Phase I and Pharmacokinetic Study of Gefitinib in Children With Refractory Solid Tumors: A Children’s Oncology Group Study
http://www.100md.com
《临床肿瘤学》
the Departments of Hematology-Oncology and Pharmaceutical Sciences, St Jude Children’s Research Hospital
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
Keck School of Medicine, University of Southern California, Los Angeles, CA
Sainte-Justine Hospital, Montreal, Quebec, Canada
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD
Texas Children’s Cancer Center/Baylor College of Medicine, Houston, TX
James Whitcomb Riley Hospital for Children, Indianapolis, IN
Children’s National Medical Center-D.C., Washington, DC
Children’s Hospital of Philadelphia, Philadelphia, PA
ABSTRACT
PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors.
PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28).
RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non–dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing’s sarcoma had a partial response. Disease stabilized for 8 to 60 weeks in two patients with Wilms’ tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults.
CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.
INTRODUCTION
Gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) is an orally active anilinoquinazoline compound that potently inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase (IC50, 0.033 μmol/L).1,2 Epidermal growth factor receptor (EGFR) activation seems to promote tumor growth by increasing cell proliferation, motility,3 adhesion, and invasive capacity4 and by blocking apoptosis.5 This receptor is expressed in a number of human tumors, and increased levels of EGFR, its ligands, or both have been correlated with a poor prognosis in several solid tumor types in adults.6-8
In preclinical studies, gefitinib treatment was associated with dose-related growth inhibition and increased apoptosis in human cancer cell lines,9 and the drug showed antitumor activity against a broad spectrum of xenografts of adult human tumors.2,9 The combination of gefitinib and standard cytotoxic agents resulted in greater antitumor activity in and greater survival of mice than did either gefitinib or cytotoxic agents alone.9 This phenomenon was observed even in tumors without high levels of EGFR expression.10
In adult studies, gefitinib was well tolerated when given in intermittent or daily dosing.1,11 Gefitinib had good oral bioavailability and a long terminal half-life (range, 24 to 85 hours). A steady state was reached by day 7, and exposure to gefitinib showed a three- to 10-fold variability; no apparent increase in variability was associated with increasing dose.12,13 Rash and diarrhea were dose limiting at daily doses of 700 to 1,000 mg,12-14 a dose range well above that required to completely inhibit EGFR activation and downstream receptor signaling in skin biopsies of patients treated with gefitinib.15 Other types of toxicity included dry skin, pruritis, nausea, vomiting, asthenia, and elevations in serum transaminases. Interstitial lung disease has occurred in approximately 1% of adult patients who received gefitinib worldwide,16,17 and approximately one third of these cases have been fatal.16
Gefitinib has shown single-agent activity in adult patients with non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, and glioblastoma.18-20 In May 2003, gefitinib (250-mg tablets) was approved by the Food and Drug Administration as monotherapy for patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.16 Objective tumor response rates were 12% to 18% when 250 mg/d of gefitinib was given and 9% to 19% when 500 mg/d of gefitinib was given as third-line treatment of NSCLC.18,21
Although the expression of EGFR has not been evaluated comprehensively in pediatric tumors, expression has been documented in neuroblastoma22,23 and rhabdomyosarcoma24,25 cell lines and in tumor samples from patients with neuroblastoma,26 Wilms’ tumor,27 osteosarcoma,28 and glioma.29 More recently, specific EGFR tyrosine kinase mutations were found to correlate with responsiveness of NSCLC to gefitinib30,31; whether similar mutations are found in pediatric tumors remains to be determined.
Between June 2002 and March 2004, the Children’s Oncology Group conducted a phase I trial of single-agent gefitinib in children with recurrent or refractory solid tumors. The primary aims of this trial were to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib administered orally once daily continuously and to characterize its pharmacokinetic behavior in children. The secondary aim was to preliminarily define its antitumor activity within the confines of a phase I study.
PATIENTS AND METHODS
Study Design
Gefitinib was administered orally once daily. A course was defined as 28 consecutive days of drug administration, and there was no interruption of dosing between courses. The starting dosage of gefitinib was 150 mg/m2 (equivalent to the absolute dose of 250 mg recommended for adults) with subsequent dosage levels of 300, 400, and 500 mg/m2. Intrapatient dosage escalation was not allowed. Protocol therapy was stopped if a patient’s disease progressed, if irreversible DLT occurred, or if a patient elected not to receive the study drug. In the absence of disease progression, any patient with DLT that resolved after temporary interruption of gefitinib administration could continue treatment at one dose level below the one that resulted in DLT.
A minimum of three patients assessable for toxicity were treated at each dose level. If one of the first three patients treated at any dose level experienced DLT during the first course of treatment, up to three additional patients were treated at that dose level. The MTD was defined as the dose level immediately below that at which two or more patients in a cohort of up to six experienced DLT during the first course of treatment. The first course was considered complete for the purpose of DLT evaluation and dose escalation if gefitinib was administered on at least 25 of the first 28 days of treatment. If a patient received the drug on less than 25 of the first 28 days for reasons other than toxicity, that patient was considered unassessable and was replaced.
Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Dose-limiting hematologic toxicity was defined as any grade 4 neutropenia or thrombocytopenia. Dose-limiting nonhematologic toxicity was defined as any grade 2 nonhematologic toxicity that resulted in the interruption of gefitinib treatment for more than 7 days and any grade 3 or 4 nonhematologic toxicity except grade 3 nausea and vomiting, grade 3 fever or infection, and grade 3 elevation in liver transaminases that returned to the baseline toxicity grade within 7 days after the interruption of gefitinib treatment. Gefitinib treatment was interrupted for any grade 2 toxicity that was unacceptable to the patient, any grade 2 toxicity that persisted for more than 3 days despite symptomatic treatment, or any grade 3 or 4 toxicity except grade 3 elevation in liver transaminases (gefitinib was continued unless this grade 3 elevation persisted for > 7 days). Gefitinib treatment was resumed when the toxicity resolved or when the toxicity grade returned to the baseline value.
