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Annals of Oncology Advance Access published online on January 20, 2007
Annals of Oncology, doi:10.1093/annonc/mdl481
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© 2007 European Society for Medical Oncology

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I–II study

I Chau1, D Cunningham1,*, T Hickish2, A Massey1, L Higgins1, R Osborne3, N Botwood4 and A Swaisland4

1 Department of Medicine, Royal Marsden Hospital, London and Surrey
2 Department of Oncology, Royal Bournemouth and Poole Hospital, Dorset
3 Department of Oncology, Poole Hospital, Dorset
4 AstraZeneca, Macclesfield, UK

* Correspondence to: Prof D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-661-3156; Fax: +44-208-643-9414; E-mail: david.cunningham{at}rmh.nhs.uk


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Appendix
 Acknowledgements
 References
 
Background: To establish the recommended dose level (RDL) and to evaluate the efficacy and safety of gefitinib plus irinotecan in patients with advanced fluoropyrimidine-refractory colorectal cancer (CRC).

Patients and methods: Patients with advanced CRC progressing on or within 12 weeks of fluoropyrimidine-based chemotherapy, irinotecan naive and performance status of two or less were recruited. During dose-finding phase, dose-limiting toxicity (DLT) was encountered at dose level 1, therefore subsequent dose de-escalation and pharmacokinetic (PK) studies were carried out. The RDL was then expanded in a multicentre setting to further evaluate safety and efficacy.

Results: From June 2002 to February 2005, 39 patients were treated in total with 27 at the RDL. The RDL was established at irinotecan 225 mg/m2 every 3 weeks and gefitinib 250 mg daily. The DLTs were neutropenia and diarrhoea. For the patients treated at RDL, the objective tumour response rate was 11.1% (95% confidence interval 2.4% to 29.2%) and median survival was 9.3 months. PK studies indicated that the addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib (P < 0.05), but gefitinib did not alter the PK profiles of irinotecan or SN-38. Grade 3–4 toxic effects in all patients included diarrhoea (35.9%), lethargy (15.4%), neutropenia (15.4%), febrile neutropenia (10.3%) and skin rash (7.7%).

Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan.

colorectal cancer, epidermal growth factor receptor, gefitinib, irinotecan


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Appendix
 Acknowledgements
 References
 
Irinotecan has been established as standard therapy in patients with fluoropyrimidine-refractory colorectal cancer (CRC) on the basis of two randomised studies demonstrating survival benefit over best supportive care or alternative schedules of infused fluorouracil [1, 2]. Median survival of only 9–11 months, however, was reported in phase III studies for irinotecan monotherapy [1–4].

Epidermal growth factor receptor (EGFR) is relevant in CRC because expression or up-regulation of the EGFR gene occurs in 60–80% of cases [5–7] and is associated with poor survival [8, 9]. Targeting EGFR pathway using a monoclonal antibody, such as cetuximab, has already been shown to be a valuable treatment in advanced CRC [10]. Gefitinib (AstraZeneca, Macclesfield, UK) is an orally active, EGFR tyrosine kinase inhibitor (TKI). In phase I studies, gefitinib treatment resulted in prolonged disease stabilisation or significant fall in carcinoembryonic antigen in patients with CRC [11–14]. In a phase II study, gefitinib was given to 28 patients at a daily dose of 750 mg [15]. One-third of assessable patients had less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions, but no objective responses were observed. Pharmacodynamic correlative work from this phase II study, however, indicated that gefitinib was biologically active in metastatic CRC [16].

In preclinical studies, irinotecan plus gefitinib has shown supra-additive activity in both human CRC [17] and paediatric solid tumour xenograft models [18]. In our clinical study, we aimed to determine the dose-limiting toxicity (DLT) of irinotecan and gefitinib administered in combination and from this to establish maximum tolerated dose (MTD) and to assess the antitumour activity of the combination of irinotecan and gefitinib.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Appendix
 Acknowledgements
 References
 
