Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors

K. Nakagawa1,+, T. Tamura2, S. Negoro3, S. Kudoh4, N. Yamamoto1, N. Yamamoto2, K. Takeda3, H. Swaisland5, I. Nakatani6, M. Hirose6, R.-P. Dong6 and M. Fukuoka1

1 Kinki University School of Medicine, Osaka; 2 National Cancer Center Hospital, Tokyo; 3 Osaka City General Hospital, Osaka; 4 Osaka City University Medical School, Osaka, Japan; 5 AstraZeneca, Alderley Park, Macclesfield, UK; 6 AstraZeneca KK, Osaka, Japan

Received 31 July 2002; revised 29 November 2002; accepted 17 February 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included.

Patients and methods:

Patients initially received a single oral dose of gefitinib followed by 10–14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT).

Results:

Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. Cmax was reached within 3–7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8–79.7 h). A partial response (duration 35–361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225–700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40–127 days).

Conclusions:

In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.

Key words: efficacy, EGFR inhibitor, gefitinib, ‘Iressa’, phase I trial, tolerability, ZD1839


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Specific inhibition of epidermal growth factor receptor (EGFR) function is an attractive therapeutic target in anticancer treatment. Potential new therapies are under development that modulate the activation of this signal transduction pathway, resulting in inhibition of mitogenesis and other cancer-promoting processes [1]. The extracellular ligand-binding region of the EGFR has been targeted by monoclonal antibodies such as cetuximab [2], while agents that target the intracellular tyrosine kinase region include small-molecule tyrosine kinase inhibitors (TKIs) such as gefitinib (‘Iressa’, ZD1839) [3] and erlotinib [4]. Advantages of these compounds compared with standard chemotherapy include their ability to inhibit specific deregulated pathways in cancer cells with minimal effects on normal cell function. This class of agents may therefore offer antitumor activity with a better-tolerated adverse event profile than traditional agents.

The rationale for targeting the EGFR comprises several key points. Activation of the EGFR tyrosine kinase has been found to be a key factor in cell proliferation and has been implicated in the control of cell survival, decreased apoptosis and increased metastasis [5]. Furthermore, the EGFR is expressed or highly expressed in a wide variety of human solid tumors, and high-level expression has been associated with advanced disease, development of a metastatic phenotype and poor prognosis [6, 7].

Gefitinib is an orally active, selective EGFR-TKI that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth. Early preclinical studies indicated that, in vitro, gefitinib potently inhibited EGFR tyrosine kinase activity at low concentrations that did not significantly affect other kinases tested [8]. Preclinical toxicology studies showed gefitinib to have a favorable tolerability profile over 6 months of oral dosing in animals, with mechanism-based, dose-dependent reversible effects on the skin, cornea, kidney, liver and ovary [9]. This range of toxicity is explained by the fact that EGFR signal transduction is involved in the normal physiology of these organs. Gefitinib has been shown to inhibit growth of a range of human tumor cell lines expressing EGFR (IC50 0.2–0.4 µmol/l) when used as a single agent, and to potentiate the activity of cytotoxic agents [10]. It also showed antitumor activity in various xenograft models [10, 11]. Gefitinib was well tolerated in healthy volunteers and demonstrated a terminal half-life of 28 h, which suggests that once-daily oral administration is appropriate [12].

Our study was performed to investigate the safety and pharmacokinetics of gefitinib in Japanese patients and to enable a comparison between Japanese patients and non-Japanese patients participating in a parallel study in the USA and Europe [13] in accordance with regulatory requirements. It was principally designed to evaluate the tolerability of increasing oral doses of gefitinib in Japanese patients with solid malignant tumors, using an intermittent dosing schedule to ensure the patients’ safety.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Trial design
We conducted an open, multicenter, non-randomized, phase I, dose-escalating study, recruiting patients at four centers in Japan. Our primary objective was to investigate the tolerability and toxicity of single and multiple oral doses of gefitinib in patients with solid malignant tumors. Secondary objectives included assessment of pharmacokinetics and antitumor activity. In addition, we compared our pharmacokinetic results with those from patients taking part in a parallel study in the USA and Europe.