Patient Eligibility
The eligibility criteria were the following: (1) age younger than 22 years at the time of study entry; (2) a diagnosis of a malignant solid tumor that was refractory to conventional therapy or for which no conventional therapy existed; (3) a Karnofsky score of 50 for patients more than 10 years and a Lansky Play-Performance Scale of 50 for children no more than 10 years of age; (4) a life expectancy that exceeded 8 weeks; (5) recovery from the toxicity because of prior therapy; (6) no chemotherapy within 2 weeks (4 weeks for prior nitrosourea therapy) and no biologic agent or growth factor therapy within 1 week of study entry; (7) no substantial radiotherapy to the bone marrow within 6 weeks of study entry (or within 6 months of study entry if prior radiotherapy to the craniospinal axis or to at least 50% of the pelvis was received; within 2 weeks of study entry if local palliative radiotherapy was received); (8) no allogeneic stem cell transplantation within 6 months of study entry and no active graft-versus-host disease; (9) no enzyme-inducing anticonvulsant therapy (because of its potential interaction with gefitinib) or drug therapy with known corneal toxicity; (10) adequate bone marrow function (an absolute neutrophil count 1,000/mm3, a platelet count 50,000/mm3, and a hemoglobin concentration 8.0 g/dL [red blood cell transfusion support allowed]; (11) adequate renal function (normal age-adjusted serum creatinine or glomerular filtration rate 70 mL/min/1.73 m2); and (12) adequate liver function (serum bilirubin concentration 1.5 x the upper limit of the normal range for age, ALT activity 3 x the upper limit of the normal range for age, and an albumin concentration 2 g/dL). Study exclusion criteria were uncontrolled infection and either pregnancy or lactation.
No limitation was placed on the number of prior chemotherapy regimens that each patient could have received. The study initially included patients with brain tumors or known metastasis to the CNS. The study was subsequently amended to exclude these patients after it was reported that intratumoral bleeding occurred in pediatric patients with brain tumors treated on a concurrent trial of concomitant administration of gefitinib and radiotherapy followed by continuous administration of gefitinib.32 Our study was approved by the institutional review boards at the individual participating institutions. Informed consent was obtained from patients 18 years and from parents or legal guardians of children, with child assent when appropriate, according to individual institutional policies.
Drug Formulation and Administration
Gefitinib was supplied by the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (IND 61,187), as biconvex, film-coated tablets containing 25, 100, or 250 mg of the drug. The calculated dose of gefitinib was rounded to the nearest 25 mg. In young children who were unable to swallow tablets or children with swallowing problems, tablets were dispersed in 30 to 60 mL of lukewarm water in a container for approximately 5 minutes. Immediately after the dispersion was complete, the container’s content was administered to the patient. The container was rinsed with a similar amount of water to ensure removal of any material that had adhered to the container’s wall, and the additional water was administered to the patient. Gefitinib was given without time specification in relation to food intake. Drugs that alter gastric pH such as proton-pump inhibitors and H2 blockers (which may decrease the absorption of gefitinib) were administered when needed at least 4 hours after gefitinib administration. In addition, because gefitinib is metabolized by hepatic CYP3A4/5, concurrent use of corticosteroids was permissible only in patients with CNS tumors who had increased intracranial pressure or were receiving a stable or decreasing dose of steroids at study entry.
Patient Evaluation
Patient histories were obtained and physical examinations and laboratory studies were performed before treatment and then weekly during the first course of treatment. Laboratory evaluation included complete blood counts and analyses of electrolytes (including calcium, phosphorus, and magnesium), blood urea nitrogen, creatinine, and liver function. These evaluations were performed before each subsequent course and as needed. A urinalysis and a pregnancy test (for female patients of childbearing age) were performed before treatment, and a total protein/albumin count was obtained before each treatment course. Because of concern about potential corneal toxicity of gefitinib, patients underwent an eye exam by an ophthalmologist before treatment, after the completion of the first course, and after every four courses thereafter. To ensure compliance with drug intake, a pill count was performed during each clinic visit.
Patients had disease evaluations performed at baseline, after the first and second courses, and then after every other course. Tumor response was determined by using the Response Evaluation Criteria in Solid Tumors.33
Pharmacokinetic Studies
Pharmacokinetic studies were performed on day 10, 11, or 12 of course one. To measure the disposition of gefitinib at steady state, 2 mL of whole blood were collected in a sodium heparin tube before gefitinib administration and 1, 2, 4, 6, 8, 12, and 24 hours after administration. Samples were processed, and their gefitinib concentrations were analyzed by a high-performance liquid chromatography/mass spectroscopy method.34 The lower limit of quantitation of gefitinib was 0.30 ng/mL, the interday coefficient of variation was 5.2%, and the intraday coefficient of variation was 6.0%.
Gefitinib concentration-time data from 14 patients from whom samples were collected at all time points were first modeled by maximum likelihood in ADAPT II.35 A one-compartment oral-absorption model was used to describe gefitinib disposition, and the parameters that were estimated included apparent volume of the central compartment (Vc/F), elimination rate constant (Ke), absorption rate constant (Ka), and half-life (t1/2). Estimates of these parameters from this group of patients then were used to develop a maximum a posteriori Bayesian model that was used to model data from three patients from whom samples were not collected at all time points. Finally, data from the entire group of 17 patients were then modeled by using maximum a posteriori Bayesian estimation as implemented in ADAPT II using prior estimates from the group of 17 patients. Apparent clearance (Cl) was calculated by standard equations, and the area under the plasma concentration-time curve (AUC0-24) was calculated by the log-linear trapezoidal method.
Gefitinib protein-binding studies were conducted. Briefly, a plasma sample was placed in a Micropartition system (Amicon Corp, Danvers, MA), and the plasma ultrafiltrate was collected. The percent of unbound gefitinib was calculated from the gefitinib concentration in the ultrafiltrate in relation to the gefitinib concentration before ultrafiltration (bound and unbound).
