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© 2003 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer
From the Cancer Research UK Clinical Centre at Leeds, Cookridge Hospital, Leeds LS16 6QB, and Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom. Address reprint requests to Matt Seymour, MA, MD, FRCP, Cookridge Hospital, Leeds LS16 6QB, UK; email: Matt.Seymour{at}cancer.org.uk.
Purpose: To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites. Patients and Methods: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m2 every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs. Results: Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m2. There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m2 and area under the curve (AUC)0-tn was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC0-24h were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level. Conclusion: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m2 every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.
IRINOTECAN (CPT-11), a topoisomerase I inhibitor, is a valuable cytotoxic agent for treatment of colorectal cancer. It has established roles as single-agent therapy after failure of fluorouracil (FU),1,2 and in combination with FU and leucovorin as first-line treatment for advanced disease.3,4 It is now being evaluated in clinical trials in the adjuvant setting. The dose-limiting toxicities of irinotecan are myelosuppression and delayed diarrhea. Diarrhea affects quality of life and, when combined with myelosuppression, can be life threatening, although aggressive management with loperamide and antibiotics reduces this risk. In a recent independent review of 44 early deaths in two trials of irinotecan in combination with bolus FU/leucovorin, patients on that treatment had a three-fold higher rate of treatment-induced or treatment-exacerbated death, compared with patients in other treatment arms.5 The pharmacokinetics and toxicity of irinotecan are unpredictable and may depend partly on genetic factors.6,7 Its clearance is highly variable and correlates poorly with body-surface area or weight.8 Nevertheless, an understanding of the metabolism and pharmacokinetics of irinotecan may identify several potential strategies aimed at improving its therapeutic index.9,10
Irinotecan is a prodrug that is activated by carboxylesterases, particularly hCE2, in many cells including liver and some tumors, forming the active metabolite SN38 (Fig 1
Ciclosporin (Cs), in addition to its role as an immunosuppressive agent, is an inhibitor of biliary excretion. Preclinical studies in rats have confirmed that Cs can inhibit the biliary excretion of irinotecan metabolites,17 probably through inhibition of MRP2 and MDR1.18 Cs is also a substrate for CYP3A4, so it could potentially affect irinotecan catabolism.19 Ratain et al have reported pharmacokinetic modulation in 53 patients who were given intravenous infusion Cs along with bolus irinotecan for 4 out of every 6 weeks. Dose-limiting diarrhea was seen in only one of nine patients at an irinotecan dose of 60 mg/m2 per week. Pharmacokinetic analysis confirmed reduced clearance (Cl) and increased half-life of irinotecan when compared with historical controls treated with irinotecan alone.16 The optimum dosing schedule of Cs as a pharmacokinetic modulator is not established. Absorption of oral Cs is variable, with mean systemic bioavailability of approximately 30% after administration of the simple gelatin capsule preparation.20 However, a newer Cs formulation, Neoral (Novartis Pharmaceuticals Corp, East Hanover, NJ), which undergoes microemulsification in water, improves oral bioavailability and reduces interpatient variability.21 Neoral has recently been demonstrated reliably to increase the systemic exposure to oral paclitaxel in a phase I trial.22 We performed a cohort-design phase I trial of fixed-dose oral Cs (Neoral) plus escalating doses of irinotecan. An administration schedule of every 2 weeks was chosen because in a previous large phase II study, irinotecan administration every 2 weeks appeared to have a preferable toxicity profile compared with the standard European schedule of every 3 weeks or the weekly schedule followed in the United States.23 The objectives of this trial were to determine the optimum irinotecan dose and the safety and tolerability of the combination in patients with metastatic colon cancer that had progressed despite at least one prior course of FU-based chemotherapy. In addition, we studied the effect of Cs on the pharmacokinetics of irinotecan and its metabolites. The underlying hypothesis was that by inhibiting biliary clearance of irinotecan and its metabolites, Cs would reduce the incidence of diarrhea and permit increased exposure of target tissues, leading to an increase in the therapeutic index of irinotecan. The new regimen was designated IrCs.
