen in six patients (21% grade 1 to 2), all at the recommended dose of capecitabine (1,000 mg/m2 twice daily). Grade 3 hand-foot syndrome was observed in one patient at cycle 9 at the first dose level, considered a DLT at subsequent cycles. Mild to moderate conjunctivitis due to capecitabine treatment was seen in two patients. Finally, mild and moderate increase of liver transaminases was noted in six (21%) and two (7%) patients, respectively, whereas mild hyperbilirubinemia was observed in two patients at the recommended dose level. All toxicities were reversible. In 39% of patients (n = 11), cycles were delayed by 1 week or more. A total of three patients (11%) required at least one dose reduction of irinotecan or capecitabine.
Pharmacokinetics
Blood samples were obtained from 26 patients, and complete pharmacokinetic profiles were available in 25 patients. The mean (± SD) irinotecan and SN-38 pharmacokinetic parameters are summarized in Table 5. Oral irinotecan was rapidly absorbed and metabolized with peak plasma concentrations of irinotecan and SN-38 within 2 to 2.5 hours. Interpatient variability was generally high, with CVs of 36% to 48% for the AUC of irinotecan and 34% to 84% for the AUC of SN-38. The SN-38–irinotecan AUC metabolic ratio was approximately 13.2%, which is similar to previous observations with single-agent oral irinotecan formulated as semisolid matrix capsules.12 Pharmacokinetic parameters of capecitabine and its metabolites were also similar to previous findings16 (Table 6) . Statistical analysis revealed that the pharmacokinetics of irinotecan (P > .21) and SN-38 (P > .041) were not altered by the coadministration of capecitabine (though there was a trend toward a higher metabolic ratio [P = .11]), and showed that the pharmacokinetics of capecitabine (P > .53) and its metabolites (P > .16) were similar on day 5 and day 14, suggesting the absence of a pharmacokinetic interaction with irinotecan.
Efficacy
Twenty-six patients were assessable for therapeutic activity. Three confirmed partial responses were documented—two in patients with metastatic gallbladder carcinoma lasting for ≥ 24 weeks, and one in a patient with metastatic melanoma lasting 42 weeks. A total of 16 patients demonstrated disease stabilization for 6 (n = 5), 12 (n = 8), 18 (n = 2), 24 (n = 2), and 30 weeks (n = 1). One patient was not assessable for response because he went off study after the first cycle due to DLT, and no tumor reassessment was done at that time.
DISCUSSION
Delayed diarrhea accompanied by nausea, anorexia, and colitis were the principal DLTs of this combination regimen. Diarrhea was easily manageable by the use of loperamide. Hematologic toxicity was mild to moderate and did not result in a DLT in the first cycle. Nonhematologic toxicities attributed to the oral combination of irinotecan and capecitabine included nausea, vomiting, stomatitis, fatigue, alopecia, and hand-foot-syndrome. The recommended dose of this oral combination for further phase II study evaluation is irinotecan 50 mg/m2/d given daily for 5 days, and capecitabine 1,000 mg/m2 given twice daily for 14 days, repeated every 3 weeks.
Currently, the combination of irinotecan and capecitabine is tested in different schedules in phase I and phase II studies in advanced colorectal cancer, though only preliminary data are yet available.17-21 In the majority of these studies IV irinotecan is used, while two studies apply flat-dose capecitabine,22,23 and a third uses oral irinotecan for 14 consecutive days every 3 weeks in combination with capecitabine.24 Two randomized phase II studies compared weekly to every-3-weeks (3-weekly) administration of irinotecan with capecitabine.6,19 Higher incidences of diarrhea and life-threatening toxicity on the weekly regimen have led to the conclusion that the 3-weekly administration is preferable. Efficacy and safety of the 3-weekly regimen were interesting and have led to the design of phase III trials that are currently being performed.
