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Logo of neuroncolAboutAuthor GuidelinesEditorial BoardNeuro-Oncology
Neuro-oncol. Jan 2006; 8(1): 67–78.
PMCID: PMC1871925

Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma1

Abstract

The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmacokinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eighty-three patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%–71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.

Keywords: EGFR, enzyme-inducing antiepileptic drugs, erlotinib, glioma, recurrent, temozolomide

Gliomas are the most common primary brain tumors in adults (CBTRUS, 2002–2003). Initial treatment includes surgery, radiation therapy, and chemotherapy. Although modest improvements in survival are observed with radiation and chemotherapy (Berg et al., 2003; Stewart, 2002), the prognosis remains poor. Targeted agents that interfere with signal transduction pathways have been identified as a possible approach to improving outcome.

Widely investigated as a target for treatment, human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR)3 dysregulation is pivotal in the growth and progression of many solid tumors, including glioblastoma multiforme (GBM) (Salomon et al., 1995; Tang et al., 1997). Therapeutic approaches in development include small-molecule tyrosine kinase inhibitors such as erlotinib (Tarceva [Genentech, South San Francisco, Calif.; OSI Pharmaceuticals, Melville, N.Y.; and F. Hoffmann-La Roche, Basel, Switzerland), gefitinib (Iressa [AstraZeneca Pharmaceuticals, Wilmington, Del.]), and GW572016 (GlaxoSmithKline, Research Triangle Park, N.C.).

Data from preclinical studies in glioma tumor cell lines suggest that erlotinib (Vogelbaum et al., 2003) and gefitinib (Guillamo et al., 2003; Learn et al., 2004) may have activity against brain cancer. In addition, erlotinib, but not gefitinib, has activity against the EGFRvIII mutant receptor in animal models (Iwata et al., 2002; Learn et al., 2004). Several studies have found this highly dysregulated mutant receptor in GBM (Moscatello et al., 1995; Wikstrand et al., 1995) and noted an association with enhanced tumorigenicity (Lund-Johansen et al., 1990; Nagane et al., 1996; Nishikawa et al., 1994).

Combining erlotinib with chemotherapy can result in added tumor growth inhibition in preclinical xenograft models. Inhibition of tumor growth was significantly greater when erlotinib was combined with gemcitabine or cisplatin in the A549 non-small-cell lung cancer (NSCLC) tumor model than when erlotinib was used alone (P [less-than-or-eq, slant] 0.05), but was not significantly different in the H460a NSCLC tumor model (Higgins et al., 2004). Erlotinib combined with gemcitabine in pancreatic adenocarcinoma cells increased apoptosis (Ng et al., 2002). A dose-dependent supra-additive increase in growth inhibition was observed in a number of cancer cell lines from ovary, breast, and colon cancer when cancer cells were treated with gefitinib in combination with various cytotoxic agents, with markedly enhanced apoptotic cell death (Ciardiello et al., 2000). Recent data from a phase 3 trial of erlotinib in combination with gemcitabine in patients with advanced pancreatic cancer showed a 23.5% improvement in survival with the addition of erlotinib (Moore et al., 2005). However, phase 3 trials combining erlotinib and standard chemotherapy in patients with advanced NSCLC failed to show additional benefit (Gatzemeier et al., 2004; Herbst et al., 2005). As monotherapy, however, phase 3 data show erlotinib significantly prolongs overall survival as compared with placebo (42.5% improvement) in patients with advanced NSCLC who have failed one or more prior chemotherapy regimens (Shepherd et al., 2005).

Temozolomide (Temodar [Schering-Plough Corp., Kenilworth, N.J.]) is an oral alkylating agent with efficacy in GBM in the first-line, advanced, and recurrent settings (Brandes et al., 2002; Stupp et al., 2005; Yung et al., 2000). We felt the combination of erlotinib and temozolomide was a rational treatment strategy because of the single-agent activity of temozolomide and because of the preclinical data that show additive and in some cases supra-additive antitumor activity when cytotoxic chemotherapy and HER1/EGFR-targeted agents are combined. The main toxicity profile of erlotinib includes diarrhea and rash, while the toxicity of temozolomide is primarily myelosuppression and mild constipation. Temozolomide is rapidly transformed to its active metabolites when given orally, and the pharmacokinetics of the metabolites is not influenced by the use of enzyme-inducing agents. The pharmacokinetics of erlotinib and its metabolite OSI-420, however, is influenced by enzyme-inducing agents. Combining both agents required a phase 1 study design with the plan to use a fixed dose of temozolomide and to escalate the dose of erlotinib with the use of enzyme-inducing anticonvulsants.