RESULTS
A total of 25 patients were enrolled on this trial, and their characteristics are summarized in Table 1. Six of these 25 patients were not fully assessable for toxicity: one patient withdrew from the study 9 days after the start of treatment because of social reasons, and five patients had disease progression within 24 days after the start of treatment. The remaining 19 patients (median age, 15 years; range, 1.8 to 21.2 years) were fully assessable for toxicity (Table 2). They received a total of 54 courses of treatment (median number of courses per patient, 1; range, 1 to 15 courses).
Toxicity
Three patients experienced DLT (Table 2). Of the six patients treated with 500 mg/m2 of gefitinib, one had a grade 2 rash that was unacceptable to him and persisted for 10 days after drug discontinuation, and a second patient had a grade 3 rash that was painful. One of the six patients treated with 400 mg/m2 had a grade 4 ALT elevation and a grade 3 AST elevation that persisted for 21 days after drug discontinuation. No DLT was observed in patients treated with gefitinib at dosages of 150 or 300 mg/m2/d. The MTD was determined to be 400 mg/m2/d. After determining the MTD, a seventh patient (younger than 12 years) was treated with the MTD to further define the tolerability and pharmacokinetics of gefitinib in young children.
Table 3 lists the toxicities that were possibly, probably, or definitely related to gefitinib in the 19 assessable patients. In addition to the toxicities listed, there was one episode each of grade 1 epistaxis, mouth dryness, pruritis, hypoalbuminemia, dry eye, keratitis, abdominal pain, and hypertension that were attributable to gefitinib. The most common toxicities were rash and dry skin, elevated liver transaminases, anemia, diarrhea, nausea, and vomiting. In patients for whom data about the dates of onset and resolution of toxicities were available, the rash started on day 11.5 (median; range, day 6 to 24) and lasted 18 days (median; range, 5 to 147 days); elevation of AST/ALT started on day 21 (median; range, day 1 to 29) and lasted 24 days (median; range, 8 to 29 days); and diarrhea started on day 10 (median; range, day 8 to 20) and lasted 1 day (median; range, 1 to 16 days). Nausea and vomiting were mild except in one patient who had grade 3 nausea and vomiting in association with progressive neuroblastoma in the abdomen. One patient with ependymoma treated with 500 mg/m2 of gefitinib experienced intratumoral bleeding associated with disease progression on day 19 of treatment. Except for the single episode of asymptomatic keratitis, no eye toxicity was observed.
Antitumor Activity
One patient with recurrent Ewing’s sarcoma had a partial response after one course of treatment with 150 mg/m2 of gefitinib, and the response lasted 10 weeks. Computed tomography of the chest in this patient showed four pleural-based pulmonary metastases (longest diameters ranged from 2 to 6.3 cm) that completely resolved after gefitinib treatment (Fig 1) with persistence of a small nonmeasurable lesion (longest diameter, < 1 cm). Disease stabilized in four patients. One patient with exophytic brainstem glioma (pilocytic astrocytoma arising in the brainstem with a small exophytic component) treated with 400 mg/m2 of gefitinib had stable disease for 40 weeks; disease in this patient had previously progressed 7 months after completing treatment with partial resection, carboplatin, and radiation. Another patient with brainstem glioma (treated with 400 mg/m2 of gefitinib), who had disease progression 5 months after the completion of radiotherapy, had stable disease for more than 60 weeks; this patient was removed from the study after 60 weeks and, at the time this article was written, continues to receive commercially available gefitinib. Two patients with Wilms’ tumor had stable disease for 8 and 16 weeks. Seventeen patients had disease progression, including five patients who had progression before completing one course of therapy and 12 patients who had progression after receiving one to two courses of therapy. Tumor response could not be determined in three patients who withdrew from study because of toxicity after receiving only one course of therapy (two patients) or because of social reasons 9 days after the start of treatment (one patient).
Pharmacokinetics
Serial samples for pharmacokinetic studies were collected from 14 patients at all time points on day 10, 11, or 12 of course one. In three patients, only a limited number of samples were collected (to 4 or 6 hours after gefitinib administration). The remaining eight patients either declined to participate in the pharmacokinetic studies (n = 5) or were removed from the study before or on day 12 (n = 3). A representative gefitinib plasma concentration-time profile is shown in Figure 2. A summary of the pharmacokinetic parameters in relation to gefitinib dosage is presented in Table 4. Although the calculated gefitinib dose was rounded to the nearest 25 mg, the actual dose administered to patients was still within 10% of the prescribed dose. Gefitinib AUC increased with increasing dosage (Fig 3). At the MTD (400 mg/m2/d), the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL), and was observed at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance for all patients studied was 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2). No difference in gefitinib apparent clearance was observed between children older than 12 years (13.7 ± 6.6 L/h/m2; n = 10) and those younger than 12 years (14.4 ± 6.9 L/h/m2; n = 7). The median gefitinib half-life for all patients studied was 11.7 hours (range, 5.6 to 22.8 hours). The median proportion of unbound gefitinib was 0.3% (range, 0.1% to 1.5%) in the analyzed samples (n = 14).
DISCUSSION
The MTD of gefitinib administered on a daily basis in children with recurrent or refractory solid tumors was 400 mg/m2/d. Overall, children tolerated gefitinib well. Similar to findings in adult patients, rash was dose limiting; this DLT was seen at a dose of 500 mg/m2/d (approximately equivalent to an absolute dose of 865 mg for adults). Although a grade 4 ALT elevation and a grade 3 AST elevation occurred in one patient (treated with 400 mg/m2), elevations in liver transaminases were generally mild to moderate. In contrast to the experience in adults,12-14 diarrhea was mild in children. The incidence of interstitial lung disease among adult patients who received gefitinib was 2% in the Japanese postmarketing experience and approximately 0.3% in an expanded-access program in the United States.16 In the randomized studies of gefitinib combined with chemotherapy, the rate of interstitial lung disease ranged from 0.3% to 2.1% in the gefitinib arms and 0.8% to 0.9% in the control arm (chemotherapy plus placebo).36,37 In our pediatric trial, patients were not assessed objectively for interstitial lung disease, but none of the patients enrolled developed symptoms of pulmonary toxicity.