Preclinical studies showed that the therapeutic efficacy of the combination of IV irinotecan and IV FU is dose- and sequence-dependent.25-28 The sequence of irinotecan preceding FU by an interval of 24 hours appeared superior. Furthermore, the toxicity associated with irinotecan could be eliminated by reducing the dose of irinotecan to at least 50% of its MTD while keeping the FU dose at 50% to 75% of its MTD, without loss of the antitumor activity.28 Increasing the dose of FU did not contribute to additional therapeutic activity, but only resulted in increased toxicity. In this combination, doses of FU are critical for therapeutic efficacy, whereas doses of irinotecan play a modulatory function in sensitizing tumor cells for the subsequent FU administration after 24 hours.28 In vitro studies in HCT-8 colon carcinoma cell lines showed that the combination of SN-38 and FU resulted in increased deoxythymidine triphosphate levels and inhibition of deoxyuridine monophosphate (dUMP) synthesis.28 This depletion of dUMP enhanced the FU-associated inhibition of thymidylate synthese, which explained the enhanced cytotoxicity of FU after irinotecan administration.28
The pharmacokinetic results of oral irinotecan and SN-38 in the present study are in agreement with results of a previously published phase I study of single-agent oral irinotecan,12 showing rapid absorption and metabolism of the drug with peak plasma concentrations of irinotecan and SN-38 within 2 to 3 hours after intake, high interpatient variability, and the same dose-independent SN-38–irinotecan AUC ratio. This ratio is substantially higher than that measured after oral administration of irinotecan than after IV administration of irinotecan,29,30 suggesting significant presystemic biotransformation of irinotecan into SN-38 within the gastrointestinal tract and/or the liver. This is consistent with the high expression levels of irinotecan-metabolizing carboxylesterases in intestinal cells.31 These enzymes are also involved in capecitabine biotransformation, and a pharmacokinetic drug-drug interaction was thus theoretically possible. However, the pharmacokinetic analysis of the present study revealed no significant interaction between oral irinotecan and capecitabine, though there was a trend toward a higher SN-38–irinotecan metabolic ratio with concomitant administration. The pharmacokinetics of capecitabine and its metabolites either at day 5 or at day 14 were not modified by the 5-day coadministration of irinotecan.
Interestingly, after correction for the BSA of each individual patient, the interpatient variability in the apparent oral clearance of irinotecan (52.4% v 40.0%), SN-38 (105% v 110%), capecitabine (84.4% v 73.9%), and FU (41% v 44%) remained in a similar order of magnitude. Indeed, the values for relative reduction in pharmacokinetic variability following parameter correction for BSA in the case irinotecan, SN-38, capecitabine, and FU were 6.36%, –5.04% (0%), 12.41%, and –7.07% (0%), respectively. This suggests that BSA is not a significant predictor of the apparent oral clearance of irinotecan and capecitabine, as predicted previously from a retrospective analysis,15 and that flat-dosing regimens might be applied in future studies with this drug combination, without compromising overall safety profiles.
Previous investigations have demonstrated that there are no relationships between capcitabine or metabolite pharmacokinetics and treatment-related toxicity (reviewed by Blesch et al16). These investigators noted that the previously attempted pharmacokinetic-pharmacodynamic modeling analyses demonstrated that the most readily available physiologic compartment for measuring patient exposure to capecitabine (ie, plasma) in the clinic is not a reliable predictor of clinical outcomes, and argue against therapeutic monitoring of plasma levels of capecitabine and metabolites. In the current study, only plasma was obtained, and the main purpose was to evaluate the potential for irinotecan and capecitabine to affect the other agent's pharmacokinetic profile. In relation to irinotecan, previous studies have shown that the demonstration of significant relationships between drug exposure and gastrointestinal toxicity requires a sample size much larger than the currently studied cohort of 28.32 The added complexity of the coadministration of irinotecan with capecitabine to the pharmacokinetic-pharmacodynamic analysis made this an issue beyond the scope of the current article. However, we are currently planning a separate analysis that specifically looks into relationships between pharmacokinetic parameters and observed toxicity using a semiphysiological population-based modeling approach.
In conclusion, the oral combination of irinotecan with prolonged administration of capecitabine seems to be feasible. Overall, the observed antitumor activity in this heterogenous group of patients was somewhat disappointing, with three confirmed partial responses and a total of 16 patients demonstrating disease stabilization for 6 or more weeks. It should be emphasized, however, that the antitumor activity was observed in patients with malignancies that are known to be drug-refractory, including gallbladder carcinoma and melanoma, and that 82% of patients had at least one line of prior chemotherapy. Overall, this indicates that the current findings provide impetus for the development of this combination in phase II trials.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
O.S. and H.D. participated equally to this study.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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19. Borner MM, Dietrich D, Popescu R, et al: A randomized phase II trial of capecitabine (CAP) and two different schedules of irinotecan (IRI) in first-line treatment of metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol 22:266, 2003 (abstr 1068)
