Annals of Oncology Advance Access originally published online on April 6, 2006
Annals of Oncology 2006 17(7):1158-1165; doi:10.1093/annonc/mdl071
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© 2006 European Society for Medical Oncology
A phase I dose-finding clinical pharmacokinetic study of an oral formulation of irinotecan (CPT-11) administered for 5 days every 3 weeks in patients with advanced solid tumours
1 Department of Clinical Oncology, UZ Gasthuisberg, Leuven, Belgium; 2 Institut Jules Bordet, Brussels, Belgium; 3 Aventis Pharma, Antony, France; 4 University of Utrecht, The Netherlands
* Correspondence to: Dr H. Dumez, Department of Clinical Oncology, UZ Gasthuisberg, Herestraat 49, B-3000 Belgium, Tel: +32-16346903; Fax: +32-16346901; E-mail: Herlinde.Dumez{at}uz.kuleuven.ac.be
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Abstract |
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Background: Oral administration of irinotecan (CPT-11) should allow sustained exposure to the drug without the inconvenience of intravenous delivery and with fewer side-effects.
Patients and methods: The present phase I trial of CPT-11, administered orally as a powder-filled capsule for 5 consecutive days every 3 weeks at doses ranging from 30 to 90 mg/m2/day, was conducted in 47 patients for whom a satisfactory standard treatment option was no longer available (24 males/23 females; median age 51 years, range 26–85). Tumour types included melanoma (11), colorectal (4), urinary tract (3), lung/pleura (4), thyroid (3), liver (3), gallbladder (2), cervix/uterus (3), breast (2), pancreas (2), carcinoma and other cancer types (10).
Results: A total of 171 cycles were administered (median 3, range 1–11). Dose limiting toxicities (DLTs) occurred during the first cycle in five of 31 patients in the dose-escalation part of the study: one patient at the 50 mg/m2/day dose level (diarrhoea grade 4); one patient at the 80 mg/m2/day dose level (prolonged neutropenia grade 4 and diarrhoea grade 3); and three patients at the 90 mg/m2/day dose level (diarrhoea, vomiting and neutropenia). The 80 mg/m2/day dose level was expanded, as a feasibility study, to include 16 additional patients, five of whom had received extensive prior pelvic irradiation. A further three patients in this cohort experienced DLTs, two of whom had received extensive prior pelvic irradiation. One patient died on study day 15 during the first cycle of oral CPT-11 following grade 3 diarrhoea, febrile neutropenia and a necrotic enterocolitis. Overall the grade 3/4 toxicities in 47 patients were asthenia (19%), anorexia (17%), neutropenia (14.9 %), diarrhoea (13%), nausea (12.7%), vomiting (8.5%) and thrombocytopenia (8.5%). Partial responses were observed in two melanoma patients and disease stabilisation was noted in 17 (36.1%) patients. Pharmacokinetic parameters were recorded for 46 patients.
Conclusions: At the maximum tolerated dose, defined as 80 mg/m2/day for 5 days every 3 weeks, oral CPT-11 was shown to be well tolerated and safe with few of the haematological toxicities associated with the intravenous formulation.
Key words: CPT-11, dose-escalation, dose-limiting toxicity, irinotecan, oral, powder-filled capsule
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introduction |
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Irinotecan (CPT-11, Campto®) is a semi-synthetic derivative of the natural alkaloid camptothecin, and is a potent inhibitor of the enzyme topoisomerase-I [1
, 2]. In clinical studies, CPT-11 has demonstrated single-agent activity against a spectrum of solid tumours, particularly colorectal, including those resistant to 5-fluorouracil (5-FU)-based therapy [3–10]. Two pivotal phase III trials of CPT-11, in combination with bolus and infusional 5-FU plus folinic acid (FA), were therefore performed in the first-line treatment of advanced and metastatic colorectal cancer [11, 12]. Both demonstrated the superiority of the CPT-11 combination over the corresponding 5-FU/FA-control regimen in terms of response rate, time to progression and overall survival. Consequently, CPT-11 in combination with either a bolus or infusional 5-FU/FA regimen has been approved in both Europe and the US for the first-line treatment of advanced and metastatic colorectal cancer.