One patient with ependymoma treated with 500 mg/m2 of gefitinib experienced intratumoral bleeding in the context of disease progression. On a concurrently conducted Pediatric Brain Tumor Consortium trial of concurrent gefitinib and radiotherapy followed by continued gefitinib therapy, symptomatic intratumoral bleeding was observed in five (15%) of 33 children with gliomas who received a daily gefitinib dose of 250 mg/m2 (n = 2) or 375 mg/m2 (n = 3).32 No relation between these events and dexamethasone administration, thrombocytopenia, or coagulation abnormality was noted. Because of these adverse events, our study was amended to exclude patients with primary tumors of or known metastases to the CNS. The frequency of intratumoral bleeding does not seem to be increased among adult patients with glioma enrolled on gefitinib trials.20,38-41 Limited information in the literature on the occurrence of spontaneous intracranial hemorrhage from brain tumors reveals that the overall frequency ranged from 2.4% to 10%, with higher frequency in pituitary adenoma (15.8%).42-45 However, the true incidence of intratumoral bleeding in children with gliomas receiving radiotherapy in the era of magnetic resonance imaging is unknown.32 Therefore, it is unclear whether the intratumoral bleeding in children with brain tumors receiving gefitinib was related to the natural history of the disease and improved detection by magnetic resonance imaging, treatment with gefitinib, radiotherapy, or a combination of these factors.
In adult patients with squamous cell carcinoma of the head and neck or colorectal cancer, the occurrence of skin toxicity significantly correlated with response to gefitinib19 or cetuximab,46 an anti-EGFR monoclonal antibody. Diarrhea, but not EGFR expression, predicted favorable overall survival for patients with glioblastoma treated with gefitinib.20 Our patient with Ewing’s sarcoma and partial tumor response had grade 1 dry skin during course two and grade 2 rash during course three, and our patients with brainstem glioma and prolonged disease stabilization had grade 1 or 2 rash during nine of 11 courses (n = 1) or 13 of 15 courses (n = 1).
The pharmacokinetics of gefitinib in children are comparable with those observed in adults. Gefitinib was absorbed slowly, with a range of 2 to 8 hours required to reach maximum plasma concentrations, similar to the 1 to 12 hours found in adult studies.14,47 The maximum gefitinib plasma concentration at each dose level was variable but increased as the gefitinib dose increased. Interpatient variability of this orally administered drug was significant (Fig 3), with an approximate eight-fold variation in apparent clearance (3.8 to 24.8 L/h/m2). Preclinical studies suggest that exposure to concentrations more than 100 ng/mL may be sufficient for biologic activity.7,48 Importantly, patients treated at all dose levels exhibited steady-state gefitinib plasma concentrations above this threshold. Moreover, gefitinib systemic exposures (AUC0-24) achieved in children were comparable with those associated with antitumor activity in adults.14
Although limited clinical activity was observed in our study, continued development of gefitinib in children, including performing additional correlative studies, seems warranted. Somatic mutations in the tyrosine kinase domain of EGFR were identified recently in 81% of patients with lung cancer exhibiting response to EGFR tyrosine kinase inhibitors.30,31,49 In addition, phosphorylation of Akt, a major EGFR-signaling pathway, is independently associated with response to gefitinib in patients with unknown receptor mutation status.50 Thus, examination of EGFR mutations and Akt phosphorylation represent a critical area for future correlative studies in pediatric patients.
Additional development of gefitinib in children will likely also be explored in combination with cytotoxic chemotherapy. Preclinical studies using human tumor xenografts in mice showed that gefitinib significantly potentiated the antitumor activity of irinotecan in six tumor lines of glioblastoma multiforme, neuroblastoma, rhabdomyosarcoma, and osteosarcoma.51 The effect of gefitinib seemed to be independent of the tumor’s ERBB1 status.51 Investigations to explain the mechanism of synergy between gefitinib and irinotecan showed that gefitinib inhibits drug efflux by breast cancer–resistance protein (BCRP; ABCG2) and, therefore, may modulate the activity of SN-38 (the active metabolite of irinotecan and a BCRP substrate) at the cellular level.52,53 Similarly, CI1033, a HER tyrosine kinase inhibitor, enhances cytotoxicity of SN-38 by inhibiting BCRP-mediated drug efflux.54 Koizumi et al55 showed that, in colorectal cancer cell lines and xenografts, administration of gefitinib and irinotecan have supra-additive effects that are potentially mediated by the increased irinotecan-mediated phosphorylation of EGFR, which leads to enhancement of gefitinib-induced apoptosis.56 To this end, a phase I trial of the combination of gefitinib and irinotecan in children with refractory solid tumors is being conducted.57
Our study has demonstrated that gefitinib was well tolerated as a once-daily oral tablet formulation. Although there is wide interpatient variability in drug exposure, biologically relevant gefitinib plasma concentrations seem to be readily maintained in children. Based on preclinical data, the development of gefitinib in combination with cytotoxic chemotherapeutic agents with a mechanism of resistance that is mediated by BCRP, such as irinotecan, is being explored.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Melissa Aguayo for assistance in coordinating the study; Dr Feng Bai for analytic support; and Dr Julia Cay Jones for editing the manuscript.