20. Bollina R, Beretta G, Toniolo D, et al: Capecitabine and irinotecan (CAPIRI): A good combination in elderly patients with advanced colorectal cancer (ACRC) as first line chemotherapy—Preliminary results of a phase II trial. Proc Am Soc Clin Oncol 22:332, 2003 (abstr 1332)
21. Munoz A, Salut A, Escudero P, et al: Irinotecan (CPT-11) and capecitabine as first line treatment of locally advanced or metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 22:317, 2003 (abstr 1271)
22. Goel S, Jhawer M, Rajdev L, et al: Phase I clinical trial of irinotecan with oral capecitabine in patients with gastrointestinal and other solid malignancies. Am J Clin Oncol 25:528-534, 2002
23. Dickson N, Burris HA, Foulke R, et al: Flat-dose continuous capecitabine with irinotecan in 1st line advanced colorectal cancer (ACRC): Early results of a phase II trial. Proc Am Soc Clin Oncol 22:369, 2003 (abstr 1480)
24. Kuppens IL, Bonneterre M-E, Beijnen JH, et al: Dose-finding phase I clinical and pharmacokinetic study of orally administered irinotecan (CPT-11) once daily for 14 days as single agent or in combination with capecitabine twice daily for 14 days every 3 weeks in patients with advanced solid tumors. Proc Am Soc Clin Oncol 22:158, 2003 (abstr 634)
25. Mullany S, Svingen PA, Kaufmann SH, et al: Effect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: Elevated dTTP pools and enhanced cytotoxicity. Cancer Chemother Pharmacol 42:391-399, 1998
26. Pavillard V, Formento P, Rostagno P, et al: Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity. Biochem Pharmacol 56:1315-1322, 1998
27. Guichard S, Hennebelle I, Bugat R, et al: Cellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line. Biochem Pharmacol 55:667-676, 1998
28. Cao S, Rustum YM: Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: Role of drug sequence and dose. Cancer Res 60:3717-3721, 2000
29. Chabot GG: Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet 33:245-259, 1997
30. Ma MK, McLeod HL: Lessons learned from the irinotecan metabolic pathway. Curr Med Chem 10:41-49, 2003
31. Ahmed F, Vyas V, Cornfield A, et al: In vitro activation of irinotecan to SN-38 by human liver and intestine. Anticancer Res 19:2067-2071, 1999
32. Xie R, Mathijssen RH, Sparreboom A, et al: Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther 72:265-275, 2002(Otto Soepenberg, Herlinde)
the Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium
Aventis Pharma, Antony Cedex, France
present address: National Cancer Institute, Bethesda, MD (A.S.)
ABSTRACT
PATIENTS AND METHODS: Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days.
RESULTS: Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 x 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients.
CONCLUSION: The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 x 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.
INTRODUCTION
Capecitabine is an oral fluoropyrimidine carbamate that is preferentially converted into fluorouracil (FU) in tumors through a cascade of three enzymes—carboxylesterase, cytidine deaminase, and thimidine phosphorylase (dThdPase).8 After oral intake of capecitabine, the parent drug passes mainly unchanged from the gastrointestinal tract and is metabolized in the liver by carboxylesterases to 5'-deoxy-5-fluorocytidine (5'-DFCR), then by cytidine deaminase to 5'-deoxy-5-fluorouridine (5'-DFUR) in the liver and tumor tissues, and finally by dThdPase to FU in tumors. This minimizes the exposure of healthy tissues to systemic active FU.
In randomized phase III studies, capecitabine has demonstrated essentially equivalent survival with decreased toxicity compared with intravenous (IV) FU regimens,9 and currently, irinotecan administered IV is being investigated in combination with capecitabine.6,7,10 The development of oral irinotecan raises the possibility of using this agent with capecitabine in an all-oral regimen, possibly increasing the convenience of therapy, and therefore potentially improving patient quality of life.
Against this background, we performed a phase I study to evaluate the combination treatment of irinotecan capsules and capecitabine given concomitantly once daily for 5 consecutive days and twice daily for 14 consecutive days every 3 weeks, respectively, in patients with refractory solid tumors. The objectives of this trial were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this combination; (2) to characterize the pharmacokinetics of irinotecan, its metabolite SN-38, capecitabine, and its major metabolites in order to assess a potential interaction between the compounds; and (3) to document any evidence of antitumor activity.
PATIENTS AND METHODS
Treatment and Dose Escalation
Irinotecan was provided as semisolid matrix capsules, containing 5, 20, or 50 mg of the active drug substance, and was stored at room temperature. The capsules also contained lecithin and lauroyl macrogolglycerides as inactive ingredients, and a yellowish waxy mass. The drug was supplied by Aventis Pharma (Antony, France) in 30-mL bottles, containing 20 capsules of the 50-mg dosage form and 40 capsules of the 5-mg and 20-mg dosage forms.
Capecitabine was provided as film-coated, oblong tablets containing 150 and 500 mg of active substance. The tablets were already packed for the study in high-density polyethene bottles, whereby the 150-mg tablet was packed in bottles containing 28 tablets, and the 500-mg tablets, in bottles containing 56 tablets. Capecitabine was provided by Hoffmann-La Roche (Basel, Switzerland).