Patient Selection Patients were recruited after institutional scientific and ethical review, with written informed consent. They were required to have metastatic colorectal cancer that had progressed during or soon after at least one prior FU-containing regimen. Other chemotherapy drugs may have been given, and prior irinotecan was not absolutely excluded, but only two patients were entered after previous irinotecan treatment. Other eligibility criteria were age older than 18 years, no chemotherapy within the 3 weeks before trial entry, World Health Organization performance status 0 to 2, life expectancy more than 3 months, adequate complete blood count (hemoglobin > 10.0 g/dL; WBC > 3.0 x 109/L; platelets > 100 x 109/L), adequate renal function (glomerular filtration rate calculated by the Cockcroft formula, or measured by EDTA clearance > 60 mL/min), and adequate hepatobiliary function (bilirubin  1.25x upper limit of normal; AST or ALT 3x upper limit of normal).
Study Design and Treatment Oral Cs was given at 5 mg/kg every 12 hours (9 AM and 9 PM) for the first 3 days of a 14-day cycle. Patients were asked to avoid consuming grapefruit juice for at least 1 hour before each dose of Cs. On the second day of the cycle, patients attended the chemotherapy day unit, and irinotecan was given starting 4 hours after the third dose of Cs. The full dose of irinotecan was infused over 15 minutes (ie, at an infusion rate of 2.7 to 8.3 mg/m2/min depending on dose level, which is comparable with 3.9 to 11.7 mg/m2/min for standard United Kingdom and European infusion of 350 mg/m2 over 30 to 90 minutes). Cohort dose escalation was performed at irinotecan doses of 40, 50, 75, 100, and 125 mg/m2. The protocol demanded that a minimum of three patients should complete three cycles at a given dose level without dose-limiting toxicity (DLT), or a minimum of six patients if one DLT episode occurred, before entering patients at the next dose level. However, accrual to the study was not interrupted, so additional patients could be entered at a given dose level while treatment was underway for earlier patients. Intrapatient dose escalation was not used. The maximum-tolerated dose was predefined as the highest dose at which no more than two of six patients developed DLT. Complete blood count, and renal and hepatic biochemistry was performed 7 and 14 days after each irinotecan administration, with a full toxicity assessment including history and physical examination at the 2-week visit. Toxicity was scored using National Cancer Institute Common Toxicity Criteria version 2.0. DLT was defined as any grade 3 or 4 nonhematologic toxicity (excluding alopecia) or grade 4 hematological toxicity. A maximum of six cycles of treatment was administered on trial. Thereafter, patients with stable or responding disease on their reassessment computed tomography scan were considered for further treatment with the same regimen off trial.
Pharmacokinetics Plasma samples were obtained, relative to the start of the 15-minute irinotecan infusion, at 0, 15, 30, 60, 90, 120, 180, and 240 minutes and 24 hours. A single sample for blood Cs level was taken at time 0. Blood was collected into lithium heparin tubes and cold-centrifuged immediately (1,200 x g; 10 minutes), and plasma was stored at -40°C until high-performance liquid chromatographic analysis. For this analysis, 200 µL plasma was precipitated with 400 µL methanol and 5% perchloric acid (50:50), and after centrifugation, the supernatant was diluted 50:50 with mobile phase. A separate 200-µL plasma sample was incubated with 800 units H5 ß-glucuronidase (Sigma Chemicals, Poole, Dorset, United Kingdom) at 37°C for 90 minutes before precipitation. SN38G concentration was taken as the difference in the SN38 concentration before and after glucuronidase hydrolysis.
Chromatographic separation was achieved using a 5-µm octadecyl silane column (Hypersil, Jones Chromatography, Hengoed, Wales) with a mobile phase containing 0.1 M potassium dihydrogen phosphate, 5 mmol/L tetrabutyl ammonium sulfate (all pH 4.0), and 30% acetonitrile. Compounds of interest were monitored by fluorescence detection at 355 nm The extraction efficiency of the high-performance liquid chromatographic assay procedure was more than 80% at concentrations of 0.20 and 2.0 µg/mL irinotecan and 0.02 and 0.20 µg/mL SN38. The reproducibility of the assay for irinotecan and SN38 at these concentrations was more than 90%. A sample taken from a patient 1.5 hours after a 250 mg/m2 dose of irinotecan was run with each assay and gave mean pre- and post-beta-glucuronidase SN38 concentrations of 0.023% ± 11% and 0.073% ± 9.2%, resulting in a mean SN38G concentration of 0.049% ± 14.8%.