Patient eligibility
We enrolled patients with solid malignant tumors that were resistant to standard therapies or for which the investigator believed no appropriate treatment was available. Tumors were among those known to commonly express or overexpress EGFR, but patients were not selected on the basis of individual EGFR status. Patients aged 20–74 years with a life expectancy of ≥3 months and World Health Organization (WHO) performance status of ≤2 were eligible for inclusion. Exclusion criteria have been described previously [13].

Prior to initiation of the study, we recorded information on each patient’s background and treatment history and conducted assessments, including a physical examination, vital signs, performance status, clinical laboratory tests (hematology, blood biochemistry, urinanalysis, fecal test), ophthalmologic assessments and 12-lead ECG with measurement of PR intervals. All patients gave written informed consent and the study was conducted in accordance with ‘Good Clinical Practice for Trials on Drugs’ [14] and the ‘Declaration of Helsinki’ [15].

Treatment
In the first part of the trial, patients received a single oral dose of gefitinib, followed by 10–14 days of observation. If drug exposure was well tolerated, patients progressed to the second part of the study and received the same dose repeated daily for 14 days, followed by 14 days of observation (one cycle), based on advice from the Efficacy and Safety Evaluation Committee. A parallel study in the USA and Europe was conducted in a similar dose-escalation manner (except that the single dose was given only at the 50 mg dose level) and we compared, on an ongoing basis, pharmacokinetic data following single and multiple dosing in this study with data from our study to determine whether similar dose dependency was observed in Western and Japanese patients and to consider whether prior single dosing to establish safety was necessary at each dose level.

The 50 mg starting dose was chosen on the basis of preclinical animal toxicology studies and two clinical studies in healthy volunteers. The Western volunteer studies at single doses up to 100 mg/day showed that the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve from 0 to 24 h (AUC0–24) increase linearly with dose. Provided the disposition of gefitinib in our patient population is similar to that in the healthy Caucasian volunteers, Cmax and AUC0–24 following the initial single 50 mg dose will be ~17 ng/ml and 220 ng·h/ml, respectively. These values represent approximately one-third and one-fifth, respectively, of the exposure at the no-effect dose in rats, the most sensitive species, in the 28-day toxicology studies (2 mg/kg/day). Following multiple dosing at 50 mg for 14 consecutive doses, predictions from the Western volunteer data suggest that the steady-state Cmax and AUC0–24 will be ~35 ng/ml and 500 ng·h/ml, respectively. These values represent approximately one-fifteenth and one-tenth, respectively, of the exposure at the NOAEL (no observed adverse effect level; 10 mg/kg/day) in the 28-day toxicology studies in rats. The single dose of 50 mg/day caused no clinically significant adverse effects in the volunteers.

We planned to escalate the dose to 100, 150, 225, 300, 400, 525, 700 and 925 mg/day, with the option to omit dose levels following consideration of the results of the parallel USA/European study. We initially entered four patients at each dose level, but if National Cancer Institute-Common Toxicity Criteria (NCI-CTC 2.0) grade 3 or 4 drug-related toxicity occurred in one of these patients, we enrolled two additional patients. Dose-limiting toxicity (DLT) was defined during the first treatment period as any grade 3/4 drug-related adverse effect, significant corneal epithelial change or PR interval (measured by 12-lead ECG) prolongation attributed to gefitinib (as prolongation of the PR interval was noted in preclinical animal toxicity studies). The dose at which DLT occurred in more than two patients was defined as the maximum tolerated dose (MTD). Dose escalation took place following a review of safety data when all patients at a dose level reached day 28 or had been removed from the trial due to drug-related toxicity, and following consideration of the results from the Western study.

Appropriate supportive care measures and symptomatic treatment were permitted, as was prophylactic use of antiemetics during the second and subsequent cycles, but not during the first 28 days. Any grade 3/4 nausea that was not readily managed with antiemetics was classed as DLT.