The objectives of this phase I study were to define the maximum tolerated dose (MTD) of erlotinib and characterize its pharmacokinetics when administered as a continuous oral daily dose on a 28-day treatment cycle, alone or in combination with temozolomide, with or without coadministration of enzyme-inducing antiepileptic drugs (EIAEDs) in patients with malignant gliomas. The safety profile of erlotinib was also evaluated.

Methods

Eligibility

Patients 18 years of age or older with histologically proven supratentorial malignant primary glioma—including GBM, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma not otherwise specified—were eligible for inclusion. A life expectancy of longer than 8 weeks and a Karnofsky performance status of [gt-or-equal, slanted]60 were required.

Patients with either stable or progressive disease were eligible for treatment. Patients who received prior therapy, including interstitial brachytherapy or stereo-tactic radiosurgery, must have had confirmation of true progressive disease rather than radiation necrosis, confirmed by positron emission tomography or thallium scanning, magnetic resonance spectroscopy, or surgical documentation of disease. Adequate bone marrow (white blood cells [gt-or-equal, slanted] 3000/μl, absolute neutrophil count (ANC) [gt-or-equal, slanted] 2000/μl, platelet count [gt-or-equal, slanted] 120,000/μl, and hemoglobin [gt-or-equal, slanted] 10 g%), liver function (serum glutamic-oxaloacetic transaminase and bilirubin < 1.5 times the upper limit of normal), and renal function (creatinine < 1.5 mg/dl or creatinine clearance [gt-or-equal, slanted] 60 ml/min) were required 14 days before patients entered the study.

Patients must have recovered from toxic effects of prior therapy with a minimum of two weeks after receiving vincristine, six weeks for nitrosoureas, three weeks for procarbazine, and one week for noncytotoxic agents. Radiation treatment had to be completed at least three weeks before study entry. Patients had to be at least seven days past tumor resection, if done, and recovered from the effects of surgery or radiation. Measurable disease following recent resection of a recurrent tumor was not required for study entry. No more than three prior chemotherapeutic regimens were permitted. Patients also had to be on stable doses of concomitant medication, especially those affecting the cytochrome P450 pathway, before entering the study. Growth factors, erythropoietin, new CYP3A/4 inhibitors, and other investigational drugs were not permitted nor was previous use of erlotinib. All patients signed an informed consent form, and the protocol was approved by the institutional review board and conducted in accordance with institutional and federal guidelines for human investigation.

Exclusion criteria included patients with major illness inadequately controlled with therapy or disease that would compromise their ability to tolerate study treatment; significant gastrointestinal risk factors within the past six months; other cancers (except nonmelanoma skin cancer or carcinoma in situ of the cervix) unless in complete remission and off therapy for a minimum of three years; active infection; or pregnancy.

Study Design and Treatment

Patients were assigned to receive erlotinib alone or combined with temozolomide. Patients with disease progression while taking temozolomide received erlotinib alone. Patients who had never taken temozolomide or were currently taking temozolomide and had stable disease (SD) received combination therapy. Patients in each treatment group were stratified by EIAED use (EIAEDs include carbamazipine, oxcarbazepine, phenytoin, fos-phenytoin, phenobarbital, and primidone). Erlotinib was administered orally as a continuous, once-daily dose, with 28 days constituting a treatment cycle. Treatment was started at 100 mg/day or the highest dose found tolerable in previously treated patients. Erlotinib dose was escalated from 100 mg/day to 500 mg/day in 50-mg/day increments.

Three patients were treated at each dose level in four treatment groups (patients not on EIAEDs who were treated with erlotinib alone [1] or erlotinib plus temozolomide [2] and patients on EIAEDs who were treated with erlotinib alone [3] or erlotinib plus temozolomide [4]). Toxicity profiles were assessed weekly during the first two weeks to determine further dose escalations. If dose-limiting toxicity (DLT) was observed in the first two weeks of treatment, another three patients were added to that dose level. If no DLT was observed within the treatment group, the next three patients enrolled in that group received a higher dose. Dose escalation did not occur until toxicity was assessed in all three patients. Dose escalation could occur every two to four weeks.