This study was approved by the local research and ethics committee of each participating institution. All patients enrolled signed a written consent form. Eligibility criteria included: histologically proven colorectal adenocarcinoma not amenable to curative surgery or radiotherapy; age ≥18 years; World Health Organisation performance status zero, one or two; unidimensionally measurable disease outside previously irradiated field as assessed by computed tomography (CT) according to the response evaluation criteria in solid tumors (RECIST) guidelines [19]; documented evidence of disease progression by CT within 12 weeks of the previous fluoropyrimidine or thymidylate synthase inhibitor-based chemotherapy; adequate organ function including bone marrow (white blood cells >3 x 109/l, neutrophil >1.5 x 109/l, platelet >100 x 109/l), liver [serum bilirubin <35 µmol/l, alanine transferase or aspartate transferase <2.5 x upper limit of normal range (ULN) if no demonstrable liver metastasis or <5 x ULN in the presence of liver metastasis] and kidneys (calculated creatinine clearance >60 ml/min). Exclusion criteria included prior treatment with irinotecan or other topoisomerase I inhibitors, prior treatment with EGFR-targeted agents, central nervous system metastasis, other malignancies within past 5 years, inability to take or absorb oral medications and systemic anticancer therapy within 4 weeks of study entry.

The original plan was to enrol patients onto dose level 1 (irinotecan 250 mg/m2, gefitinib 250 mg/day; cohort 1). Two DLTs were observed at this level and dose de-escalation at two dose levels were carried out: irinotecan 200 mg/m2, gefitinib 250 mg/day (cohort 2) and irinotecan 225 mg/m2, gefitinib 250 mg/day (cohort 3). In addition, pharmacokinetic (PK) studies were initiated. Irinotecan was administered intravenously over 30–90 min once every 3 weeks starting on day 1 of the first cycle. Gefitinib was administered at a daily oral dose of 250 mg, starting on day 3 of the first cycle. Figure 1 shows the treatment schedule.


Figure 1
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  		Figure 1. Treatment schedule.

 
Three patients would be included at each dose level and dose escalation would only continue if all three patients completed the first treatment cycle without suffering from inappropriate toxicity. If one patient experienced DLT, a further three patients would be included at the same dose level. As two DLTs were observed at our starting dose level, the protocol was amended to allow a further six patients to be treated in cohort 2 and if tolerated, another six patients would be treated at cohort 3. If the dose level at cohort 3 (irinotecan 225 mg/m2, gefitinib 250 mg/day) was tolerable, then this dose would be defined as the recommended dose level (RDL) and the RDL would be expanded in the continuation phase of the study to establish efficacy.

Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria version 2. DLT was defined as grade 4 neutropenia lasting for >7 days or associated with fever ≥38.5°C at any time; platelet count <25 x 109/l; treatment-related grade 2 hepatic or renal toxicity (except reversible grade 3 liver transaminase elevation); grade ≥3 diarrhoea despite aggressive antidiarrhoeal therapy; other grade ≥3 nonhaematological toxicity except nausea or vomiting and treatment delay >2 weeks due to toxicity.

The details of drug assay and PK analyses are given in Appendix 1.

During the continuation phase of the study, tumour assessments were carried out by CT scan every 12 weeks until evidence of disease progression. Objective tumour response assessment was made using the RECIST criteria [19]. Once the RDL had been defined, the appropriate dose level would be expanded. Using the Fleming's method, 27 patients would be sufficient to reject a baseline response rate of 5% when the true response was 20% (one-sided {alpha} = 0.05, 80% power). Therefore, if four or more than four responses were observed out of 27 patients, the hypothesis that the response rate was ≤5% would be rejected. The patients recruited to the RDL level during the dose escalation would also be included within the sample of 27 patients to establish efficiency.

Time to progression (TtP) was defined as the time from first dose of study medication (irinotecan or gefitinib) to death from any cause or progression on the last on-study tumour assessment or censored at the date of trial closure. Overall survival (OS) was defined as the time from first dose of study medication (irinotecan or gefitinib) to death from any cause or censored at last follow-up. All time to event analyses were carried out using Kaplan–Meier method [20]. Toxicity was analysed for the intention-to-treat population (n = 39) whereas efficacy analyses (disease response and time to event) were carried out for patients treated at RDL (n = 27). The database was locked in December 2005 and analyses were carried out using SAS version 8.2 (SAS Institute, Cary, NC).