Pharmacokinetic analysis was carried out with Kinetica v4.0 software (Innaphase Corp, Philadelphia, PA) using noncompartmental methods. Area under the concentration-time curve (AUC) was determined by the trapezoidal method, using the linear rule for ascending concentrations and the log linear rule for descending concentrations. The AUC was extrapolated to infinity by dividing the concentration at 24 hours by the elimination rate constant ( Differences between pharmacokinetic parameters were investigated by Wilcoxon signed ranks matched pairs test. The data were also analyzed according to recommendations for bioequivalence studies.25 Derived pharmacokinetic parameters were log-transformed, and the mean and 95% confidence interval (CI) of the difference between log-transformed parameters with and without Cs was calculated. These values were then back-transformed to give an estimate of the geometric mean and 95% CI of the ratio. Parameters were considered equivalent when the CI for the ratio fell entirely within the range 0.80 to 1.25.
Forty-one patients were recruited over a 20-month period; 40 were from a single center. Four were withdrawn after registration but before receiving the first dose of irinotecan because of intercurrent illness or deterioration in biochemical eligibility parameters. Thirty-seven patients are therefore assessable (Table 1  ). This was a heavily pretreated population; 62% had received two or more prior chemotherapy regimens, and 57% had received other drugs in addition to FU/leucovorin.
The number of patients treated at each dose level is shown in Table 2 . A total of 157 cycles of IrCs were administered on trial, with 27 (73%) patients receiving the full planned trial of six cycles (five cycles for patients participating in the pharmacokinetic study, who also received one cycle of irinotecan alone). Seventeen patients, who had stable or responding disease, subsequently went on to receive additional cycles of IrCs off trial, up to a maximum of 16 cycles.
Dose Escalation and DLT Toxicities directly attributable to Cs, occurring before administration of irinotecan, were common and in keeping with the known toxicity profile of this drug. These included abdominal cramps, flushing, sweats, and paresthesia. In three patients, this was graded as severe (grade 3), in one case leading to withdrawal from the trial at the patient’s request. The only renal toxicity seen in this study was grade 1 in three patients. Some patients found the taste or smell of Cs capsules unpleasant, in which case they were offered, and usually preferred, the liquid formulation (Neoral oral solution). Irinotecan dose-escalation proceeded as planned up to level 5 (125 mg/m2). The most common DLT was neutropenia. Other common toxicities were alopecia (at the higher dose levels) and lethargy (at all dose levels), but diarrhea was rarely seen. There were no treatment-related deaths; only one patient died within 40 days of the last chemotherapy administration (at 22 days), with clearly documented disease progression and no evidence of myelosuppression or diarrhea.
Toxicity at each irinotecan level is shown in Table 2 At dose level 5 (irinotecan 125 mg/m2), dose-limiting neutropenia was encountered. Two thirds of the patients experienced grade 4 neutropenia, and one episode of febrile neutropenia occurred (with full recovery). Alopecia was universal at this level. Thus, dose level 4 (irinotecan 100 mg/m2 every 2 weeks) was identified as the MTD of irinotecan in this schedule and is the dose recommended for further study.
Antitumor Activity
Pharmacokinetics
For all patients, at each dose level, plasma concentrations of irinotecan increased when irinotecan was administered with Cs, resulting in increases in AUC (Figs 2
Cs also increased the plasma concentrations of SN38 and SN38G, resulting in an approximate doubling in AUC0-24h (Fig 3  ) and maximum concentration (Cmax) values. However, the relative amounts of metabolite formed (shown in Table 3 as molar ratios) was unchanged.
Median Cs level at the time of starting irinotecan infusion (4 hours after the third oral Cs dose) was 238 µg/L (range, 97 to 735 µg/L). Wide variability was seen in Cs levels at all irinotecan dose levels. The measured blood Cs level did not correlate with its pharmacokinetic level in individual patients as assessed by the change in AUC of SN38 (Fig 4A ). Conversely, there was no evidence that the trough Cs level was affected by irinotecan dose (Fig 4B).