Irinotecan and capecitabine were concomitantly administered orally during the first 5 days of each cycle, and afterwards, treatment with capecitabine continued for 9 additional consecutive days. Irinotecan capsules were taken once daily in the morning, at the same time during the day, with approximately 180 mL of water, after an overnight fasting of at least 4 hours before the daily oral dose and 1 hour following dosing. Irinotecan was taken in fasting conditions because the effect of food on the pharmacokinetics of this drug was not yet known when this combination phase I study was initiated.
Capecitabine tablets were taken twice daily at the end of a meal (ie, breakfast and dinner), as recommended,11 in the morning, 2 hours after intake of irinotecan capsules and approximately 10 to 12 hours later, for 14 consecutive days, with a glass of water. Cycles were repeated every 3 weeks. Compliance with the scheduled treatment was assessed at the end of each cycle by counting the used and returned capsules and tablets. With the exception of days 5, 6, 14, and 15 of the first cycle, during which patients were hospitalized for pharmacokinetic sampling, patients were treated on an outpatient basis. Regarding oral irinotecan, taking this drug in fasting conditions is the usual recommendation when the effect of food on the pharmacokinetics of a drug is not yet known. In the first part of this phase I study, irinotecan was given as a single agent, in fasting or fed conditions, indeed to evaluate the effect of food on irinotecan pharmacokinetics in patients. The results of that study were not yet available when the combination phase I study was initiated.
Prophylactic antiemetics (either metoclopramide or a serotonin receptor antagonist) were allowed 1 hour before irinotecan dosing and as many as two additional times daily if necessary during all cycles of treatment.
For irinotecan-induced delayed-type diarrhea, high-dose loperamide therapy was administered orally and consisted of a starting dose of 4 mg at the first episode of diarrhea followed by 2 mg every 2 hours for at least 12 hours. The patient was allowed to stop loperamide only after a 12-hour diarrhea-free interval. If the diarrhea persisted for more than 48 hours despite the recommended loperamide treatment, a 7-day prophylactic oral antibiotic therapy (ciprofloxacine 500 mg bid) was added during subsequent cycles.
In case of severe acute cholinergic symptoms, patients were treated curatively and as secondary prevention with either orally or subcutaneously administered atropine.
The starting doses for irinotecan and capecitabine were 50 mg/m2/d given once daily and 800 mg/m2 given twice daily. The starting dose of irinotecan was based on results of a previous phase I study with single-agent oral irinotecan, and was 20 mg/m2/d lower than the single-agent MTD.12
Further dose escalations were based on the prior dose level toxicity. If no DLT was observed during the first cycle at a given dose level, then the dose was escalated to the next higher dose level, with 10-mg/m2/d increments for irinotecan. After the determination of the MTD for oral irinotecan with 2 x 800 mg/m2/d of capecitabine, the dose of capecitabine was increased to 1,000 mg/m2 given twice daily for 14 consecutive days, and the dose of irinotecan tapered to the next previous dose in combination with capecitabine 800 mg/m2 twice daily.
At least three patients were entered at each dose level. If one of three patients experienced DLT at the first cycle, three additional patients were entered at that dose level. The MTD was defined as one dose level below the dose that induced DLTs in two of six patients during the first cycle. DLTs were defined as National Cancer Institute Common Toxicity Criteria version 2.0 (NCI-CTC) grade 3 neutropenia before day 7, or grade 4 neutropenia during the treatment cycle, or grade 4 neutropenia lasting ≥ 5 days; neutropenic fever (defined as grade 4 neutropenia with fever ≥ 38.5°C); neutropenic infection (defined as grade 3-4 neutropenia with ≥ grade 3 infection or documented infection); thrombocytopenia less than 25 x 109/L; diarrhea ≥ grade 3, despite maximal intensive loperamide support; nausea or vomiting ≥ grade 2, despite maximal oral antiemetic therapy, or vomiting leading to discontinuation of the study drugs intake ≥ 3 days; other nonhematological toxicities ≥ grade 3 (eg, grade 3 stomatitis, grade 3 palmar-plantar erythrodysesthesia [hand-foot syndrome]); and treatment delay due to toxicities attributed to the study drugs laster longer than 2 weeks.13 Intrapatient dose escalation was not allowed. The treatment was resumed when the neutrophil count had recovered to ≥ 1.5 x 109/L, the platelet count to ≥ 100 x 109/L, when diarrhea was absent, and when any other treatment-related toxicities were ≤ grade 1. The need to interrupt the study treatment due to toxicity, as well as the need for any kind of supportive care, led to the investigator's evaluation of the clinical situation. At the time the study protocol was drafted, the stopping rules for capecitabine, especially in the case of even moderate diarrhea, were not yet established. Hence, the interruption of the cycle was recommended in case of diarrhea grade 3 or 4, with a dose reduction of both drugs for further cycles.