Intrapatient dose escalation was allowed after the two-week assessment period if enrollment to the next dose level was open and the physician believed it was appropriate.

Clinical and radiographic tumor restaging took place after two cycles of treatment (every eight weeks). Patients were eligible to receive another treatment cycle if their tumor was stable or smaller and if their condition was clinically stable or improved with no evidence of DLT.

Temozolomide was administered orally at 150 mg/m2 for five consecutive days in the first cycle, beginning seven days after the start of erlotinib administration. For patients already on temozolomide, erlotinib treatment was started seven days before the next scheduled temozolomide cycle. The dose of temozolomide was increased to 200 mg/m2 for subsequent cycles provided there was no DLT or grade 3 myelosuppression at the initial dose. Treatment was repeated every 28 days to a maximum of one year.

Subsequent courses of temozolomide were delayed if patients had not recovered from prior treatment-related adverse events. Recovery was defined as ANC [gt-or-equal, slanted] 1500/μl, platelet count [gt-or-equal, slanted] 100,000/μl, and drug-associated nonhematologic toxicities stabilized at grade 0 or 1. The temozolomide dose in subsequent courses was determined according to the lowest ANC and platelet count for the previous temozolomide cycle.

DLT was defined as any nonhematologic grade 3 toxicity; grade 4 hematologic toxicity; or grade 2 cardiac, pulmonary, renal, gastrointestinal, skin, or CNS toxicity lasting longer than two weeks. Erlotinib was discontinued in patients with symptomatic corneal erosions and aberrant or inward growth of eyelashes associated with corneal erosions.

The MTD was based on DLT during the first two weeks of treatment at the relevant dose, which was defined as the dose at which fewer than one third of the patients experienced a DLT to erlotinib. The MTD was the dose level at which none of three or one of six patients experienced DLT, with the next higher dose causing DLT in at least two of three or two of six patients.

Dose reductions or interruptions of the study because of adverse events were permitted. Toxicity was based on the National Cancer Institute Common Toxicity Criteria scale, version 2 (NCI, 1999). If drug-related toxicity did not improve at least one grade, to grade 1 or lower, within two weeks of dose interruption or reduction, another dose reduction by one level was required. No more than two dose reductions were allowed.

Evaluations

Laboratory tests and neurologic examination were conducted, and a complete medical history was recorded at the start of the study. Evaluable disease was measured by MRI within 14 days prior to the start of erlotinib administration and while patients were on a cortico-steroid dose that had been stable for five to seven days. HER1/EGFR expression was not mandatory in this study, but data from a subset of patients with available tissue from primary or recent surgery will be reported separately.

Toxicity Assessment

Complete blood counts and platelet counts were performed weekly during the first four weeks of treatment, every two weeks during treatment, and with each increase in dose level. Prothrombin, partial thromboplastin time, serum electrolytes, calcium, phosphorus, magnesium, albumin, alkaline phosphatase, serum creatinine, bilirubin, serum glutamic–oxaloacetic transaminase, serum glutamic–pyruvic transaminase, bilirubin (total and conjugated), and blood urea nitrogen was assessed every four weeks before each cycle. Toxicity was assessed weekly for the first four weeks of treatment and every week for four weeks following an increased dose of erlotinib or temozolomide.

Pharmacokinetic Evaluations

Blood samples were collected on day 1 before drug administration, day 8 prior to drug administration, and 0.5, 1, 2, 3, 4, 5, 8, and 24 h after administration. Blood samples were also collected after erlotinib dose escalation on day 8 before drug administration and 0.5, 1, 2, 3, 4, 5, 8, and 24 h after administration.

Heparinized blood samples (5 ml; 2.5 ml of plasma) were centrifuged within 30 min of collection. Plasma was removed and frozen at −20°C or lower until analysis. Plasma concentration data for erlotinib and its O-demethylated metabolite (OSI-420) were analyzed by noncompartmental methods by using the WinNonlin software program (version 3.2; Pharsight, Mountain View, Calif.). The area under the plasma concentration–time curve from 0 to 24 h (AUC0–24) was calculated by using the linear trapezoidal rule. The maximum plasma concentration (Cmax) and the time to the maximum plasma drug concentration (Tmax) were determined by using WinNonlin. The metabolic ratio was calculated by dividing OSI-420 exposure (AUC0–24) by erlotinib exposure (AUC0–24).