CPT-11 is one of the most active agents in both the first- and second-line treatment of colorectal cancer and a variety of CPT-11 schedules continue to be investigated, principally in combination with 5-FU/FA, but more recently with oxaliplatin [13–15] and the oral fluoropyrimidines capecitabine and UFT-tegafur [16–18].
In vivo, CPT-11 is converted to its active metabolite SN-38 [19, 20]. The highest dose intensity of CPT-11 is achieved by short infusions every 2 or 3 weeks [21, 22], and the lowest with protracted continuous infusion schedules. The efficacy of CPT-11 is known to be dose-dependent and seems also to be schedule-dependent, with prolonged low-dose administration being more effective than short duration high-dose schedules [25, 26]. This is consistent with the known S-phase specificity of CPT-11; a longer infusion duration results in more cells being exposed to CPT-11 during S-phase [27].
An alternative approach to prolong exposure is to use the oral route. This also avoids the technical difficulties associated with a protracted infusion, and patients are known to prefer oral to intravenous administration, provided that the efficacy of the drug is not compromised [28].
To date, the efficacy of orally administered CPT-11 has been demonstrated in a preclinical study of childhood neuroblastoma xenografts [29], and in a phase I study of 20–100 mg/m2 for 5 days every 3 weeks in patients with previously treated refractory tumours [30]. A confirmed partial response was seen in a colorectal cancer patient previously treated with 5-FU. The biological activity and favourable pharmacokinetic (PK) profile has led to further clinical studies of oral CPT-11 using the same [31, 32] and alternative schedules [33, 34].
The present dose-finding study of oral CPT-11 was conducted using the schedule described above. The aim was to determine the maximum tolerated dose (MTD) for further phase II/III studies, the dose-limiting toxicities (DLTs), particularly gastrointestinal toxicities, and to document any evidence of activity. The PK profile in plasma and erythrocytes of orally administered CPT-11 was also investigated.
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patients
Patients were eligible if they had a pathologically confirmed solid tumour for which no standard therapy was available. Inclusion criteria included: age
18 years, WHO performance status 
2, life expectancy of 12 weeks, normal values for absolute neutrophil count (2 x 109/l), haemoglobin (10 g/l), platelets (150 x 109/l), liver function [serum bilirubin within the normal institutional ranges, aspartate aminotransferase (AST) 3 x the upper limit of normal (ULN) in the absence of liver metastases, and AST 5 x ULN in the presence of liver metastases], and serum creatinine 1.5 mg/dl (135 µmol/l). No prior anticancer therapy was permitted within 4 weeks of study entry (6 weeks for nitrosourea or mitomycin C). Patients had to be able to swallow normally and take capsules. Patients were excluded in cases of leukaemia or lymphoma, prior treatment with high-dose chemotherapy with progenitor blood cell transplantation, prior treatment with CPT-11, brain metastases or carcinomatous leptomeningitis, concomitant infection (including prior documentation of HIV positivity) or severe organ failure, active inflammatory bowel disease, or evidence of alcoholism or addiction. The study was conducted in two centres with full local ethics committee approval. All patients provided written informed consent.
treatment
CPT-11 (Aventis Pharma, Antony, France) was supplied as powder filled capsules (PFC) containing 5 mg, 20 mg or 50 mg, for oral administration. The gelatin PFCs were administered orally with a glass of tap water, after at least 4 h of fasting and at least 1 h prior to the next meal, once/day for 5 consecutive days every 3 weeks.