NOTES
Supported by grant No. CA 97452 from the National Cancer Institute, Bethesda, MD, and by AstraZeneca, Wilmington, DE.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Bai F, Iacono LC, Johnston B, et al: Determination of gefitinib in plasma by liquid chromatography with a C12 column and electrospray tandem mass spectrometry detection. J Liq Chromatogr 27:2743-2758, 2004
D’Argenio DZ, Schumitzky A: ADAPT II User’s Guide. Los Angeles, CA, Biomedical Simulations Resource, USC, 1990
Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004
Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial–INTACT 2. J Clin Oncol 22:785-794, 2004
Peery TS, Reardon DA, Quinn J, et al: Phase II trial of ZD1839 for patients with first relapse glioblastoma. Proc Am Soc Clin Oncol 22:99, 2003 (abstr 396)
Chakravarti A, Seiferheld W, Robins HI, et al: An update of phase I data from RTOG 0211: A phase I/II clinical study of gefitinib + radiation for newly-diagnosed glioblastoma (GBM) patients. Proc Am Soc Clin Oncol 22:124s, 2004 (abstr 1571)
Prados M, Yung W, Wen P, et al: Phase I study of ZD1839 plus temozolomide in patients with malignant glioma. A study of the North American Brain Tumor Consortium. Proc Am Soc Clin Oncol 22 No 14S:108s, 2004 (abstr 1504)
Lieberman FS, Cloughesy T, Fine H, et al: NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas. Proc Am Soc Clin Oncol 22:109s, 2004 (abstr 1510)
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Furman W, Daw N, Crews K, et al: A phase I study of gefitinib and irinotecan (IRN) in pediatric patients with refractory solid tumors. Proc Am Soc Clin Oncol 14S:804s, 2004 (abstr 8521)(Najat C. Daw, Wayne L. Fu)
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
Keck School of Medicine, University of Southern California, Los Angeles, CA
Sainte-Justine Hospital, Montreal, Quebec, Canada
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD
Texas Children’s Cancer Center/Baylor College of Medicine, Houston, TX
James Whitcomb Riley Hospital for Children, Indianapolis, IN
Children’s National Medical Center-D.C., Washington, DC
Children’s Hospital of Philadelphia, Philadelphia, PA
ABSTRACT
PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors.
PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28).
RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non–dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing’s sarcoma had a partial response. Disease stabilized for 8 to 60 weeks in two patients with Wilms’ tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults.
CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.
INTRODUCTION
Gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) is an orally active anilinoquinazoline compound that potently inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase (IC50, 0.033 μmol/L).1,2 Epidermal growth factor receptor (EGFR) activation seems to promote tumor growth by increasing cell proliferation, motility,3 adhesion, and invasive capacity4 and by blocking apoptosis.5 This receptor is expressed in a number of human tumors, and increased levels of EGFR, its ligands, or both have been correlated with a poor prognosis in several solid tumor types in adults.6-8
In preclinical studies, gefitinib treatment was associated with dose-related growth inhibition and increased apoptosis in human cancer cell lines,9 and the drug showed antitumor activity against a broad spectrum of xenografts of adult human tumors.2,9 The combination of gefitinib and standard cytotoxic agents resulted in greater antitumor activity in and greater survival of mice than did either gefitinib or cytotoxic agents alone.9 This phenomenon was observed even in tumors without high levels of EGFR expression.10
In adult studies, gefitinib was well tolerated when given in intermittent or daily dosing.1,11 Gefitinib had good oral bioavailability and a long terminal half-life (range, 24 to 85 hours). A steady state was reached by day 7, and exposure to gefitinib showed a three- to 10-fold variability; no apparent increase in variability was associated with increasing dose.12,13 Rash and diarrhea were dose limiting at daily doses of 700 to 1,000 mg,12-14 a dose range well above that required to completely inhibit EGFR activation and downstream receptor signaling in skin biopsies of patients treated with gefitinib.15 Other types of toxicity included dry skin, pruritis, nausea, vomiting, asthenia, and elevations in serum transaminases. Interstitial lung disease has occurred in approximately 1% of adult patients who received gefitinib worldwide,16,17 and approximately one third of these cases have been fatal.16
Gefitinib has shown single-agent activity in adult patients with non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, and glioblastoma.18-20 In May 2003, gefitinib (250-mg tablets) was approved by the Food and Drug Administration as monotherapy for patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.16 Objective tumor response rates were 12% to 18% when 250 mg/d of gefitinib was given and 9% to 19% when 500 mg/d of gefitinib was given as third-line treatment of NSCLC.18,21
Although the expression of EGFR has not been evaluated comprehensively in pediatric tumors, expression has been documented in neuroblastoma22,23 and rhabdomyosarcoma24,25 cell lines and in tumor samples from patients with neuroblastoma,26 Wilms’ tumor,27 osteosarcoma,28 and glioma.29 More recently, specific EGFR tyrosine kinase mutations were found to correlate with responsiveness of NSCLC to gefitinib30,31; whether similar mutations are found in pediatric tumors remains to be determined.
Between June 2002 and March 2004, the Children’s Oncology Group conducted a phase I trial of single-agent gefitinib in children with recurrent or refractory solid tumors. The primary aims of this trial were to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib administered orally once daily continuously and to characterize its pharmacokinetic behavior in children. The secondary aim was to preliminarily define its antitumor activity within the confines of a phase I study.
PATIENTS AND METHODS
Study Design
Gefitinib was administered orally once daily. A course was defined as 28 consecutive days of drug administration, and there was no interruption of dosing between courses. The starting dosage of gefitinib was 150 mg/m2 (equivalent to the absolute dose of 250 mg recommended for adults) with subsequent dosage levels of 300, 400, and 500 mg/m2. Intrapatient dosage escalation was not allowed. Protocol therapy was stopped if a patient’s disease progressed, if irreversible DLT occurred, or if a patient elected not to receive the study drug. In the absence of disease progression, any patient with DLT that resolved after temporary interruption of gefitinib administration could continue treatment at one dose level below the one that resulted in DLT.
A minimum of three patients assessable for toxicity were treated at each dose level. If one of the first three patients treated at any dose level experienced DLT during the first course of treatment, up to three additional patients were treated at that dose level. The MTD was defined as the dose level immediately below that at which two or more patients in a cohort of up to six experienced DLT during the first course of treatment. The first course was considered complete for the purpose of DLT evaluation and dose escalation if gefitinib was administered on at least 25 of the first 28 days of treatment. If a patient received the drug on less than 25 of the first 28 days for reasons other than toxicity, that patient was considered unassessable and was replaced.
Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Dose-limiting hematologic toxicity was defined as any grade 4 neutropenia or thrombocytopenia. Dose-limiting nonhematologic toxicity was defined as any grade 2 nonhematologic toxicity that resulted in the interruption of gefitinib treatment for more than 7 days and any grade 3 or 4 nonhematologic toxicity except grade 3 nausea and vomiting, grade 3 fever or infection, and grade 3 elevation in liver transaminases that returned to the baseline toxicity grade within 7 days after the interruption of gefitinib treatment. Gefitinib treatment was interrupted for any grade 2 toxicity that was unacceptable to the patient, any grade 2 toxicity that persisted for more than 3 days despite symptomatic treatment, or any grade 3 or 4 toxicity except grade 3 elevation in liver transaminases (gefitinib was continued unless this grade 3 elevation persisted for > 7 days). Gefitinib treatment was resumed when the toxicity resolved or when the toxicity grade returned to the baseline value.
Patient Eligibility
The eligibility criteria were the following: (1) age younger than 22 years at the time of study entry; (2) a diagnosis of a malignant solid tumor that was refractory to conventional therapy or for which no conventional therapy existed; (3) a Karnofsky score of 50 for patients more than 10 years and a Lansky Play-Performance Scale of 50 for children no more than 10 years of age; (4) a life expectancy that exceeded 8 weeks; (5) recovery from the toxicity because of prior therapy; (6) no chemotherapy within 2 weeks (4 weeks for prior nitrosourea therapy) and no biologic agent or growth factor therapy within 1 week of study entry; (7) no substantial radiotherapy to the bone marrow within 6 weeks of study entry (or within 6 months of study entry if prior radiotherapy to the craniospinal axis or to at least 50% of the pelvis was received; within 2 weeks of study entry if local palliative radiotherapy was received); (8) no allogeneic stem cell transplantation within 6 months of study entry and no active graft-versus-host disease; (9) no enzyme-inducing anticonvulsant therapy (because of its potential interaction with gefitinib) or drug therapy with known corneal toxicity; (10) adequate bone marrow function (an absolute neutrophil count 1,000/mm3, a platelet count 50,000/mm3, and a hemoglobin concentration 8.0 g/dL [red blood cell transfusion support allowed]; (11) adequate renal function (normal age-adjusted serum creatinine or glomerular filtration rate 70 mL/min/1.73 m2); and (12) adequate liver function (serum bilirubin concentration 1.5 x the upper limit of the normal range for age, ALT activity 3 x the upper limit of the normal range for age, and an albumin concentration 2 g/dL). Study exclusion criteria were uncontrolled infection and either pregnancy or lactation.
No limitation was placed on the number of prior chemotherapy regimens that each patient could have received. The study initially included patients with brain tumors or known metastasis to the CNS. The study was subsequently amended to exclude these patients after it was reported that intratumoral bleeding occurred in pediatric patients with brain tumors treated on a concurrent trial of concomitant administration of gefitinib and radiotherapy followed by continuous administration of gefitinib.32 Our study was approved by the institutional review boards at the individual participating institutions. Informed consent was obtained from patients 18 years and from parents or legal guardians of children, with child assent when appropriate, according to individual institutional policies.
Drug Formulation and Administration
Gefitinib was supplied by the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (IND 61,187), as biconvex, film-coated tablets containing 25, 100, or 250 mg of the drug. The calculated dose of gefitinib was rounded to the nearest 25 mg. In young children who were unable to swallow tablets or children with swallowing problems, tablets were dispersed in 30 to 60 mL of lukewarm water in a container for approximately 5 minutes. Immediately after the dispersion was complete, the container’s content was administered to the patient. The container was rinsed with a similar amount of water to ensure removal of any material that had adhered to the container’s wall, and the additional water was administered to the patient. Gefitinib was given without time specification in relation to food intake. Drugs that alter gastric pH such as proton-pump inhibitors and H2 blockers (which may decrease the absorption of gefitinib) were administered when needed at least 4 hours after gefitinib administration. In addition, because gefitinib is metabolized by hepatic CYP3A4/5, concurrent use of corticosteroids was permissible only in patients with CNS tumors who had increased intracranial pressure or were receiving a stable or decreasing dose of steroids at study entry.
Patient Evaluation
Patient histories were obtained and physical examinations and laboratory studies were performed before treatment and then weekly during the first course of treatment. Laboratory evaluation included complete blood counts and analyses of electrolytes (including calcium, phosphorus, and magnesium), blood urea nitrogen, creatinine, and liver function. These evaluations were performed before each subsequent course and as needed. A urinalysis and a pregnancy test (for female patients of childbearing age) were performed before treatment, and a total protein/albumin count was obtained before each treatment course. Because of concern about potential corneal toxicity of gefitinib, patients underwent an eye exam by an ophthalmologist before treatment, after the completion of the first course, and after every four courses thereafter. To ensure compliance with drug intake, a pill count was performed during each clinic visit.
Patients had disease evaluations performed at baseline, after the first and second courses, and then after every other course. Tumor response was determined by using the Response Evaluation Criteria in Solid Tumors.33
Pharmacokinetic Studies
Pharmacokinetic studies were performed on day 10, 11, or 12 of course one. To measure the disposition of gefitinib at steady state, 2 mL of whole blood were collected in a sodium heparin tube before gefitinib administration and 1, 2, 4, 6, 8, 12, and 24 hours after administration. Samples were processed, and their gefitinib concentrations were analyzed by a high-performance liquid chromatography/mass spectroscopy method.34 The lower limit of quantitation of gefitinib was 0.30 ng/mL, the interday coefficient of variation was 5.2%, and the intraday coefficient of variation was 6.0%.
Gefitinib concentration-time data from 14 patients from whom samples were collected at all time points were first modeled by maximum likelihood in ADAPT II.35 A one-compartment oral-absorption model was used to describe gefitinib disposition, and the parameters that were estimated included apparent volume of the central compartment (Vc/F), elimination rate constant (Ke), absorption rate constant (Ka), and half-life (t1/2). Estimates of these parameters from this group of patients then were used to develop a maximum a posteriori Bayesian model that was used to model data from three patients from whom samples were not collected at all time points. Finally, data from the entire group of 17 patients were then modeled by using maximum a posteriori Bayesian estimation as implemented in ADAPT II using prior estimates from the group of 17 patients. Apparent clearance (Cl) was calculated by standard equations, and the area under the plasma concentration-time curve (AUC0-24) was calculated by the log-linear trapezoidal method.