The pharmacokinetics (PK) of erlotinib and OSI-420 were evaluated for 73 treatment courses. Data from 10 courses were insufficient to give accurate PK parameter estimates and so were not included in the analysis. The number of patients used from each dose group is listed in Table 1. Patients whose doses were escalated to the next level had repeat PK studies conducted.

Table 1
Pharmacokinetic parameter estimates for erlotinib

Efficacy Assessment

A brain MRI was performed before every other cycle. Tumor-response status, measured and recorded at each evaluation, was defined as measurable disease (bidimensional measurable lesions with clearly defined margins by computed tomography or MRI scan) or evaluable disease (unidimensional measurable lesions with margins not clearly defined). Status was measured and recorded at each evaluation. A non-study neuroradiologist independently reviewed patients who were claimed to have an objective response by MRI. Progression-free survival (PFS) and death were recorded. Definitions of response were as follows:

  • Complete response (CR): Absence of all measurable and evaluable disease, no new lesions, and no evidence of nonevaluable disease. Patients must be on physiologic replacement doses or not taking steroids.
  • Partial response (PR): A [gt-or-equal, slanted]50% decrease below baseline in the sum of the products of perpendicular diameters of all measurable lesions. No new lesions or progression of evaluable disease. Patients must be on the same or decreasing doses of dexamethasone
  • Stable or no response: Does not qualify as CR, PR, or progression. Must remain stable for a minimum of eight weeks.
  • Progression: A 25% increase in the sum of all measurable lesions over the smallest sum observed (or over baseline if no decrease) by using the same techniques at baseline, obvious worsening of any evaluable disease, appearance of any new lesion/site, or failure to return for evaluation because of death or deteriorating condition clearly unrelated to cancer.

Patients were removed from the study if disease progressed after a treatment cycle or toxicity delayed treatment for longer than 42 days from the start of the preceding cycle.

Statistical Analyses

The primary end point was safety using the NCI Common Toxicity Criteria, and the secondary end point was the drug disposition. A three-way analysis of variance was carried out for log10 (AUC0–24) for erlotinib and OSI-420 in a model with EIAED (yes/no), temozolomide (yes/no), dose (as a categorical variable), and two-way interactions. To enable direct comparison between the EIAED and non-EIAED groups, data from patients in groups receiving erlotinib at 100, 150, 200, and 250 mg/day only were included in the analysis. PK data from patients at all dose levels were collected. Patients were eligible for retreatment at higher erlotinib doses if the initial dose was well tolerated. However, for statistical analysis, only the PK data from a patient’s initial treatment were used. In some cases, PK data were collected from patients at several dose levels, and the contribution in each instance is shown in the PK summary in Table 1. Response and six-month PFS data are summarized in Table 2. PFS was defined as the time from start of study to a scan indicating progression. Response duration was defined as the time from first scan indicating PR until time of progression. Data for patients whose disease had not progressed at the time of the analysis were censored at the time of the last on-study scan.

Table 2
Details of eight partial responders and patients with PFS for six months or longer among the 57 patients evaluable for response

Results

The 83 patients who entered the trial are included in this report. Patients were enrolled from February 6, 2001, through April 19, 2004. Data for the two-week DLT assessment period are included for all patients. Otherwise, data are based on a data cutoff of May 1, 2004. Demographics and baseline characteristics are listed in Table 3. All patients were previously treated with radiation, 17 also had prior nitrosourea-based chemotherapy, 61 had prior non-nitrosourea-based chemotherapy, and five had received no prior chemotherapy. Of the 30 patients not taking EIAEDs, 16 received erlotinib alone and 14 received erlotinib combined with temozolomide. Of the 53 patients taking EIAEDs, 28 received erlotinib alone and 25 received erlotinib plus temozolomide. Eleven patients were enrolled at two doses (three from the non-EIAED group and eight from the EIAED group). Three patients in the EIAED group were enrolled at four doses.

Table 3
Demographics and baseline characteristics of 83 patients with stable or recurrent malignant glioma who entered the study.

Toxicity

In the non-EIAED group, the dose of erlotinib alone and combined with temozolomide ranged from 100 to 250 mg/day. In the EIAED group, the dose of erlotinib alone and combined with temozolomide ranged from 100 to 500 mg/day.