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Appendix
 Acknowledgements
 References
 
From June 2002 to February 2005, 39 patients were recruited into the study from three oncology centres in the UK. Table 1 shows the baseline characteristics of the patients. Only 13 (33.3%) patients were female. All patients were either Caucasians (94.9%) or non-oriental Asians (5.1%). Figure 2 shows the trial profile during the dose-finding part of the study. Two patients developed DLTs in the starting dose level (cohort 1; 250 mg/m2 irinotecan). One patient had prolonged grade 4 neutropenia lasting for >7 days. Another patient developed grade 3 diarrhoea with neutropenic sepsis. No patients developed DLT in cohort 2 (200 mg/m2 irinotecan). One patient developed febrile neutropenia in cohort 3 and this dose level (irinotecan 225 mg/m2 once every 3 weeks and gefitinib 250 mg once daily) was considered the RDL and was expanded in the continuation phase.


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  		Table 1. Baseline characteristics

 

Figure 2
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  		Figure 2. Trial profile. DLT, dose-limiting toxicity; MTD, maximum tolerated dose; RDL, recommended dose level; PK, pharmacokinetic.

 
Table 2 shows the worst grade toxicity within the study irrespective of causality. No patients died due to drug-related adverse events. Fifteen (39%) patients had drug-related grade 3 or 4 adverse events. The most encountered drug-related grades 3–4 toxic effects were diarrhoea, lethargy, neutropenia, febrile neutropenia, abdominal pain and skin rash, consistent with those expected from each individual drug. No grade 3 or 4 hepatic and renal toxic effects were observed.


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  		Table 2. Worst grade toxicity experienced by the intention-to-treat population (n = 39)

 
Table 3 shows a summary of PK parameters for gefitinib, irinotecan and SN-38 following administration alone or in combination. Figure 3A, B and C shows the geometric mean steady-state plasma concentrations of gefitinib, irinotecan and SN-38. For gefitinib, the concentration on day 8 of cycle one before the dose and 24 h after the dose was similar. This indicated that steady state of gefitinib had been reached by the doses at which the samples were taken. Table 4 shows the mean PK parameter ratios of gefitinib + irinotecan/gefitinib alone and gefitinib + irinotecan/irinotecan alone. The mean ratios for Cssmax, area under the curve (AUC)ss(0–24) and Cssmin at 24 h for gefitinib plus irinotecan/gefitinib alone were 1.30, 1.49 and 1.76 respectively. The lower limits of 95% confidence interval (CI) of all three ratios were above one, indicating statistically significant increase in the exposure to gefitinib in the presence of irinotecan. The PK parameters for irinotecan and SN-38 on day 1 of cycle one (in the absence of gefitinib) and day 1 of cycle two (in combination of gefitinib) were similar without any significant differences. The ratios of Cmax, AUC and AUC(0–t) were slightly greater than unity for irinotecan and SN-38, indicating a slight trend for higher exposure in combination with gefitinib. Only in the case of SN-38 AUC did the effect achieve statistical significance. Paradoxically, the mean half-life ratios were less than unity, but this was not statistically significant.


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  		Table 3. Average PK parameter values for gefitinib, irinotecan and SN-38

 

Figure 3
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  		Figure 3. (A) Geometric mean steady-state plasma concentration of gefitinib alone and in combination with irinotecan. (B) Plasma concentration of irinotecan and SN-38 at irinotecan dose of 200 mg/m2. (C) Plasma concentration of irinotecan and SN-38 at irinotecan dose of 225 mg/m2.

 

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  		Table 4. Mean ratios of PK parameters

 
For the patients treated at RDL (n = 27), there were no complete response, three (11.1%) partial responses, eight (29.6%) stable disease and 12 (44.4%) disease progression. Four patients (14.8%) had nonevaluable disease. The overall response rate was 11.1% (95% CI 2.4% to 29.2%) and the disease control rate was 40.7% (partial responses and stable disease lasting for ≥12 weeks). Complete response (CR) was defined as the disappearance of all target lesions, without the appearance of new lesion(s). Partial response (PR) was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameters. Progressive disease (PD) was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameters since the treatment started. At the time of this final analysis, 24/27 (89%) patients had experienced disease progression and 18/27 (67%) patients had died. Three patients died without prior documented disease progression. Figure 4 shows the TtP and OS for patients treated at RDL. The median TtP was 4.2 months and 6-month probability of freedom from progression was 22.2% (95% CI 6.5% to 37.9%). The median survival was 9.5 months and 6-month OS rate was 73.4% (95% CI 56.5% to 90.3%).