The starting dose was 30 mg/m2/day, 60% of the MTD of the intravenous formulation administered orally on 5 consecutive days [30]. The planned dose levels were 30, 40, 50, 60, 70, 80 and 90 mg/m2/day, with the increases to be made in a stepwise fashion in cohorts of at least three patients. A treatment course was defined as 5 consecutive days of CPT-11 administration, and a treatment cycle was a treatment course plus the time needed for recovery from any toxicities. A minimum of 1 week was required between the entry of the first patient and the entry of the subsequent two patients at any given dose-level. Before dose escalation, all three patients had to receive at least one treatment cycle. The first patient was observed for cumulative toxicity or any new grade 2 toxicity for at least 1 week into the second cycle. If toxicity occurred, an extra week of observation was required prior to dose escalation. The second and third patients were observed for at least 3 weeks from the start of the treatment cycle.
A DLT was defined as any of the following events, according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC), attributable to oral CPT-11 and observed during cycle one: grade 4 neutropenia lasting longer than 5 days; neutropenic fever (grade 4 neutropenia with grade 2 fever); neutropenic infection (grade 4 neutropenia with grade 3 infection or documented infection); grade 4 thombocytopenia; diarrhoea grade 3 despite the use of loperamide; nausea or vomiting grade 3 despite maximal oral anti-emetic therapy; or any non-haematological toxicity grade 3, except alopecia.
If no patients experienced significant toxicity (one grade below DLT) or DLT at the first dose level, then the dose was escalated in the next three patients. Treatment at any dose level could be continued until tumour progression, unacceptable toxicity or patient refusal. If one of three patients experienced significant toxicity (one grade below DLT) or DLT, then three more patients were accrued at the same dose level. If none of these additional patients experienced DLT, then the dose was escalated for the subsequent three patients. No intra-patient dose escalations were allowed. Once a DLT occurred CPT-11 was stopped. If one of the three additional patients experienced DLT, the MTD was considered to have been exceeded, and further patients were recruited into the dose level immediately below. The MTD was considered to have been reached if zero or one of six patients experienced DLT, with at least two of three or six patients at the next dose level experiencing DLT.
feasibility step
Once the MTD was confirmed, additional patients were enrolled at this dose level to ensure that this dose was feasible for phase II/III studies. Six cycles of therapy were planned in order to detect any cumulative toxicity. A group of patients with prior extensive pelvic radiation therapy was also selected, in order to establish whether this treatment reduced tolerability, thereby necessitating redefinition of the MDT in this patient group.
patient evaluation
All pretreatment evaluations were conducted within 2 weeks prior to the start of treatment. These included a complete medical history and physical examination, WHO performance status, blood count, biochemical profile, tumour markers, chest X-ray and staging using radiographic imaging.
The first dose of each cycle was administered in hospital, and on the first cycle patients were monitored for 10 h for symptoms of early cholinergic syndrome. A complete blood count was obtained on day 5 of the first cycle and twice weekly thereafter, until recovery. Blood chemistry and toxicity assessments were made on days 8 and 15 of the first cycle and weekly thereafter, until recovery. On the second and subsequent treatment cycles, patients were assessed on day 1 (pre-dose) by physical examination and with blood counts, blood chemistries, serum markers and toxicity assessment, and on days 8, 15 and weekly thereafter until recovery. Tumour assessments were performed after every two courses by physical examination and repeat radiological examination using the same pretreatment technique. Response to therapy was assessed according to ‘WHO Criteria for Evaluation of Response’. All adverse events were graded according to NCI-CTC. Loperamide was not given routinely, only with development of diarrhoea. Initially 4 mg was given, followed by 2 mg every 2 h until the diarrhoea had ceased for at least 12 h (4 mg was permitted every 4 h at night). Prophylactic anti-emetics were not administered on the first day of the first course of treatment, but could be given on subsequent treatment days and in the following cycles. However, prophylactic anti-emetics were used on the first cycle onwards in the feasibility step. The routine use of growth factor support was not recommended, but could be given for recurrent neutropenia or infectious complications during neutropenic episodes. Similarly, atropine could be administered as required for the treatment of cholinergic syndrome, but not prophylactically.
bioanalytical procedure
A slightly modified version of the method described by Chollet et al. [35] was used to analyse CPT-11 and its metabolite SN-38.