Irinotecan is widely regarded as the first major advance in four decades for the nonsurgical management of colorectal cancer. However, its benefits are not without cost, and enthusiasm at its introduction into standard practice has been tempered by concerns about toxicity. In particular, unpredictable late diarrhea, sometimes coinciding with myelosuppression, has led to occasional toxic deaths.5 Strategies that reduce this toxicity will be of considerable value. This study used a rationally designed strategy that was based on knowledge of the metabolism of irinotecan, which was originally proposed by Ratain et al,16,24 to inhibit the biliary clearance of irinotecan metabolites. This strategy is now the subject of a United States patent.26 The hypothesis is that by reducing SN38 and SN38G clearance into the small bowel lumen, late diarrhea may be avoided or reduced. The lack of severe diarrhea observed in our study is encouraging and supports the study hypothesis. Only one patient out of 37 experienced grade 3 diarrhea, and we saw no grade 4 diarrhea. This compares favorably with recent phase III trials in which grade 3 or 4 diarrhea occurred in 22% of patients receiving the standard European schedule of 350 mg/m2 every 3 weeks,1,2 in 31% of patients receiving the standard North American schedule of 125 mg/m2 once per week for 4 weeks,4 and in 18.4% of patients receiving irinotecan once every 2 weeks at 250 mg/m2.23 The systemic toxicity profile of IrCs (myelosuppression, lethargy, or alopecia) was similar to irinotecan as a single agent. This confirms the success of the pharmacokinetic modulation because it demonstrates that active systemic drug levels were achieved despite the small doses being used. Cs itself added some toxicity (abdominal cramps, flushing or sweats, and paresthesia), which was usually brief and low grade, but in one patient was considered intolerable. The pharmacokinetic results were consistent with the clinical findings. In the absence of Cs, we observed mean irinotecan Cl of 13.4 ± 3.4 L/h/m2, which is in line with other reports describing Cl of 13.5 ± 3.5 L/h/m2 in phase I studies.9 In the presence of Cs, plasma irinotecan levels increased as a result of both reduction in plasma Cl and reduced Vd. Total irinotecan exposure (AUC) increased, in the presence of Cs, by factors of 2.2 to 2.3 for irinotecan, SN38, and SN38G. The effect is to bring the AUC achieved by 100 mg/m2 irinotecan into line with that expected after 250 mg/m2 standard-dose irinotecan alone. Thus, patients treated with 100 mg/m2 IrCs had a mean irinotecan AUC of 16.4 mg/mL • h (27.8 mmol/L • h). Data from all patients studied showed a mean AUC of 18.7 mg/mL • h (31.7 mmol/L • h) per 100 mg/m2 irinotecan administered. These values correspond closely with the previously published values for mean irinotecan AUC in patients receiving 230 to 260 mg/m2 irinotecan, without Cs, of 15.9 mg/mL • h (27.0 mmol/L • h)27 and 19.7 mg/mL • h (33.4 mmol/L • h).28 For comparison, irinotecan at 350 mg/m2 (the standard dose every 3 weeks) produces an irinotecan AUC of 24.7 mg/mL • h (41.9 mmol/L • h).29 The increase in irinotecan AUC in the presence of Cs was mirrored by increased AUC and Cmax values for SN38 and SN38G, which is again consistent with decreased hepatic clearance. Although these AUC values were altered by Cs, the ratio of each metabolite to the parent drug remained remarkably constant. This is in contrast to the previous study in rats, which reported similar conversion of irinotecan to SN38 in the presence of Cs but decreased glucuronidation to SN38G,17 and in humans, in which the ratio of SN38 and SN38G to parent drug were increased in the presence of Cs.16,24 Thus, the clinical dose determination, which was completed before analysis of the pharmacokinetic samples, resulted in a recommended irinotecan dose that produces approximately the same AUC of irinotecan and its metabolites as does single-agent irinotecan at the full dose of 250 mg/m2 every 2 weeks. In addition to reducing small bowel SN38 exposure, our strategy might potentially have reduced the interpatient variability in plasma pharmacokinetics of irinotecan and SN38 caused by variability in biliary clearance. In practice, this was not observed: the coefficient of interpatient variability (SD/mean, %) for irinotecan plasma clearance was similar in the absence or presence of Cs (25% v 26%, respectively), with similar observations for irinotecan AUC (26% v 25%), SN38 AUC (61% v 75%), and SN38G AUC (38% v 34%). It is possible that a greater pharmacokinetic effect might be achievable with higher or more consistent Cs exposure (for example, by intravenous Cs); however no correlation between Cs levels and pharmacokinetic effect was observed in this study. We found that irinotecan clearance in the presence of Cs was 43% of the single-agent clearance rate; this compares with 30% observed in a previous study24 using intravenous infusion Cs. The variability in blood Cs levels that we observed were consistent with its known bioavailability21 and, to the best of our knowledge, was not related to patient compliance. Interestingly, there was no apparent correlation between Cs levels and Cs side effects. Other oral Cs regimens could be considered: one group observed pharmacokinetic modulation of paclitaxel using a single high dose (15 mg/kg) administered 10 minutes before paclitaxel.22 Another alternative would be to explore other drugs that interfere with biliary transport. PSC833 is a nonimmunosuppressive, non-nephrotoxic derivative of ciclosporin D, which can also inhibit MDR1. In P-glycoprotein-deficient mice, PSC833 significantly reduced biliary transport of SN38 and SN38G.30 However, like Cs, PSC833 also has highly variable oral bioavailability,31 and it may be less active than Cs as an inhibitor of MRP2.32