Treatment Assessment
Before initiating therapy, a complete medical history was taken, and a physical examination was performed. A CBC, including hemoglobin, white cells with differential count, platelets, and serum biochemistry, was performed, as were ECG and chest x-ray. Weekly evaluations included history, physical examination, CBC, and toxicity assessment according to the NCI-CTC. CBC was done twice weekly throughout cycle 1 and weekly thereafter, and serum biochemistry was performed on days 8 and 15 of cycle 1 and weekly thereafter until recovery, and then every 3 weeks at every subsequent cycle. Tumor evaluation was performed after every two cycles, and response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST).14 Patients were treated for at least two cycles of therapy unless disease progression or unacceptable toxicity was encountered.
Sample Collection and Drug Analysis
For pharmacokinetic analysis, a total of 34 blood samples (total volume of approximately 170 mL; corresponding to 11 samples for irinotecan and 23 samples for capecitabine) were obtained from an indwelling IV canula and were collected into heparin-coated tubes for irinotecan and into EDTA-containing tubes for capecitabine on days 5 (irinotecan and capecitabine) and 14 (capecitabine only) of the first cycle. The samples were taken immediately before intake of irinotecan and at 0.5, 1, 1.5, 2, 2.25, 2.50, 3, 4, 5, 6, 7, 8, 10, 12, 18, and 24 hours after administration on day 5 at cycle 1. Samples were also taken immediately before intake of capecitabine, and at 0.25, 0.50, 1, 2, 3, 4, 5, 6, 8, and 10 hours after the morning intake of capectabine on day 14 of cycle 1. After sampling, all blood specimens were immediately put in an ice-water bath (4°C) until centrifugation at 2,000 rpm for 15 minutes at 4°C. Plasma samples were stored frozen at a temperature below –20°C, until analysis.
Concentrations of irinotecan and its active metabolite SN-38 were quantified as total drug (ie, the total of lactone and carboxylate forms) with a validated high-performance liquid chromatographic (HPLC) assay with fluorescence detection following solid-phase extraction of 50-μL samples. The lower limit of quantitation was 1 ng/mL. The accuracy of the assay was defined as the present difference between the nominal and the mean measured concentrations of quality controls, and ranged from –2.1% to 5.4% for irinotecan, and from –0.11% to 1.2% for SN-38 in plasma during the analysis period. The precision of the assay, established by the coefficients of variation (CVs) of the quality controls, was lower than 6.5% for both compounds. Concentrations of capecitabine and its metabolites 5'-DFCR, 5'-DFUR, FU, and {alpha}-fluoro--alanine (FBAL) were determined by HPLC with tandem mass-spectrometric detection. The lower limits of quantitation were 50 ng/mL for 5'-DFUR, 11.3 ng/mL for FBAL, 10 ng/mL for capecitabine and 5'-DFCR, and 2 ng/mL for FU. The accuracy of the assay ranged from –4.3% to 3.3% for FU, and from –5.8% to 4.0% for FBAL. The precision of the assay was lower than 8%, 13%, 6.2%, 11%, and 16% for capecitabine, 5'-DFCR, 5'-DFUR, FU, and FBAL, respectively.
Pharmacokinetic Data Analysis
Pharmacokinetic parameters were calculated by standard noncompartmental methods using WINNonlin (Scientific Consultant, Apex, NC) software version 3.3 (Pharsight Corp, Mountain View, CA). The following parameters were determined for irinotecan, capecitabine, and their metabolites in the dosing interval ({tau}): peak concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), half-life of the terminal phase (T1/2), and the metabolic ratio of AUCs of SN-38 and irinotecan.
Statistical Analysis
The effect of capecitabine on irinotecan pharmacokinetics was assessed by comparing Cmax and AUC on day 5 of this study (concomitant combination step) with day 5 of monotherapy with oral irinotecan (single-agent step12). The comparison was made with 25 patients treated at 70 mg/m2/d or 80 mg/m2/d for 5 days with the single agent. The statistical analysis was carried out on dose-normalized Cmax and AUC(0-24 hours) of irinotecan and SN-38 and after log transformation. The Proc-Mixed procedure of SAS (SAS Institute, Cary, NC) software version 8.2 was used with treatment (concomitant intake of irinotecan and capecitabine v oral irinotecan monotherapy) taken as fixed effect. For comparison of the metabolic ratios, the t test was used.