As the active lactone forms of both CPT-11 and SN-38 exist in pH-dependent equilibrium with their respective less potent open-ring hydroxy acid species, the simultaneous monitoring of both forms of both compounds is relevant. CPT-11 and SN-38 derivatives have quite different fluorescence responses. To avoid any compromise on the wavelength setting, we developed chromatographic conditions allowing simple automated wavelength setting changes, which are not possible with existing methods involving conventional C-18 columns. A gradient elution programme, using acetonitrile and 75 mM ammonium acetate plus 7.5 mM tetrabutylammonium bromide at pH 6.4, was employed with a Symmetry C-18 column. These conditions allowed an elution order suitable for a simple automated wavelength change and reliable peak integration. CPT-11 and SN-38 derivatives were detected at 
(x) = 362 nm/(m) = 425 nm and (x) = 375 nm/(m) = 560 nm respectively. The method allowed the detection of less than 3 pg of each derivative injected on column, and was successfully applied to plasma pharmacokinetic studies.
For the simultaneous analysis of substances in both RBC and plasma (n = 5; total number of samples n = 250), a slightly revised method according to De Jong et al. [36] was used.
Sample pretreatment involved deproteinisation of whole blood or plasma-diluted RBCs isolated by the MESED instrument, with a mixture of aqueous perchloric acid and methanol (1:1, v/v). Separation was carried out using isocratic elution on a Hypersil ODS stationary phase, with detection at excitation and emission wavelengths of 355 and 515 nm, respectively. The lower limit of quantitation in blood was 5.00 ng/ml for both compounds, with values for within-run precision and between-run precision of less than 10%.
pharmacokinetics
The pharmacokinetics of CPT-11 and its metabolite SN-38 in plasma were evaluated in all patients on days 1 and 5 of the first cycle during the dose-escalation and feasibility steps, and on day 1 of the third cycle of the feasibility step. Heparinised blood samples (7 ml) were collected before administration on day 1, at 15, 30, 60 and 90 min and 2, 3, 4, 6, 8, 10 and 24 h after the first oral dose (prior to administration on day 2), and up to 48 h after the day 5 administration. Blood samples were immediately chilled on ice, centrifuged, and plasma removed and stored at –30°C until analysis. In five patients in the dose escalation step, 1 ml of blood was transferred into a MESED instrument at all the sample time points for separation of red blood cells and plasma. Both fractions were frozen at –20°C until analysis.
Urine samples were also collected prior to dosing, over 0–10 h and 10–24 h periods after the first administration and up to 48 h following administration on day 5 of the first cycle. CPT-11 and SN-38 concentrations were measured, as total lactone forms, by a reverse-phase HPLC method using fluorescence detection. The limit of quantitation was 1.00 ng/ml for both compounds. Pharmacokinetic analysis was carried out by non-compartmental analysis using WinNonlin software (Pharsight, version 3.3). The following parameters were calculated: Cmax; tmax; the area under the plasma concentration time profile estimated by the linear-logarithmic trapezoidal method from time 0 to the last quantifiable concentration [AUC (0–t)], or over one dosing interval [AUC(0–24 h)] and, when possible, extrapolated to infinity (AUC); and the apparent terminal half-life (t1/2). Accumulation of CPT-11 was calculated by dividing the AUC (0–24 h) on day 5 by the AUC on day 1. For SN-38, the percentage of extrapolated AUC was higher than 25% in 70% of the patients, and therefore the AUC on day 1 is not reported and the accumulation ratio of SN-38 was calculated by dividing the AUC (0–t) on day 5 by AUC (0–t) on day 1. The statistical analysis was undertaken using SAS software (version 8.2).