In addition to its effects on biliary clearance, Cs may have influenced metabolic clearance of irinotecan through CYP3A4 (Fig 1 Although not a defined end point of this trial, the antitumor activity observed in this patient group is encouraging, even when we include patients treated at all dose levels, and is consistent with the activity of single-agent irinotecan at standard doses. For more than 60% of the patients on this study, IrCs was being offered as third- or even fourth-line treatment, and yet objective partial responses occurred in 11% of patients, with evidence of clinical benefit (response or stable disease for more than 12 weeks) in 57% of patients. The median progression-free and overall survival times of 3.7 and 7.9 months, respectively, are also consistent with full-dose single-agent irinotecan. The recent multicenter phase II trial of single-agent irinotecan at 250 mg/m2 every 2 weeks as second-line therapy gave responses in 12% of 99 patients, with median progression-free and overall survival of 4.5 and 9.2 months, respectively.23 A randomized trial would be required to compare activity before the IrCs regimen could be recommended outside clinical trials. Health economics was not an end point of this trial. However, it is an accidental consequence of reduced irinotecan clearance and, therefore, dose to reduce the cost of treatment. At current prices in the United Kingdom, the approximate drug costs (including Cs and antiemetics) for IrCs at the recommended doses for a 1.8-m2 patient are UK £370 per 2-week cycle or £2,220 for a 12-week course. In comparison, the drug costs per 12 weeks for single-agent irinotecan at 250 mg/m2 per 2-week cycle are £4,160, whereas the European standard dose schedule of irinotecan 350 mg/m2 every 3 weeks costs £4,000 (exchange rates as of January 2003: UK £1.00 = US $1.61 = European €1.51). Irinotecan is now commonly used in combination with FU/leucovorin,4 and current studies are investigating its use with oral FU prodrugs, especially capecitabine.34 Strategies to reduce irinotecan toxicity will be of particular interest if they can be incorporated into these combination schedules. In vitro studies assessing the transepithelial transport of irinotecan have suggested that Cs may increase the oral absorption of irinotecan,35 raising the possibility of an all-oral regimen—capecitabine, irinotecan, and Cs—for colorectal cancer. Our data support the hypothesis that oral Cs alters the pharmacokinetics of irinotecan, possibly by reducing biliary clearance of irinotecan metabolites. Our preliminary toxicity data would also support the prediction that this approach may reduce the dose-limiting diarrhea seen with single-agent irinotecan, although further studies would be needed to optimize scheduling, to compare the efficacy of the combination with standard schedules, and thereby to establish whether the therapeutic index of irinotecan is improved by this strategy.
This protocol was developed at the 1st EORTC/AACR/ASCO Cancer Clinical Trials Workshop, Flims, Switzerland, July 1999. We thank Stan Kaye, Gary Clark, and Marie-Christine Bissery for their help in its preparation at that time.
Supported by Cancer Research UK and by the Cookridge Hospital Gastrointestinal Research Unit Fund.
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17. Gupta E, Safa AR, Wang X, et al: Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A. Cancer Res 56:1309–1314, 1996 18. Foxwell BM, Mackie A, Ling V, et al: Identification of the multidrug resistance-related P-glycoprotein as a cyclosporine binding protein. Mol Pharmacol 36:543–546, 1989[Abstract] 19. Kivisto KT, Kroemer HK, Eichelbaum M: The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: Implications for drug interactions. Br J Clin Pharmacol 40:523–530, 1995[Medline] 20. Fahr A: Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 24:472–495, 1993[Medline]
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29. Canal P, Gay C, Dezeuze A, et al: Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 14:2688–2695, 1996 30. Iyer L, Ramirez J, Shepard DR, et al: Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice. Cancer Chemother Pharmacol 49:336–341, 2002[CrossRef][Medline] 31. Lush RM, Meadows B, Fojo AT, et al: Initial pharmacokinetics and bioavailability of PSC 833, a P-glycoprotein antagonist. J Clin Pharmacol 37:123–128, 1997[Abstract]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
ex and at more than 460 nm 
) and 