To assess a possible influence of irinotecan and SN-38 on the pharmacokinetics of capecitabine, a Proc-Mixed procedure was applied on log-transformed Cmax and AUC(0-10 hours) of capecitabine and its metabolites at day 5 (concomitant intake of irinotecan with capecitabine) versus day 14 (intake of capecitabine only) taken as fixed effect and patient as random effect. Of note, 10 hours corresponds to the time between the first and second daily intake of capecitabine. All tests results with a P < .05 were considered statistically significant. The effect of body-surface area (BSA) on the pharmacokinetic parameters of irinotecan and capecitabine was evaluated as described previously.15 In brief, the apparent oral clearance for irinotecan and capecitabine, as well as the apparent metabolic clearance of the metabolites SN-38 and FU was expressed either as liters per hour (L/h) or as L/h normalized to BSA in meters squared (L/h/m2). Interpatient variation in this parameter was calculated by dividing the standard deviation by the mean and was expressed as a percentage (ie, the CV). The previously described, arbitrarily defined criterion relative reduction in variability (RIV) was used to determine if BSA-based dosing was statistically significantly associated with a reduction in interpatient variation in clearance. The RIV was calculated according to the following formula
and was considered to reach statistical significance when ≥ 15%.
RESULTS
Dose-Limiting Toxicity
Grade 3 colitis associated with grade 3 anorexia, and grade 3 delayed diarrhea with grade 2 nausea, despite maximal antiemetic support with a serotonin antagonist, were the DLTs in the first cycle at the second dose level irinotecan 60 mg/m2/d and capecitabine 800 mg/m2 twice daily, in two of six patients (Table 2). Three additional patients were entered at the next lower dose level (ie, the study starting dose level [irinotecan 50 mg/m2/d and capecitabine 2 x 800 mg/m2/d]). No DLTs were observed in the first cycle in these patients. Subsequently, the dose level irinotecan 50 mg/m2/d and capecitabine 1,000 mg/m2 twice daily was explored. No DLTs were observed in the first six patients at this dose level. Since capecitabine 1,000 mg/m2 twice daily is the most commonly used combination dose, it was unlikely that a higher dose in combination with irinotecan would be feasible; therefore, the dose of capecitabine was not further escalated. Hence, the recommended dose for phase II trials of the oral irinotecan and capecitabine combination was set at 50 mg/m2/d for 5 consecutive days (ie, total dose of 250 mg/m2) and 1,000 mg/m2 twice daily for 14 consecutive days every 3 weeks, respectively. Thirteen additional patients were treated at this dose level to confirm its feasibility. Ultimately, two of 16 patients experienced DLTs in the first cycle, viz grade 3 delayed diarrhea, grade 2 nausea despite maximal antiemetic supportive treatment, and grade 3 fatigue, thereby confirming the recommended dose level. These 16 patients received a total of 92 cycles (median, 6 cycles; range, 1 to 11 cycles). Among them, 43.8% (seven of 16, including four for toxicity and three for reasons other than toxicity) required a treatment delay during least one cycle, and 12.5% (two of 16, both for nonhematologic toxicity) required at least one dose reduction (in both cases, dose reduction of capecitabine only, each time at cycle 2).
Hematologic Toxicity
Worst-grade hematologic toxicities per patient are listed in Table 3. Overall, hematologic toxicity was mild to moderate across all dose levels, with no grade 4 observed. Although grade 3 leukocytopenia and grade 3 neutropenia were observed in four patients at irinotecan doses of 50 mg/m2/d and capecitabine 1,000 mg/m2/d x 2, this was not considered a DLT because the adverse event occurred after the first cycle, and the grade 3 myelosuppression occurred after day 7 of the cycle. Grade 3 anemia was seen in two patients at the feasibility dose level of irinotecan 50 mg/m2/d and capecitabine 1,000 mg/m2/d x 2, and was considered a DLT at subsequent cycles.