To compare the pharmacokinetic parameters on days 1 and 5 of cycle 1, a SAS PROC mixed procedure was carried out after logarithmic transformation of the dose normalised Cmax and exposure [AUC (0–t) for SN 38; AUC on day 1 and AUC (0–24 h) on day 5 for CPT-11), with the patient taken as the ‘random effect’ and the day of treatment as the ‘fixed effect’.
At the recommended dose (80 mg/m2/day), the intra-patient variability in dose normalised CPT-11 and SN-38 Cmax, CPT-11 AUC or SN 38 AUC (0–t) were estimated using the SAS PROC mixed procedure after log-transformation, with the patient taken as the random effect and the cycle (day 1–cycle 3 versus day 1–cycle 1) as the fixed effect.
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patient characteristics
Thirty-one patients were enrolled into the dose-escalation step and 16 into the feasibility step, which was subdivided into two subsets F1 and F2. Five of the patients in the feasibility step had received extensive pelvic radiation therapy and were evaluated as a separate subset (F2), with the other 11 patients forming the F1 subset. The previous treatment histories of the F1 cohort were similar to those of patients recruited into the dose escalation step. The characteristics of all the patients are summarised in Table 1.
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In total 24 male and 23 female patients were included, with a median age of 51 years (range 26–85 years). Two patients had received no prior therapy. Forty-five patients had received prior chemotherapy and 21 patients had received prior combined chemotherapy and radiotherapy. The median number of prior chemotherapy regimens for advanced disease was 2 (range 0 to
5), and the median time from diagnosis to study entry was 25.1 months. All 47 patients were evaluable for toxicity and 41 were evaluable for response. Of the six patients not assessable for response, five had their therapy discontinued after one or two cycles due to toxicity.
dosing
The number of patients treated at each dose-level during the dose-escalation step is presented in Table 2. A total of 105 cycles of therapy were administered and the median number of cycles per patient was three (range 1–8). The total number of cycles administered to all patients (dose-escalation plus feasibility step) was 171, with the median number of cycles per patient again being three (range 1–11). The patients in the feasibility step received 80 mg/m2/day; 56 cycles (median 4, range 1–11) and 10 cycles (median 2, range 1–4) were given to the F1 and F2 cohorts, respectively.
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dose-limiting toxicities
No DLTs were observed during the first cycles of the dose-escalation at the 30, 40, 60 and 70 mg/m2/day dose levels. One patient receiving 50 mg/m2/day experienced grade 4 diarrhoea and grade 3 asthenia and anorexia. Four additional patients were treated at this dose level, but no further DLTs occurred. DLTs were reported in one of six and three of five patients at the 80 mg/m2/day and 90 mg/m2/day dose levels, respectively. At the former level, one patient experienced grade 4 neutropenia lasting more than 5 days, grade 3 diarrhoea and grade 3 anorexia plus grade 3 nausea. Treatment was therefore stopped after the first cycle. At the 90 mg/m2/day dose level three patients experienced DLTs: the first had grade 3 diarrhoea, grade 4 vomiting, grade 4 asthenia and grade 4 anorexia, the second experienced grade 3 diarrhoea, and the third had grade 4 neutropenia lasting more than 5 days, which led to a dose reduction. Apart from neutropenia, the DLTs were predominantly gastrointestinal toxicities.
The MTD was 80 mg/m2/day and this dose level was expanded for the feasibility step. Three DLTs occurred in the 16 patients in the feasibility step subsets F1 and F2. One heavily pretreated 67-year-old in subset F1, who had a Merkel cell carcinoma with lymph node and liver metastases, developed grade 3 diarrhoea and died from septic shock, which was considered drug related. One patient in the F2 subset had grade 3 asthenia, and a second grade 4 diarrhoea, grade 4 neutropenia lasting more than 5 days and grade 4 thrombocytopenia. In both cases, treatment was stopped after one cycle. One patient in the F1 subset and two in the F2 subset required a dose reduction, and seven patients in the former group and two in the latter group had a dose delay of more than 3 days. The relative dose intensity was 96% in the F1 subset and 88% in the F2 subset.
overall tolerability
All 47 patients were evaluable for toxicity. No haematological toxicities were observed up to 80 mg/m2/day, except for one patient at 50 mg/m2/day. Grade 4 neutropenia was reported in two of 31 patients in the dose-escalation; one at 80 mg/m2/day and one at 90 mg/m2/day. Grade 3 febrile neutropenia and grade 4 thrombocytopenia was reported in one patient in the feasibility step. The grade 3/4 haematological toxicities in all patients at all dose levels are summarised in Table 3.