The recommended phase 2 dose of erlotinib was established as 200 mg/day for patients not receiving an EIAED, 450 mg/day for those receiving erlotinib and temozolomide with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED (Table 4). The MTD was not reached in patients receiving erlotinib alone with an EIAED, because although only one DLT was observed, the study was stopped at 500 mg/day. This was because a higher dose of 650 mg/day had already been reached with the same type of patients in a parallel phase 1 study being conducted by the North American Brain Tumor Consortium (NABTC) (Raizer et al., 2005). Given the preliminary evidence of efficacy in our trial (described below), and the objective of identifying the MTD of erlotinib in combination with EIAEDs in the NABTC study, our trial was stopped early in order to start a phase 2 trial.

Table 4
Dose-limiting toxicities*

Safety

Adverse events were generally minimal to moderate in severity, and the most common were rash, fatigue, and diarrhea (Table 5). Severe adverse events occurred in 22 patients (Table 6). Rash and abnormal platelet counts were the most common severe adverse events, reported by 11 and 10 patients, respectively. There was one treatment-related death, which was felt to be secondary to temozolomide-associated myelosuppression with infection. Five patients stopped treatment, four because of an adverse event and one who withdrew from the study. Eleven patients had a dose reduction during the trial, 10 because of rash and one because of dysphagia.

Table 5
Adverse events in 83 patients with stable or recurrent malignant glioma who received erlotinib alone or combined with temozolomide
Table 6
Severe adverse events in 22 patients according to treatment and dose of erlotinib

Antitumor Activity

Of 57 patients evaluable for response, eight had a PR (Table 2). Of the eight patients with a PR, two were not on EIAEDs, one of whom received erlotinib alone. Of the six patients who were on EIAEDs, five received erlotinib alone. Four patients with a PR had a PFS of longer than six months. Two patients, one on temozolomide without an EIAED and one on temozolomide with an EIAED, had stable disease resulting in a PFS of six months or longer (Table 2).

Pharmacokinetics

The PK parameter estimates for erlotinib are summarized in Table 1, including dose escalations within individual patients. Half-life was not assessed because of the limited sample collection period.

Following administration of erlotinib alone, systemic exposure to the drug (AUC0–24) and Cmax levels were similar in the 100-, 150-, and 200-mg/day groups (Fig. 1A). The 250 mg/day dose group had a nearly twofold higher AUC0–24 and Cmax than the other dose groups. Concentrations of OSI-420 were similar to those of erlotinib and were consistently 10% to 13% of the parent drug.

Fig. 1
Plasma concentration–time profiles of erlotinib following four doses of erlotinib alone or with enzyme-inducing antiepileptic drug (EIAEDs): (A) erlotinib alone and (B) erlotinib in combination with EIAEDs (E).

Coadministration of EIAEDs with erlotinib resulted in a marked reduction in exposure (33%–71%) to erlotinib (Fig. 1B) compared with that observed for erlotinib alone (Fig. 1A). A similar reduction in Cmax was observed. Exposure to erlotinib at 400 to 500 mg/day with EIAEDs was similar to that observed with erlotinib alone at 100 to 150 mg/day. The ratio of OSI-420 to erlotinib when coadministered with EIAED was higher than that with erlotinib alone. The AUC0–24 of OSI-420 with EIAEDs was similar to that without EIAEDs for most patients in all dose groups.

When erlotinib was combined with temozolomide, dose-related increases in drug exposure were observed across the 100- to 250-mg/day dose range (Table 1). OSI-420 concentrations were similar to erlotinib concentrations (data not shown) and were consistently 9% to 10% of erlotinib. Reduced exposure to erlotinib with concomitant administration of temozolomide and EIAEDs was similar to that observed with EIAEDs alone. The ratio of OSI-420 to erlotinib was 22% to 24% of the parent drug (Table 1).

Statistical analysis showed a significant effect of erlotinib dose and EIAED use on erlotinib exposure (P < 0.001). EIAED use lowered the AUC0–24, and the AUC0–24 increased with increasing dose. However, the increase in AUC0–24 with dose differed, depending on whether temozolomide was coadministered (P = 0.01 for a statistical interaction between dose and temozolomide). As described above, the data of OSI-420 AUC0–24 were highly variable and the pattern was unclear. Also, the differences among the dose levels differed, depending on whether temozolomide or EIAEDs were coadministered (P = 0.04 for a statistical interaction between dose and EIAED, and between dose and temozolomide).