Figure 4
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  		Figure 4. Time to progression and overall survival for patients treated at recommended dose level (n = 27).

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Appendix
 Acknowledgements
 References
 
In this study, the DLTs of irinotecan and gefitinib in combination were diarrhoea and neutropenia. These toxic effects were as anticipated given the toxicity profile of each individual drug, although they occurred at an unexpectedly low dose of irinotecan (250 mg/m2) in combination with gefitinib. The addition of irinotecan to gefitinib increased the steady-state concentration of gefitinib, although gefitinib did not alter the PKs of irinotecan and SN-38 significantly. In our study, irinotecan plus gefitinib produced an objective tumour response rate of 11.1%, median TtP of 4.2 months and median OS of 9.1 months, all very similar to irinotecan monotherapy in phase III studies [1–4]. Gefitinib did not appear to add substantial efficacy to irinotecan in this setting.

When gefitinib was given alone in phase I and II studies [11–15], no objective responses were observed, although some patients experienced prolonged disease stabilisation. In a further study (E6200) carried out by Eastern Cooperative Oncology Group, 110 patients were randomised to 250 or 500 mg gefitinib in patients pretreated with irinotecan/bolus 5-FU/leucovorin [21]. One partial response (1%; 95% CI 0.01% to 5%) was seen in the 500 mg group with 20 (18%) patients achieving stable disease as best response in both groups. The median survival for patients in 250 and 500 mg groups were 5.2 and 8.2 months, respectively. Similar results were also seen with erlotinib monotherapy in a phase II study of patients with metastatic CRC with no objective response seen [22]. This contrasts with cetuximab in which objective response rates of 9%–11% were seen when given alone [10, 23].

Nevertheless, when paired liver biopsies were obtained in a phase-II gefitinib monotherapy study [16], the pharmacodynamic studies showed that decreased proliferation occurred after gefitinib treatment and this was associated with decrease in tumour burden as determined radiologically. Four different markers of EGFR activity, including activated EGFR, phosphorylated Akt, phosphorylated ERK and nuclear p27Kip1, were evaluated. Whereas individual markers were only detected in a small number of patients, when taken together, the data from the four markers provided evidence that gefitinib was able to inhibit EGFR signalling in metastatic CRC and these results were unlikely to occur by chance (P = 0.001). Similarly, erlotinib also significantly decreased levels of phosphorylated EGFR (P < 0.01) and phosphorylated ERK (P < 0.01) in patients with metastatic CRC [22].

Responsiveness to gefitinib in non-small-cell lung cancer (NSCLC) has been linked with somatic mutations of EGFR that affect critical amino acids in the adenosine triphosphate (ATP)-binding cleft of the tyrosine kinase domain of the receptor to which gefitinib binds. These mutations centred on exons 18–21 of the EGFR kinase domain. Such mutations, however, occurred at a very low frequency in CRC [24–28], which might have explained the lack of partial responses seen in the gefitinib monotherapy studies. Although EGFR mutations appeared to predict for responsiveness to EGFR TKIs, however, they did not appear to predict survival in patients receiving TKI for NSCLC [29–31], nor did they predict response to cetuximab [28, 32] or gefitinib [24] in advanced CRC. Indeed, NSCLC cell line studies showed that EGFR mutations were associated with sensitivity to gefitinib, but not to cetuximab [33]. Other predictors such as increased copy number of EGFR gene as detected by fluorescent in situ hybridisation or proteome profiling may be more relevant in CRC [32, 34].