Following completion of the first 14 days of treatment and 14 days of observation, patients demonstrating clear clinical benefit could remain on gefitinib (14-day treatment period, every 28 days) if there was no drug-related DLT and if they fulfilled eligibility criteria. Gefitinib treatment was discontinued in the event of ocular toxicity, cardiac conduction defects, disease progression, any DLT, withdrawal of consent or if it was in the patient’s best interest to discontinue treatment. Following withdrawal, patients were monitored for 30 days for reversibility of drug-related adverse effects or occurrence of new adverse effects. No intra-patient dose escalation or reduction was allowed.

Safety assessments
We recorded the incidence, type and severity of adverse effects at each dose level. If grade 3/4 myelosuppression was observed, we carried out hematology assessments at least every 2 days until values returned to grade 1/2. All clinical laboratory tests were conducted at screening, pre-first dose, 24 h after the single dose, on days 1, 3, 8, 15, 22 and 29, and at withdrawal. Ophthalmologic assessments, including slit-lamp examination, were carried out at screening, 48 h after the single dose, on days 8, 15 and 22 and at withdrawal. The other safety parameters were also reassessed periodically throughout the trial.

Pharmacokinetic analysis
During the first cycle, plasma concentrations of gefitinib were determined from blood samples (4 ml) using liquid–liquid extraction and high-performance liquid chromatography with mass spectrometric detection [16]; pharmacokinetic parameters were calculated by standard methods. Blood samples were taken pre-first dose, and at 1, 3, 5, 7, 12, 24, 48, 72, 96, 120 and 144 h after administration of the single dose. The same sampling times were used following the last dose of the multiple dosing administration (i.e. day 14) and samples were also taken pre-dose on days 1, 3, 7 and 10 during multiple dosing.

Derived pharmacokinetic parameters included the maximum plasma drug concentration (Cmax), time to Cmax (tmax), area under the plasma drug concentration–time curve from 0 to 24 h (AUC0–24) and to {infty} (AUC0–{infty}) and terminal half-life (t1/2).

Efficacy assessments
We assessed tumor response in accordance with the ‘criteria for direct response of solid tumors to chemotherapy’ of the Japan Society for Cancer Therapy, which are very similar to those used by the WHO. Measurable lesions were assessed in the same manner before and after dosing, by X-ray, computed tomography (CT) scan, magnetic resonance imaging or echogram. Complete response, partial response or no change in disease status had to be confirmed by a second assessment after 4 weeks.

Serum tumor markers including carcinoembryonic antigen (CEA), prostate-specific antigen, CA 125, CA 19-9, squamous-cell carcinoma-related antigen and thyroglobulin were recorded in patients with relevant tumor types, at screening, on days 1, 8, 15 and 29, and at withdrawal.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
We recruited 31 patients, all of whom had received prior chemotherapy. The median age was 61 years and all patients had a WHO performance status of 0–1 (Table 1). Most patients (74%) had advanced non-small-cell lung cancer (NSCLC) and had been pretreated with chemotherapy (1–4 regimens); 70% of these had received platinum-based regimens.


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Table 1.  Patient demographics
 
Of the 31 patients, 30 completed one cycle of treatment (28 days); eight completed ≥2 cycles and six ≥3 cycles. One patient (50 mg group) was withdrawn due to grade 3 atrial fibrillation on day 2 of cycle 1 (due to respiratory failure associated with disease progression); therefore, another patient was added to this group in order that we could collect data on plasma gefitinib concentrations from four patients.

Based on the safety data from the parallel USA/European study, it was judged unnecessary to repeat the 150 and 300 mg dose levels in Japan. In our study, patients in the 50, 100 and 225 mg dose-level groups received the single dose plus the 14-day daily dose. Following comparison of our data with those from the Western study, the pharmacokinetic and adverse effect profiles were found to be similar in the two populations; therefore, the initial single dose was omitted for patients in the 400, 525 and 700 mg dose-level groups.