Discussion

This phase 1 study sought to determine the MTD of erlotinib and characterize its pharmacokinetics alone and when combined with temozolomide in the presence and absence of EIAEDs.

Mild to moderate rash, fatigue, and diarrhea were the most common adverse events with erlotinib monotherapy in patients not taking an EIAED. Grade 3 rash with 250 mg/day was the main DLT, and based on these data, the MTD and recommended phase 2 dose of erlotinib with or without temozolomide is 200 mg/day (Table 7). When erlotinib was administered alone with EIAEDs, similar adverse events were reported, but DLT was observed at a higher dose (at least 500 mg). This is because EIAEDs reduced exposure to single-agent erlotinib. The MTD was not reached in patients receiving EIAEDs and erlotinib alone because the trial was stopped, as a higher dose (650 mg) had been reached in a parallel study by the NABTC. When temozolomide was given with erlotinib, the MTD was 450 mg/day. Based on these data, a dose of 450 mg/day is recommended for phase 2 trials in patients receiving erlotinib with temozolomide and EIAEDs, and a dose of 650 mg/day is recommended for patients receiving erlotinib alone with EIAEDS, based on the NABTC trial (Table 7).

Table 7
Recommended phase 2 dose of erlotinib

The adverse events observed in this study were similar to those in a phase 1 trial of erlotinib monotherapy in patients with various solid tumors: Mild to moderate rash and diarrhea were the most common adverse events, and diarrhea was dose limiting at 200 mg/day (Hidalgo et al., 2001). Rash is a common adverse event with all HER1/EGFR small-molecule tyrosine kinase inhibitors (Baselga et al., 2002; Herbst et al., 2005) and anti-HER1/EGFR monoclonal antibodies (Baselga et al., 2000). Although the exact etiology of this rash is unclear, it is likely to be associated with HER1/EGFR inhibition in the skin (Hidalgo et al., 2001). A similar safety profile has been reported in other phase 1/2 studies with erlotinib or gefitinib monotherapy (alone or combined with EIAEDs) in glioma. The most frequent adverse events were mild to moderate rash and diarrhea (Lieberman et al., 2004; Raizer et al., 2004; Rich et al., 2004; Uhm et al., 2004; Vogelbaum et al., 2004; Yung et al., 2004).

In this study, a total of eight patients had a PR, one on erlotinib not on an EIAED, five on erlotinib plus EIAEDs, and two on erlotinib combined with temozolomide (one with EIAEDs). Six patients had a PFS of six months or longer, four of whom also had a PR. This study was not designed to assess efficacy, but these preliminary data are encouraging and indicate that this combination is worthy of further study. Data from two phase 2 studies of erlotinib in glioma also suggest activity. In the first study, patients with recurrent, pretreated GBM who were not taking EIAEDs received erlotinib monotherapy at 150 mg/day. Of the 16 patients enrolled to date, four had a PR, one a mixed response, and four SD for more than three months. Enrollment is continuing (Vogelbaum et al., 2004). In the second study, GBM patients with measurable disease at first relapse received a starting dose of 150 mg/day (no EIAEDs) or 300 mg/day (with EIAEDs). Doses were increased until DLT or to 200 mg/day in the no-EIAED group and 500 mg/day in the EIAED group. Preliminary analysis of 47 patients showed one CR, two PRs, and 18 SDs. The median duration of response was 15.6 weeks and median time to progression eight weeks. Eight patients (17%) were progression free at 24 weeks (Yung et al., 2004).

In contrast, response data from study of erlotinib monotherapy at 150 mg/day in 45 patients with recurrent malignant gliomas who were not on EIAEDs (30 patients with GBM and 15 with anaplastic gliomas) were less encouraging. Four of the patients with GBM had SD, and the median PFS for all GBM patients was 12 weeks. For patients with anaplastic gliomas, PFS was 8.6 weeks, with one partial responder (unconfirmed) and two patients with SD (Raizer et al., 2004). Response was limited in this monotherapy study as compared with others, possibly because of differences in the treatment regimen or patient population in terms of factors like prior therapy and disease type. Further studies are needed to determine accurately the efficacy of different regimens in different patient groups.