The synergistic interaction between gefitinib and irinotecan had been evaluated in preclinical models. It had been shown that irinotecan increased EGFR phosphorylation and this activation was completely inhibited by gefitinib [17, 35]. Furthermore, gefitinib-induced apoptosis was enhanced by combination with irinotecan [17]. Gefitinib also caused an increase in the formation of Topo I-specific protein-linked DNA double-strand breaks and down-regulation of Topo II{alpha} protein levels [35]. In addition, gefitinib reversed SN-38 resistance through inhibition of breast cancer resistance protein (ABCG2), an ATP-binding cassette half-transporter that efficiently transports SN-38 outside tumours cells with a high affinity [18, 36].

These preclinical studies, however, did not adequately address the potential supra-additive toxic effects when irinotecan was combined with an EGFR TKI. When irinotecan, infused 5-FU and leucovorin (FOLFIRI) was combined with erlotinib in patients with advanced CRC, this phase I study was halted early after only six patients were recruited due to excessive toxic effects including disfiguring skin rash, diarrhoea and grade ≥3 neutropenia [37]. In this study, no plasma PK interaction was seen to explain the observed increased toxicity. In a phase II study combining FOLFIRI with gefitinib in 13 patients [38], excessive toxicity from gastrointestinal symptoms and neutropenia were again seen necessitating early termination of the study. Despite excessive toxicity, synergistic efficacy of gefitinib with FOLFIRI was not seen as only one patient achieved partial response (objective response rate = 8%; 95% CI 0% to 38%) [38]. In another phase I–II study of gefitinib with either FOLFIRI or IFL [24], 12 out of 35 (39%) patients experienced partial response, more consistent with that achieved with FOLFIRI or IFL alone. No toxicity data, however, were reported in this study.

In the present study, we have also observed diarrhoea and neutropenia at a relatively low dose of irinotecan requiring dose de-escalation to be implemented in our study. In our PK studies, careful timing of the doses and sampling schemes had enabled a within-patient investigation of potential PK interaction between the two agents. Our PK investigation represents the largest reported to date evaluating the combination of topoisomerase I inhibitor and EGFR TKI. The addition of irinotecan to gefitinib caused an average 50% increase in the exposure to gefitinib, which was statistically significant. This might in part explain the increased incidence of diarrhoea. In the phase I study of paclitaxel, carboplatin with gefitinib, the systemic exposure to gefitinib was also higher in the presence of chemotherapy [39]. Gefitinib, irinotecan and paclitaxel are all cytochrome P3A4 substrates [40–42], so substrate competition may be a relevant explanation of these results. However, since there was no change in exposure to irinotecan or SN-38, this is not an explanation for the neutropenia observed, which was more likely to be associated with chemotherapy rather than gefitinib. There was a trend for gefitinib Cssmin to be higher at the start of cycle 2 than during cycle 1. It was possible therefore that some of the observed change in gefitinib PK in the presence of irinotecan was the result of continued accumulation of gefitinib. This was particularly a possibility for those patients sampled on day 8 of cycle one where there may have been insufficient doses to have reached steady state. Previous studies have indicated that 10-day dosage of gefitinib was required to achieve steady state, [14] therefore it is possible for those patients sampled on day 8 of cycle one that the six doses of gefitinib were insufficient to reach the steady state.

In addition, gefitinib down-regulated ABCG2 [35, 36] and significantly increased the intracellular accumulation of topotecan, another topoisomerase I inhibitor [36]. Therefore, aside from PK interaction, intracellular interference of both drugs might have occurred. Cetuximab, however, has been combined with irinotecan ± 5-FU/leucovorin (LV) without severe toxicity [10], indicating the observed interaction was more likely to be pharmacological rather than due to EGFR blockade.

Due to the excessive toxicity seen thus far with irinotecan plus gefitinib, clinical activity was unimpressive with only one (8%) response seen in the phase II study of FOLFIRI and gefitinib [38]. Frequent dose reductions were required and tolerable doses of FOLFIRI with gefitinib were one-third less than those commonly used with FOLFIRI alone [38]. In our study, the objective response rate was only 11%. Again our RDL for irinotecan (225 mg/m2) in combination with gefitinib was about one-third less than that commonly used with irinotecan alone (350 mg/m2). Our survival data were also similar to other published phase III studies evaluating irinotecan alone, without any apparent additional benefit with gefitinib. On the other hand, the combination of oxaliplatin plus 5-FU/LV or capecitabine with EGFR TKIs has been more successful. Manageable toxic effects were seen with response rates of ~70% in patients receiving first-line therapy [43–45] and 25%–33% in patients pretreated with chemotherapy [46, 47] for advanced CRC. When oxaliplatin alone was combined with gefitinib, no objective responses, however, were seen during the phase I dose escalation and therefore the preplanned randomised phase II part of oxaliplatin ± gefitinib was never carried out [48].