Gefitinib protein-binding studies were conducted. Briefly, a plasma sample was placed in a Micropartition system (Amicon Corp, Danvers, MA), and the plasma ultrafiltrate was collected. The percent of unbound gefitinib was calculated from the gefitinib concentration in the ultrafiltrate in relation to the gefitinib concentration before ultrafiltration (bound and unbound).
RESULTS
A total of 25 patients were enrolled on this trial, and their characteristics are summarized in Table 1. Six of these 25 patients were not fully assessable for toxicity: one patient withdrew from the study 9 days after the start of treatment because of social reasons, and five patients had disease progression within 24 days after the start of treatment. The remaining 19 patients (median age, 15 years; range, 1.8 to 21.2 years) were fully assessable for toxicity (Table 2). They received a total of 54 courses of treatment (median number of courses per patient, 1; range, 1 to 15 courses).
Toxicity
Three patients experienced DLT (Table 2). Of the six patients treated with 500 mg/m2 of gefitinib, one had a grade 2 rash that was unacceptable to him and persisted for 10 days after drug discontinuation, and a second patient had a grade 3 rash that was painful. One of the six patients treated with 400 mg/m2 had a grade 4 ALT elevation and a grade 3 AST elevation that persisted for 21 days after drug discontinuation. No DLT was observed in patients treated with gefitinib at dosages of 150 or 300 mg/m2/d. The MTD was determined to be 400 mg/m2/d. After determining the MTD, a seventh patient (younger than 12 years) was treated with the MTD to further define the tolerability and pharmacokinetics of gefitinib in young children.
Table 3 lists the toxicities that were possibly, probably, or definitely related to gefitinib in the 19 assessable patients. In addition to the toxicities listed, there was one episode each of grade 1 epistaxis, mouth dryness, pruritis, hypoalbuminemia, dry eye, keratitis, abdominal pain, and hypertension that were attributable to gefitinib. The most common toxicities were rash and dry skin, elevated liver transaminases, anemia, diarrhea, nausea, and vomiting. In patients for whom data about the dates of onset and resolution of toxicities were available, the rash started on day 11.5 (median; range, day 6 to 24) and lasted 18 days (median; range, 5 to 147 days); elevation of AST/ALT started on day 21 (median; range, day 1 to 29) and lasted 24 days (median; range, 8 to 29 days); and diarrhea started on day 10 (median; range, day 8 to 20) and lasted 1 day (median; range, 1 to 16 days). Nausea and vomiting were mild except in one patient who had grade 3 nausea and vomiting in association with progressive neuroblastoma in the abdomen. One patient with ependymoma treated with 500 mg/m2 of gefitinib experienced intratumoral bleeding associated with disease progression on day 19 of treatment. Except for the single episode of asymptomatic keratitis, no eye toxicity was observed.
Antitumor Activity
One patient with recurrent Ewing’s sarcoma had a partial response after one course of treatment with 150 mg/m2 of gefitinib, and the response lasted 10 weeks. Computed tomography of the chest in this patient showed four pleural-based pulmonary metastases (longest diameters ranged from 2 to 6.3 cm) that completely resolved after gefitinib treatment (Fig 1) with persistence of a small nonmeasurable lesion (longest diameter, < 1 cm). Disease stabilized in four patients. One patient with exophytic brainstem glioma (pilocytic astrocytoma arising in the brainstem with a small exophytic component) treated with 400 mg/m2 of gefitinib had stable disease for 40 weeks; disease in this patient had previously progressed 7 months after completing treatment with partial resection, carboplatin, and radiation. Another patient with brainstem glioma (treated with 400 mg/m2 of gefitinib), who had disease progression 5 months after the completion of radiotherapy, had stable disease for more than 60 weeks; this patient was removed from the study after 60 weeks and, at the time this article was written, continues to receive commercially available gefitinib. Two patients with Wilms’ tumor had stable disease for 8 and 16 weeks. Seventeen patients had disease progression, including five patients who had progression before completing one course of therapy and 12 patients who had progression after receiving one to two courses of therapy. Tumor response could not be determined in three patients who withdrew from study because of toxicity after receiving only one course of therapy (two patients) or because of social reasons 9 days after the start of treatment (one patient).
Pharmacokinetics
Serial samples for pharmacokinetic studies were collected from 14 patients at all time points on day 10, 11, or 12 of course one. In three patients, only a limited number of samples were collected (to 4 or 6 hours after gefitinib administration). The remaining eight patients either declined to participate in the pharmacokinetic studies (n = 5) or were removed from the study before or on day 12 (n = 3). A representative gefitinib plasma concentration-time profile is shown in Figure 2. A summary of the pharmacokinetic parameters in relation to gefitinib dosage is presented in Table 4. Although the calculated gefitinib dose was rounded to the nearest 25 mg, the actual dose administered to patients was still within 10% of the prescribed dose. Gefitinib AUC increased with increasing dosage (Fig 3). At the MTD (400 mg/m2/d), the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL), and was observed at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance for all patients studied was 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2). No difference in gefitinib apparent clearance was observed between children older than 12 years (13.7 ± 6.6 L/h/m2; n = 10) and those younger than 12 years (14.4 ± 6.9 L/h/m2; n = 7). The median gefitinib half-life for all patients studied was 11.7 hours (range, 5.6 to 22.8 hours). The median proportion of unbound gefitinib was 0.3% (range, 0.1% to 1.5%) in the analyzed samples (n = 14).