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Gastrointestinal toxicity was dose-limiting in six of the eight patients who experienced DLT during both the dose-escalation and feasibility steps.
anti-tumour activity
Two confirmed partial responses (4.25%) were documented in melanoma patients, one at 40 mg/m2/day (six cycles), and the other at 80 mg/m2/day (seven cycles) in the feasibility study. Seventeen (36%) of the 47 patients had stable disease.
pharmacokinetics
The pharmacokinetic parameters of CPT-11 and SN-38 were determined in 46 patients on days 1 and 5 of the first cycle. Absorption was rapid, with peak plasma concentrations of both CPT-11 and SN-38 occurring within 1.5–3 h on days 1 and 5 (Tables 4 and 5). Despite a high inter-patient variability, a near linear relationship between the dose of CPT-11 and Cmax of both CPT-11 and SN-38 on days 1 and 5 was seen.
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Significant increases in the Cmax (40%, P = 0.004) and exposure (51%, P = 0.002) of CPT-11 was observed when comparing days 1–5. However, the Cmax of SN-38 remained unchanged between day 1 and day 5, whilst the AUC (0–t) of SN-38 only increased by 33% on day 5 (P = 0.01), but this is likely to be an overestimate because the AUC extrapolated to infinity could not be calculated on day 1. Similar results were obtained when only patients treated at the recommended dose of 80 mg/m2/day were considered. Significant increases in the Cmax (41%, P = 0.01) and AUC (54%, P = 0.006) of CPT-11 were seen. SN-38 Cmax remained unchanged, but a statistically significant increase of 42% in AUC (0–t) was observed (P = 0.03).
On comparing the pharmacokinetic parameters after the first administration of 80 mg/m2/day on cycles 1 and 3 (seven patients, data not presented), no cycle effect was observed. At this dose level, the intra-patient variability of CPT-11 Cmax and AUC was 26% and 37%, respectively. The intra-patient variability of SN-38 was higher, with 41% for Cmax and 90% for AUC (0–t). The metabolic ratio [AUC (0–t) SN-38/AUC (0–t) CPT-11] was 0.1 ± 0.1 (mean ± SD) on day 1 and 0.09 ± 0.08 on day 5, and was stable over the dose range investigated.
CPT-11, but not SN-38, whole blood concentrations were significantly higher on day 5 compared with day 1 (P = 0.007, paired Student t-test). A linear relationship was established between the Cmax of CPT-11 in plasma and the red blood cell (P < 0.0001), but was not found for SN-38.
Urinary excretion of CPT-11 0–24 h post-dosing on day 1 accounted for 1.25 ± 1.42% of the administered dose and for 1.39 ± 2.30% 0–48 h post-dosing on day 5. SN-38 recovery represented 0.071 ± 0.062% and 0.077 ± 0.075% of the CPT-11 dose on days 1 and 5, respectively.