Dose-limiting toxicity
The highest dose administered was 700 mg/day with two of six patients experiencing DLT [grade 3 diarrhea (one patient) and grade 3 elevation of alanine aminotransferase (ALT; one patient)]. Grade 3 drug-related adverse effects were observed in two additional patients: elevated transaminases in one patient each at 225 and 525 mg/day. Consequently, two additional patients were enrolled, so that a total of six patients were treated at these dose levels. No dose level other than 700 mg/day had more than one of six patients with DLT. No additional DLT occurred.

Tolerability
All 31 patients were evaluable for tolerability and safety. The majority of adverse effects were mild (grade 1/2) and reversible on cessation of treatment. The most frequently reported adverse effects included gastrointestinal tract disorders (77.4%; including diarrhea, nausea, vomiting, anorexia), skin reactions (74.2%; including acne-like rash, seborrhea, dry skin) and increased hepatic enzymes.

Drug-related adverse effects occurring in ≥10% of the patient population are detailed by dose level in Table 2. The most common drug-related adverse effects were grade 1/2 acne-like rash and seborrhea, observed in 32.3 and 22.6% of patients, respectively. Acne-like rash (or folliculitis) covers descriptions such as maculopapular and pustular. These skin disorders tended to occur more often with higher doses of gefitinib and were resolved without treatment or with symptomatic treatments. They tended to recur after the start of treatment with gefitinib in subsequent cycles and often disappeared on cessation of treatment.


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Table 2.  Number of patients with drug-related adverse events that occurred in ≥10% of the patient population in all cycles
 
Drug-related diarrhea was observed in 19.4% of patients. At doses up to 525 mg/day it was grade 1/2 (loose stools occurring 2–3 days a week) and manageable with routine treatment. Diarrhea generally occurred within the first 2 weeks of a treatment cycle. Drug-related nausea and vomiting were observed in six and four patients, respectively, with most adverse effects resolving on the day of onset or within a few days after treatment cessation with or without adverse effect management.

Drug-related increases in the hepatic transaminases ALT and aspartate aminotransferase (AST) were each seen in 19.4% of patients, and drug-related increases in alkaline phosphatase were seen in 16.4% of patients.

Following frequent and specific ophthalmologic tests, adverse effects were reported in 14 patients (45.2%). Five patients had conjunctivitis (recorded as conjunctivitis, conjunctival congestion and conjunctival epithelial disorder), four had corneal disease (corneal epithelial disorder, corneal erosion and abnormal Rose Bengal staining), keratitis and blepharitis were reported in three patients each and two patients had eye disorders. All ophthalmological events were mild (grade 1/2). In six patients the adverse effects were considered to be drug-related; they resolved in five cases without intervention and in one case following treatment with eye drops (ofloxacin and flavin adenine dinucleotide). Drug-related hematological toxicity occurred in four patients (12.9%) over a range of doses (100–400 mg/day) and was limited to anemia, leukopenia and eosinophilia, all mild in nature (grade 1/2). One patient (gefitinib 400 mg/day) had drug-related prolongation of the PR interval (grade 1), which recovered without intervention. One patient (gefitinib 525 mg/day) had mild alopecia, which also resolved without intervention.

Grade 3/4 adverse effects
No grade 4 adverse effects were observed. A total of 19 grade 3 adverse effects was reported in eight patients. Six of these, in four patients, were considered to be drug related; elevated AST and ALT in one patient each at the 225 and 525 mg/day dose levels, elevated ALT in one patient at 700 mg/day and diarrhea in one patient at 700 mg/day. The grade 3 diarrhea appeared 5 days after withdrawal of treatment. The grade 3 drug-related increases in hepatic enzymes resolved, either with or without treatment. In two of these patients onset of increased hepatic enzymes occurred on day 8 of the second treatment cycle; one (gefitinib 225 mg/day) recovered to normal range within 3 weeks while the other (gefitinib 525 mg/day) recovered 5 days after gefitinib treatment was withdrawn. In the third patient (gefitinib 700 mg/day), onset of increased hepatic enzymes occurred on day 21 of the first cycle (during the treatment interval) and recovered within 1 week. The grade 3 adverse effects in the remaining four patients were considered to be disease related.