Nonhematologic Toxicity
Other nonhematologic toxicities were mild to moderate, with no grade 4 toxicity observed, as summarized in Table 4. Overall, gastrointestinal toxicity (ie, diarrhea, nausea and vomiting) was the most common adverse event. Most patients (82%) experienced grade 1 to 2 nausea (mean durations of grade 1 and 2 nausea, 8.0 days and 10.6 days, respectively), and 17 (61%) of 28 patients experienced grade 1 to 2 vomiting (mean durations of grade 1 and 2 vomiting, 3.4 days and 5.5 days, respectively). Prophylactic antiemetics, either metoclopramide or serotonin antagonists, were used to manage nausea and vomiting. Grade 3 delayed diarrhea was observed in five patients (18%) across all dose levels, including one patient at the first dose level (irinotecan 50 mg/m2/d and capecitabine 2 x 800 mg/m2), considered a DLT at subsequent cycle, and two patients at the second dose level (irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2), not considered DLTs because of inappropriate supportive treatment with loperamide. Grade 1 and 2 diarrhea was noted in 19 patients (70%), and was manageable with supportive treatment with loperamide. The mean durations of grade 1, 2, and 3 diarrhea were 6.1 days, 4.2 days, and 8.2 days, respectively. Grade 2 anorexia was observed in 9 patients (32%), and one patient had grade 3 anorexia, considered a DLT at the second dose level (mean durations of grade 1 and ≥ 2 anorexia, 16.3 days and 15.8 days, respectively). In addition, grade 1 and 2 asthenia was seen in nine patients (32%), and one patient experienced dose-limiting (grade 3) asthenia in the first cycle at dose levels of irinotecan 50 mg/m2/d and capecitabine 1,000 mg/m2/d x 2 after 5 days of the treatment. Mild alopecia (grade 1) was seen in eight patients, and moderate alopecia (grade 2) was encountered in four patients. Across all dose levels, mild to moderate abdominal pain was noted in eight (29%) and two (7%) patients, respectively. Hand-foot syndrome (palmar-plantar erythrodysesthesia), a well-known adverse event of capecitabine, was seen in six patients (21% grade 1 to 2), all at the recommended dose of capecitabine (1,000 mg/m2 twice daily). Grade 3 hand-foot syndrome was observed in one patient at cycle 9 at the first dose level, considered a DLT at subsequent cycles. Mild to moderate conjunctivitis due to capecitabine treatment was seen in two patients. Finally, mild and moderate increase of liver transaminases was noted in six (21%) and two (7%) patients, respectively, whereas mild hyperbilirubinemia was observed in two patients at the recommended dose level. All toxicities were reversible. In 39% of patients (n = 11), cycles were delayed by 1 week or more. A total of three patients (11%) required at least one dose reduction of irinotecan or capecitabine.
Pharmacokinetics
Blood samples were obtained from 26 patients, and complete pharmacokinetic profiles were available in 25 patients. The mean (± SD) irinotecan and SN-38 pharmacokinetic parameters are summarized in Table 5. Oral irinotecan was rapidly absorbed and metabolized with peak plasma concentrations of irinotecan and SN-38 within 2 to 2.5 hours. Interpatient variability was generally high, with CVs of 36% to 48% for the AUC of irinotecan and 34% to 84% for the AUC of SN-38. The SN-38–irinotecan AUC metabolic ratio was approximately 13.2%, which is similar to previous observations with single-agent oral irinotecan formulated as semisolid matrix capsules.12 Pharmacokinetic parameters of capecitabine and its metabolites were also similar to previous findings16 (Table 6) . Statistical analysis revealed that the pharmacokinetics of irinotecan (P > .21) and SN-38 (P > .041) were not altered by the coadministration of capecitabine (though there was a trend toward a higher metabolic ratio [P = .11]), and showed that the pharmacokinetics of capecitabine (P > .53) and its metabolites (P > .16) were similar on day 5 and day 14, suggesting the absence of a pharmacokinetic interaction with irinotecan.
Efficacy
Twenty-six patients were assessable for therapeutic activity. Three confirmed partial responses were documented—two in patients with metastatic gallbladder carcinoma lasting for ≥ 24 weeks, and one in a patient with metastatic melanoma lasting 42 weeks. A total of 16 patients demonstrated disease stabilization for 6 (n = 5), 12 (n = 8), 18 (n = 2), 24 (n = 2), and 30 weeks (n = 1). One patient was not assessable for response because he went off study after the first cycle due to DLT, and no tumor reassessment was done at that time.
DISCUSSION
Delayed diarrhea accompanied by nausea, anorexia, and colitis were the principal DLTs of this combination regimen. Diarrhea was easily manageable by the use of loperamide. Hematologic toxicity was mild to moderate and did not result in a DLT in the first cycle. Nonhematologic toxicities attributed to the oral combination of irinotecan and capecitabine included nausea, vomiting, stomatitis, fatigue, alopecia, and hand-foot-syndrome. The recommended dose of this oral combination for further phase II study evaluation is irinotecan 50 mg/m2/d given daily for 5 days, and capecitabine 1,000 mg/m2 given twice daily for 14 days, repeated every 3 weeks.
Currently, the combination of irinotecan and capecitabine is tested in different schedules in phase I and phase II studies in advanced colorectal cancer, though only preliminary data are yet available.17-21 In the majority of these studies IV irinotecan is used, while two studies apply flat-dose capecitabine,22,23 and a third uses oral irinotecan for 14 consecutive days every 3 weeks in combination with capecitabine.24 Two randomized phase II studies compared weekly to every-3-weeks (3-weekly) administration of irinotecan with capecitabine.6,19 Higher incidences of diarrhea and life-threatening toxicity on the weekly regimen have led to the conclusion that the 3-weekly administration is preferable. Efficacy and safety of the 3-weekly regimen were interesting and have led to the design of phase III trials that are currently being performed.