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Currently CPT-11 is routinely administered intravenously either as a single agent or in combination with 5-FU/FA and/or oxaliplatin to treat advanced colorectal cancer, using a variety of different schedules [10
–12]. The DLTs following intravenous administration irrespective of schedule are diarrhoea, with or without neutropenia. Severe grade 3/4 diarrhoea or neutropenia occurs in about 22% and 20% of patients, respectively. The DLTs in eight of the 47 patients given the oral PFC formulation in this study were diarrhoea (12.7%), neutropenia (4.2%), complicated neutropenia (4.2%), thrombocytopenia (2.1%), vomiting (2.1%), anorexia (6.4%) and asthenia (6.4%), with six patients having more than one DLT. These figures are consistent with our previously published preliminary observations [31], and with those of a US study using the same schedule [33]. This US study recommended 50 mg/m2/day for 5 consecutive days every 3 weeks [33]. The recommended dose for daily oral CPT-l1 for 14 days every 3 weeks is 30 mg/m2/day, which represents a total dose of 420 mg/m2 [34]. In the present study, the recommended dose for oral CPT-11 as a PFC is 80 mg/m2/day for 5 consecutive days every 3 weeks representing, a total dose of 400 mg/m2; a more favourable toxicity profile was also seen compared to the US study.
A large inter-patient variability in the pharmacokinetic parameters was observed over the dose range investigated. The Cmax of both CPT-11 and SN-38 in plasma on days 1 and 5 increased significantly with the dose of CPT-11, and a moderate accumulation of CPT-11 and SN-38 was observed between days 1 and 5, resulting in a 54% and 42% increase, respectively, in exposure at the recommended dose. There was no accumulation when CPT-11 formulated as a PFC (as in the present study) was administered once a day for 14 consecutive days at a lower daily dose than in the present study [32].
The pharmacokinetics remained unchanged throughout three consecutive cycles. The mean relative metabolic ratio of total SN-38 AUC to total CPT-11 AUC was stable over the dose range investigated. Thus, the fraction of the drug metabolised to SN-38 was unaffected by dose. The metabolic ratio (9%–12%) was similar to that observed in other studies when CPT-11 was given orally, but was much higher than that reported after a bolus or short intravenous infusion (3%–5%) [38].
The systemic exposure to CPT-11 following oral administration during one cycle (3 weekly) at the recommended dose of 80 mg/m2/day in the present study was approximately 18% of the exposure measured after the intravenous administration of 350 mg/m2 during one cycle (3 weekly) [39]. Allowing a two to four-fold higher metabolic ratio for the oral route compared with a short intravenous infusion, the cumulative exposure to the active metabolite SN-38 would be approximately 35%–70% of the exposure after 350 mg/m2 CPT-11 administered intravenously. Urinary excretion of CPT-11 and SN-38 after five daily oral administrations were 10 and three-fold lower, respectively, than those estimated (14%) after intravenous administration [38].
The preliminary antitumour data reported here suggest that the efficacy of the oral schedule is not dissimilar to that achieved with the intravenous schedules of previous phase I studies. Two partial responses were seen, and 36.2% of patients achieved stable disease. These response rates are in keeping with those of phase I trials of a 14-day continuous low-dose intravenous infusion [23], and of oral administration of an intravenous solution of CPT-11 given daily for 5 days every 3 weeks, which reported a partial response in one (4%) and stable disease in 17 (61%) of 28 patients with solid tumours [30]. Similarly, another phase I study of CPT-11 administered as a PFC daily for 14 days every 3 weeks in mixed solid tumours reported disease stabilisation in 10 of 19 patients (53%) [34]. As different schedules have reported similar response rates [23, 31, 37], the optimal administration schedule for oral CPT-11 should be based on toxicity and convenience.
The development of oral fluoropyrimidines should improve the quality of life for patients with colorectal cancer. In randomised phase III comparisons with 5-FU/FA regimens, both capecitabine (Xeloda®) and UFT have demonstrated essentially equivalent survival with decreased toxicity [40–42] and, currently, intravenous CPT-11 is being investigated in combination with oral fluoropyrimidines [16–18, 43]. The development of oral CPT-11 raises the possibility of future chemotherapeutic strategies, for the treatment of colorectal cancer in particular, based on oral fluoropyrimidines in combination with oral CPT-11, which should optimise the cancer cell exposure to cytotoxic drugs, reduce toxicity and be more convenient and therefore potentially improve quality of life.
Received for publication January 18, 2006. Revision received February 27, 2006. Accepted for publication March 2, 2006.
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