Withdrawals
In addition to patients withdrawn from the trial due to progressive disease, four patients were withdrawn due to adverse effects. A female patient with NSCLC with multiple lung micrometastases receiving the 525 mg/day dose was withdrawn due to grade 3 increased transaminases (AST and ALT) on day 8 of cycle 2. AST returned to normal levels without medical intervention, as did serum ALT 54 days after withdrawal. These events were considered to be related to gefitinib. A male patient with rectal cancer, receiving 700 mg/day, withdrew due to grade 2 diarrhea during cycle 3 (day 7), which resolved after 3 days. The patient experienced grade 3 diarrhea 2 days later and, after a further 2 days, had dehydration associated with grade 2 diarrhea. He was hospitalized 8 days after withdrawal and treated with fluid replacement; the diarrhea and dehydration resolved within 2 days. Diarrhea in this patient was judged to be drug related. A male patient with NSCLC was withdrawn due to grade 3 atrial fibrillation judged to be caused by increased heart burden due to respiratory failure associated with progression of primary NSCLC. A male patient with colorectal cancer receiving gefitinib 225 mg/day was withdrawn due to grade 1 infectious keratoconjunctivitis during cycle 2, which was considered by the investigator to be related to adenovirus infection. In this trial, a total of seven patients remained on study for ≥3 months and three for ≥12 months.

Pharmacokinetics
The derived pharmacokinetic parameters following a single dose and multiple dosing of gefitinib are given in Table 3. At the starting dose of 50 mg/day, absorption of gefitinib was moderately slow, median tmax being 3 h from the single dose (range 3–5 h). For the dose range 50–225 mg/day, the mean t1/2 was similar for all single doses (30–38 h). Single doses higher than 225 mg/day were not given.


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Table 3.  Derived pharmacokinetic parameters following single dose (50, 100 and 225 mg) and 14 days of multiple dosing of gefitinib
 
Figure 1 shows the mean plasma concentration–time profile following single and multiple dose administration of 50, 100 and 225 mg/day gefitinib. Multiple dosing resulted in at least a two-fold increase in Cmax compared with single dosing; for the 50 mg/day dose, exposure (Cmax) to gefitinib increased two-fold following 14 days of administration compared with the single dose (60 versus 31 ng/ml, respectively) and median tmax was 6 h (range 5–7 h).



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Figure 1. Mean plasma concentration–time profile for gefitinib single dose and multiple doses at (A) 50 mg, (B) 100 mg and (C) 225 mg.

 
Multiple dosing with gefitinib (50–700 mg/day) for 14 days resulted in dose-related increases in mean Cmax (from 60 to 1156 ng/ml) and mean AUC0–24 (from 1021 to 21 580 ng·h/ml). Figure 2 shows the mean plasma concentration–time profile following multiple dose administration of 225 and 525 mg/day gefitinib. Day-14 AUC0–24 values across the dose range indicate an increase in exposure to gefitinib with dose, with up to six-fold interpatient variability at each dose level (Figure 3). Steady-state plasma concentrations were achieved by days 7–10 at all doses (Figure 4). The mean t1/2 across the range 50–700 mg/day was 50.1 h (range 27.8–79.7 h).



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Figure 2. Mean plasma concentration–time profile for gefitinib multiple doses at 225 and 525 mg.

 


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Figure 3. Relationship between exposure to gefitinib (AUC0–24) and dose (mg/day).

 


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Figure 4. Mean pre-dose plasma concentrations of gefitinib during the multiple dosing phase.

 
Pharmacokinetic parameters were comparable with results from the parallel study in the USA and Europe [13]; for example, Figure 5 compares multiple dose AUC0–24 values for the two patient populations. We did not analyze the relationship between pharmacokinetic parameters and toxicity due to the limited sample size.