Preclinical studies showed that the therapeutic efficacy of the combination of IV irinotecan and IV FU is dose- and sequence-dependent.25-28 The sequence of irinotecan preceding FU by an interval of 24 hours appeared superior. Furthermore, the toxicity associated with irinotecan could be eliminated by reducing the dose of irinotecan to at least 50% of its MTD while keeping the FU dose at 50% to 75% of its MTD, without loss of the antitumor activity.28 Increasing the dose of FU did not contribute to additional therapeutic activity, but only resulted in increased toxicity. In this combination, doses of FU are critical for therapeutic efficacy, whereas doses of irinotecan play a modulatory function in sensitizing tumor cells for the subsequent FU administration after 24 hours.28 In vitro studies in HCT-8 colon carcinoma cell lines showed that the combination of SN-38 and FU resulted in increased deoxythymidine triphosphate levels and inhibition of deoxyuridine monophosphate (dUMP) synthesis.28 This depletion of dUMP enhanced the FU-associated inhibition of thymidylate synthese, which explained the enhanced cytotoxicity of FU after irinotecan administration.28
The pharmacokinetic results of oral irinotecan and SN-38 in the present study are in agreement with results of a previously published phase I study of single-agent oral irinotecan,12 showing rapid absorption and metabolism of the drug with peak plasma concentrations of irinotecan and SN-38 within 2 to 3 hours after intake, high interpatient variability, and the same dose-independent SN-38–irinotecan AUC ratio. This ratio is substantially higher than that measured after oral administration of irinotecan than after IV administration of irinotecan,29,30 suggesting significant presystemic biotransformation of irinotecan into SN-38 within the gastrointestinal tract and/or the liver. This is consistent with the high expression levels of irinotecan-metabolizing carboxylesterases in intestinal cells.31 These enzymes are also involved in capecitabine biotransformation, and a pharmacokinetic drug-drug interaction was thus theoretically possible. However, the pharmacokinetic analysis of the present study revealed no significant interaction between oral irinotecan and capecitabine, though there was a trend toward a higher SN-38–irinotecan metabolic ratio with concomitant administration. The pharmacokinetics of capecitabine and its metabolites either at day 5 or at day 14 were not modified by the 5-day coadministration of irinotecan.
Interestingly, after correction for the BSA of each individual patient, the interpatient variability in the apparent oral clearance of irinotecan (52.4% v 40.0%), SN-38 (105% v 110%), capecitabine (84.4% v 73.9%), and FU (41% v 44%) remained in a similar order of magnitude. Indeed, the values for relative reduction in pharmacokinetic variability following parameter correction for BSA in the case irinotecan, SN-38, capecitabine, and FU were 6.36%, –5.04% (0%), 12.41%, and –7.07% (0%), respectively. This suggests that BSA is not a significant predictor of the apparent oral clearance of irinotecan and capecitabine, as predicted previously from a retrospective analysis,15 and that flat-dosing regimens might be applied in future studies with this drug combination, without compromising overall safety profiles.
Previous investigations have demonstrated that there are no relationships between capcitabine or metabolite pharmacokinetics and treatment-related toxicity (reviewed by Blesch et al16). These investigators noted that the previously attempted pharmacokinetic-pharmacodynamic modeling analyses demonstrated that the most readily available physiologic compartment for measuring patient exposure to capecitabine (ie, plasma) in the clinic is not a reliable predictor of clinical outcomes, and argue against therapeutic monitoring of plasma levels of capecitabine and metabolites. In the current study, only plasma was obtained, and the main purpose was to evaluate the potential for irinotecan and capecitabine to affect the other agent's pharmacokinetic profile. In relation to irinotecan, previous studies have shown that the demonstration of significant relationships between drug exposure and gastrointestinal toxicity requires a sample size much larger than the currently studied cohort of 28.32 The added complexity of the coadministration of irinotecan with capecitabine to the pharmacokinetic-pharmacodynamic analysis made this an issue beyond the scope of the current article. However, we are currently planning a separate analysis that specifically looks into relationships between pharmacokinetic parameters and observed toxicity using a semiphysiological population-based modeling approach.
In conclusion, the oral combination of irinotecan with prolonged administration of capecitabine seems to be feasible. Overall, the observed antitumor activity in this heterogenous group of patients was somewhat disappointing, with three confirmed partial responses and a total of 16 patients demonstrating disease stabilization for 6 or more weeks. It should be emphasized, however, that the antitumor activity was observed in patients with malignancies that are known to be drug-refractory, including gallbladder carcinoma and melanoma, and that 82% of patients had at least one line of prior chemotherapy. Overall, this indicates that the current findings provide impetus for the development of this combination in phase II trials.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
O.S. and H.D. participated equally to this study.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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