In conclusion, DLTs, especially neutropenia, occurred at an unexpectedly low dose of irinotecan in combination of gefitinib. Recommended dose was established at irinotecan 225 mg/m2 once every 3 weeks and gefitinib 250 mg daily. The addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib which was statistically significant. Changes of this magnitude, however, might not be clinically important, given the low toxicity profile of gefitinib, thereby could not solely explain the increased toxicity seen with this combination in our study. Irinotecan and gefitinib at the recommended dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan. The relative low dose of irinotecan at the RDL and the rarity of EGFR somatic mutation in CRC might be contributory to the modest activity of irinotecan and gefitinib combination.


   Appendix
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Appendix
Acknowledgements
 References
 
drug assay and pharmacokinetic analysis
At prespecified timepoints, serial blood samples were collected to measure the plasma concentration of gefitinib, irinotecan and its metabolite SN-38. Seven serial blood samples were obtained within 48 h after the first irinotecan dose (before gefitinib) on day 1, cycle one to evaluate irinotecan disposition in the absence of gefitinib. This sampling regimen was then repeated on day 1 of cycle two to determine irinotecan and SN-38 disposition in the presence of steady-state exposure to gefitinib. Steady-state plasma concentration profiles for gefitinib were determined from five serial blood samples taken in the absence of irinotecan, on either day 8 or day 15 of cycle one and, after coadministration with irinotecan, on day 22 (day 1 of cycle two).

gefitinib.
Plasma concentrations of gefitinib were determined using high-performance liquid chromatography (HPLC) with tandem mass spectrometric detection.

The maximum plasma concentration (Cmax) and the time to reach the maximum plasma concentration (tmax) for each patient was taken directly from their plasma concentration–time profiles. The Cssmin level [minimum (trough) steady-state drug concentration in plasma during dosing interval] for gefitinib in cycle one was calculated as the mean of the concentrations in the samples taken before and 24 h after the dose. For cycle two, Cssmin was taken as the concentration in the 24-h sample. The area under the plasma concentration–time curve, AUCss(0–24) for gefitinib was calculated using the linear trapezoidal rule.

irinotecan and SN-38.
Plasma concentrations of irinotecan and SN-38 were analysed by a validated HPLC method with fluorescence detection. The maximum plasma concentration (Cmax) and the time to reach the maximum plasma concentration (tmax) for each patient was taken directly from their plasma concentration–time profiles. The rate constant of the slowest disposition rate constant ({lambda}z) was calculated by log-linear regression of the terminal portion of the concentration–time profiles and the terminal half-life (t1/2) was calculated from the equation 0.693/{lambda}z. The AUC up to the time of the last quantifiable plasma concentration, AUC(0–t), was calculated by the linear trapezoidal rule. AUC(0–t) was extrapolated to infinity using {lambda}z to obtain the AUC from zero to infinity.

The effect of each drug on the exposure to the other was calculated for each patient as the ratio of the PK parameter value determined following the combination versus that following the drug alone. Statistical significance was inferred if the 95% CI excluded unity. For irinotecan and SN-38, the AUC(0–t), the values used to calculate the ratios were to a common time value for both cycles of treatment within a patient. PK analyses were conducted using WinNonlin Enterprise version 4.1 (Pharsight Corp., Paulo Alto, CA).


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Appendix
 Acknowledgements
References
 
Supported by research funding from AstraZeneca. This paper was presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 2004, New Orleans, LA.

Received for publication September 6, 2006. Accepted for publication November 30, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Appendix
 Acknowledgements
 References
 
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A. Santoro, A. Comandone, L. Rimassa, C. Granetti, V. Lorusso, C. Oliva, M. Ronzoni, S. Siena, M. Zuradelli, E. Mari, et al.
A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer
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