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Figure 5. Relationship between dose and exposure in Japanese patients and in USA/European patients after the final dose of the first multiple dosing cycle.

 
Antitumor activity
We observed partial responses (duration 35–361 days) in five of the 23 patients with NSCLC. The five patients had adenocarcinoma histology (Table 4) and were receiving a range of gefitinib doses. The first patient, a 51-year-old woman receiving gefitinib 225 mg/day, had previously shown no change in disease status as best response, then progressed on platinum-based combination therapy for 3 months, then progressed following a best response of no change in disease status on cyclophosphamide/etoposide/tegafur–uracil for 1.5 months. Her partial response was observed at the end of cycle 1 and was sustained for 119 days. The second patient, a 63-year-old woman (400 mg/day), had previously had no change in disease status as best response, then progressed on treatment with bleomycin, cisplatin/etoposide and etoposide for 1 month each. Her partial response, initially observed at the end of cycle 2, had a response duration of 361 days. This patient also had a fall in CEA levels over 13 cycles. The third patient was a 70-year-old woman (gefitinib 525 mg/day) who had previously had progressive disease following cisplatin/etoposide/radiotherapy (3 months) followed by no change in disease status as best response, then progression on docetaxel treatment (6 months). This patient experienced a partial response from the end of cycle 1 that was sustained for 35 days. Also at this dose level, a 68-year-old woman who had previously had no change in disease status as best response, then progressed on vindesine/mitomycin C/cisplatin (10 months) followed by docetaxel (2 months) and irinotecan/docetaxel (3 months) had a partial response first observed at the end of cycle 2 (response duration 340 days). This patient demonstrated a partial response on a CT scan (Figure 6A), with a reduction in lesion size visible after 4 months of treatment, and also had a reduction in CEA levels over 12 cycles. This patient continued to receive gefitinib (500 mg/day) for a further 6 months in an open-label extension study (20 months on gefitinib in total). The fifth patient with a partial response (observed from cycle 3; response duration 307 days) was a 67-year-old man receiving gefitinib 700 mg/day, who had previously shown no change in disease status as best response, then progressed after 3 months of treatment with irinotecan/docetaxel. The CT scan demonstrating this partial response is shown in Figure 6B, with a reduction in tumor size visible after 3 months of treatment. This patient continued to receive gefitinib (500 mg/day) for a further 6 months in the open-label extension study (18 months on gefitinib in total).


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Table 4.  Patients with partial response (PR) or no change in disease status
 


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Figure 6. Computed tomography (CT) scan of patients with non-small-cell lung cancer (NSCLC) pre- and post-treatment with gefitinib (A) 525 mg/day and (B) 700 mg/day.

 
An additional seven patients [colorectal cancer (three patients), NSCLC (two patients), head and neck cancer (one patient), breast cancer (one patient)] had no change in disease status as their best response (duration 40–127 days). Three of these patients remained on study for ≥3 months. One of the patients with colorectal cancer (gefitinib 700 mg/day) experienced a considerable fall in CEA and CA 19-9 levels over three cycles.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our study demonstrates that once-daily oral gefitinib, administered for 14 consecutive days every 28 days, has an acceptable tolerability profile in Japanese patients with solid malignant tumors. The safety profile observed in Japanese patients is comparable to that observed in patients from the USA/European phase I trial of gefitinib using similar dose administration and escalation schedules [13]. The incidence of reported drug-related adverse effects was similar in the two studies: 77.4% of patients in our study and 75% in the parallel study, with most adverse effects being grade 1 or 2 in severity. Toxicity increased with dose in both studies and dose escalation stopped at 700 mg/day, with grade 3 diarrhea and increased ALT being the DLTs at this dose.