DISCUSSION
The MTD of gefitinib administered on a daily basis in children with recurrent or refractory solid tumors was 400 mg/m2/d. Overall, children tolerated gefitinib well. Similar to findings in adult patients, rash was dose limiting; this DLT was seen at a dose of 500 mg/m2/d (approximately equivalent to an absolute dose of 865 mg for adults). Although a grade 4 ALT elevation and a grade 3 AST elevation occurred in one patient (treated with 400 mg/m2), elevations in liver transaminases were generally mild to moderate. In contrast to the experience in adults,12-14 diarrhea was mild in children. The incidence of interstitial lung disease among adult patients who received gefitinib was 2% in the Japanese postmarketing experience and approximately 0.3% in an expanded-access program in the United States.16 In the randomized studies of gefitinib combined with chemotherapy, the rate of interstitial lung disease ranged from 0.3% to 2.1% in the gefitinib arms and 0.8% to 0.9% in the control arm (chemotherapy plus placebo).36,37 In our pediatric trial, patients were not assessed objectively for interstitial lung disease, but none of the patients enrolled developed symptoms of pulmonary toxicity.
One patient with ependymoma treated with 500 mg/m2 of gefitinib experienced intratumoral bleeding in the context of disease progression. On a concurrently conducted Pediatric Brain Tumor Consortium trial of concurrent gefitinib and radiotherapy followed by continued gefitinib therapy, symptomatic intratumoral bleeding was observed in five (15%) of 33 children with gliomas who received a daily gefitinib dose of 250 mg/m2 (n = 2) or 375 mg/m2 (n = 3).32 No relation between these events and dexamethasone administration, thrombocytopenia, or coagulation abnormality was noted. Because of these adverse events, our study was amended to exclude patients with primary tumors of or known metastases to the CNS. The frequency of intratumoral bleeding does not seem to be increased among adult patients with glioma enrolled on gefitinib trials.20,38-41 Limited information in the literature on the occurrence of spontaneous intracranial hemorrhage from brain tumors reveals that the overall frequency ranged from 2.4% to 10%, with higher frequency in pituitary adenoma (15.8%).42-45 However, the true incidence of intratumoral bleeding in children with gliomas receiving radiotherapy in the era of magnetic resonance imaging is unknown.32 Therefore, it is unclear whether the intratumoral bleeding in children with brain tumors receiving gefitinib was related to the natural history of the disease and improved detection by magnetic resonance imaging, treatment with gefitinib, radiotherapy, or a combination of these factors.
In adult patients with squamous cell carcinoma of the head and neck or colorectal cancer, the occurrence of skin toxicity significantly correlated with response to gefitinib19 or cetuximab,46 an anti-EGFR monoclonal antibody. Diarrhea, but not EGFR expression, predicted favorable overall survival for patients with glioblastoma treated with gefitinib.20 Our patient with Ewing’s sarcoma and partial tumor response had grade 1 dry skin during course two and grade 2 rash during course three, and our patients with brainstem glioma and prolonged disease stabilization had grade 1 or 2 rash during nine of 11 courses (n = 1) or 13 of 15 courses (n = 1).
The pharmacokinetics of gefitinib in children are comparable with those observed in adults. Gefitinib was absorbed slowly, with a range of 2 to 8 hours required to reach maximum plasma concentrations, similar to the 1 to 12 hours found in adult studies.14,47 The maximum gefitinib plasma concentration at each dose level was variable but increased as the gefitinib dose increased. Interpatient variability of this orally administered drug was significant (Fig 3), with an approximate eight-fold variation in apparent clearance (3.8 to 24.8 L/h/m2). Preclinical studies suggest that exposure to concentrations more than 100 ng/mL may be sufficient for biologic activity.7,48 Importantly, patients treated at all dose levels exhibited steady-state gefitinib plasma concentrations above this threshold. Moreover, gefitinib systemic exposures (AUC0-24) achieved in children were comparable with those associated with antitumor activity in adults.14
Although limited clinical activity was observed in our study, continued development of gefitinib in children, including performing additional correlative studies, seems warranted. Somatic mutations in the tyrosine kinase domain of EGFR were identified recently in 81% of patients with lung cancer exhibiting response to EGFR tyrosine kinase inhibitors.30,31,49 In addition, phosphorylation of Akt, a major EGFR-signaling pathway, is independently associated with response to gefitinib in patients with unknown receptor mutation status.50 Thus, examination of EGFR mutations and Akt phosphorylation represent a critical area for future correlative studies in pediatric patients.
Additional development of gefitinib in children will likely also be explored in combination with cytotoxic chemotherapy. Preclinical studies using human tumor xenografts in mice showed that gefitinib significantly potentiated the antitumor activity of irinotecan in six tumor lines of glioblastoma multiforme, neuroblastoma, rhabdomyosarcoma, and osteosarcoma.51 The effect of gefitinib seemed to be independent of the tumor’s ERBB1 status.51 Investigations to explain the mechanism of synergy between gefitinib and irinotecan showed that gefitinib inhibits drug efflux by breast cancer–resistance protein (BCRP; ABCG2) and, therefore, may modulate the activity of SN-38 (the active metabolite of irinotecan and a BCRP substrate) at the cellular level.52,53 Similarly, CI1033, a HER tyrosine kinase inhibitor, enhances cytotoxicity of SN-38 by inhibiting BCRP-mediated drug efflux.54 Koizumi et al55 showed that, in colorectal cancer cell lines and xenografts, administration of gefitinib and irinotecan have supra-additive effects that are potentially mediated by the increased irinotecan-mediated phosphorylation of EGFR, which leads to enhancement of gefitinib-induced apoptosis.56 To this end, a phase I trial of the combination of gefitinib and irinotecan in children with refractory solid tumors is being conducted.57
Our study has demonstrated that gefitinib was well tolerated as a once-daily oral tablet formulation. Although there is wide interpatient variability in drug exposure, biologically relevant gefitinib plasma concentrations seem to be readily maintained in children. Based on preclinical data, the development of gefitinib in combination with cytotoxic chemotherapeutic agents with a mechanism of resistance that is mediated by BCRP, such as irinotecan, is being explored.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Melissa Aguayo for assistance in coordinating the study; Dr Feng Bai for analytic support; and Dr Julia Cay Jones for editing the manuscript.
NOTES
Supported by grant No. CA 97452 from the National Cancer Institute, Bethesda, MD, and by AstraZeneca, Wilmington, DE.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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