In both our trial and the USA/European trial, among the most frequently reported drug-related adverse effects at doses ≤525 mg/day were an acne-like rash and gastrointestinal adverse effects. The incidence was similar in the two trials for these and other drug-related adverse effects. Results from studies evaluating chronic daily administration of gefitinib also support the conclusions of the present study, that gefitinib is generally well tolerated, with the most frequent adverse effects being grade 1 or 2 skin and gastrointestinal effects [17, 18]. In common with this study, an acne-like rash has been reported as the most common adverse effect of treatment with other EGFR-targeted treatments, including the anti-EGFR antibody cetuximab [19] and the EGFR-TKI erlotinib [4, 2022], which was also associated with gastrointestinal effects. In our study, all skin-related adverse effects were grade 1/2 and manageable, in some cases without intervention. Similarly, hepatic enzyme elevations resolved with or without management. In our study there were no severe ophthalmological events and all adverse effects considered by the investigators to be possibly related to gefitinib were reversible. Further study will be required in more patients to determine whether any of the observed ophthalmological effects are due to gefitinib. With such intense monitoring in this elderly, ill population, the significance of these findings is not clear. Neither our study nor the parallel trial reported significant or consistent cardiac or renal toxicity. In the USA/European study, hematological toxicity was uncommon and limited to cases of anemia that showed no clear relation to gefitinib dose [13]. We observed a similar low incidence of hematologic effects, contrasting with the tolerability profile of cytotoxic agents. As the tolerability profile of gefitinib was acceptable with the intermittent dosing schedule used in these studies, subsequent studies have been conducted using continuous once-daily oral dosing.

Our study confirmed previous reports that gefitinib is orally bioavailable in both healthy volunteers and cancer patients and is suitable for once-daily dosing [12, 13]. The t1/2 data following multiple-dose administration, observed in patients from the USA/European study (range 24–85 h) [13] and our study (range 27.8–79.7 h) were similar. Pharmacokinetic analysis of the data from the current study showed dose-related exposure to gefitinib, which is consistent with the results from the USA/European trial.

We observed very encouraging evidence of antitumor activity across a range of gefitinib doses that are well below the MTD. Interestingly, five of 23 patients (22%) with NSCLC (all five with adenocarcinoma) had a partial response. This supports results seen in the USA/European study, in which partial responses were observed in four of 16 patients with NSCLC, each of whom had received at least two prior chemotherapy regimens [13]. There was no tumor regrowth or symptomatic progression observed during the off-treatment period in the Japanese phase I study using the intermittent dosing schedule. This suggests that the efficacy of gefitinib treatment would be maintained in patients requiring treatment interruption for safety reasons during chronic continuous treatment with gefitinib.

The findings of this study, in conjunction with those from other phase I studies [13, 17, 18], support the use of 250 and 500 mg/day doses for subsequent trials of gefitinib in advanced NSCLC. The 250 mg/day dose is higher than the lowest dose level at which objective tumor regression was seen, while 500 mg/day is the highest dose that was well tolerated when taken chronically in phase I trials. Two large-scale, randomized, double-blind, phase II studies, ‘Iressa’ Dose Evaluation in Advanced Lung cancer (IDEAL) 1 and 2, have been undertaken to evaluate the efficacy and tolerability of gefitinib monotherapy in patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy. In both these studies, gefitinib was generally well tolerated and provided clinically significant antitumor activity [23, 24].

In conclusion, gefitinib is a novel agent designed to inhibit the EGFR signaling pathway, which is a relevant target in cancer biology. Gefitinib has a favorable tolerability profile and has demonstrated promising antitumor activity, especially in patients with NSCLC. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study of Japanese patients are comparable to those observed in patients from the USA and Europe. Therefore, an international phase II study of gefitinib can include Japanese patients. The potential for gefitinib monotherapy in the treatment of NSCLC has been confirmed by randomized phase II trials.


    Footnotes
 
+ Correspondence to: Dr K. Nakagawa, Kinki University School of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-0014, Japan. Tel: +81-723-66-0221; Fax: +81-723-60-2286; E-mail: nakagawa{at}med.kindai.ac.jp Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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