Several studies are complete or ongoing with gefitinib, another HER1/EGFR inhibitor, in patients with glioma. In one phase 2 trial (Rich et al., 2004), 53 patients with GBM at first relapse receiving gefitinib at 500, 750, or 1000 mg/day and EIAEDs failed to show objective tumor responses or improved survival when compared with historical data (Wong et al., 1999). In another trial, patients with recurrent GBM, recurrent anaplastic glioma, or unresectable benign or malignant meningioma who received gefitinib at 500 mg/day without EIAEDs, or up to 1500 mg/day with EIAEDS, failed to show an increase in time to disease progression compared with historical controls (Lieberman et al., 2004). A phase 2 trial of patients with newly diagnosed, stable GBM who received gefitinib (500 mg/day, or escalated to 1000 mg/day in patients receiving dexamethasone and/or EIAEDs) did not show an improvement in overall PFS in comparison with historical controls (Uhm et al., 2004). Finally, preliminary data from an ongoing trial with gefitinib and temozolomide, similar to the erlotinib trial in this report, show that in 28 patients there was one CR and 14 patients with SD, four of whom did not have disease progression (Prados et al., 2004). Because of different eligibility and various treatment combinations examined in these studies, and as they are often not designed to assess response, interpretation of the relative efficacy of erlotinib and gefitinib in this setting is unclear. However, preliminary data with erlotinib may be more encouraging than with gefitinib. It is interesting to consider whether this is because of the potentially greater activity of erlotinib against the EGFRvIII mutant receptor (Iwata et al., 2002), frequently found in GBM (Moscatello et al., 1995; Wikstrand et al., 1995). Additional studies are needed to investigate further the efficacy of these agents in patients with malignant glioma.

The pharmacokinetic findings of this study support the recommended phase 2 dose of 200 mg/day for patients not taking an EIAED and a minimum of 450 mg/day for those taking an EIAED. At these doses (450–500 mg/day), exposure in patients receiving EIAED is expected to be approximately 50% lower than in those not receiving EIAEDs at the 200-mg/day dose. Systemic exposure and Cmax were similar in the dose ranges of 100 to 200 mg/day with erlotinib alone. A nearly twofold increase in AUC0–24 and Cmax was observed when the dose of erlotinib was increased to 250 mg/day, suggesting possible saturation of drug-clearance mechanisms.

Concomitant treatment with EIAED significantly reduced exposure to erlotinib, probably as the result of activation of cytochrome P450 enzymes responsible for the metabolism of erlotinib. A similar interaction has been reported in other studies with erlotinib (Yung et al., 2004) and gefitinib (Chakravarti et al., 2004). This interaction should be accounted for in future trial design.

The ratio of OSI-420 to erlotinib when coadministered with EIAED was higher than that for erlotinib alone. This was primarily because of a reduction in erlotinib level, possibly as a result of increased OSI-420 metabolism.

In contrast to the dramatic effect of coadministration with EIAEDs, only a modest pharmacokinetic interaction between erlotinib and temozolomide was observed. The nature of this interaction is paradoxical, as temozolomide tended to increase erlotinib exposure in the lower-dose groups (100–150 mg/day) not receiving EIAEDs. These effects are also more pronounced in the lower-dose groups receiving EIAEDs (Table 1). The reasons for these observations are unknown and could be attributed to the small group sizes or an imbalance in other factors that alter clearance.

In summary, erlotinib in combination with temozolomide, with or without EIAEDs, is well tolerated, and there is evidence of antitumor activity. Further investigation of this combination is warranted. Studies to evaluate the safety of erlotinib at doses higher than used in this study combined with EIAEDs are completed, and data will be reported shortly from the NABTC phase 1 trial. Phase 2 studies combining these two agents during and after radiotherapy in patients with newly diagnosed disease have begun.

Footnotes

1This clinical research has been funded by NIH P01-NS42927; NIH P50-CA097257; General Clinical Research Center at University of California, San Francisco, M01-RR00079, and Genentech, Inc. Some data from this study have been presented at the 12th European Cancer Conference (Prados et al. 2003a) and at the American Society for Clinical Oncology 2003 Annual Meeting (Prados et al. 2003b).

Dong Xie holds Genentech stock. Sean K. Kelley holds Genentech common stock and nonqualified stock options.

3Abbreviations used are as follows: ANC, absolute neutrophil count; AUC, area under the curve; AUC0–24, area under the plasma concentration–time curve from 0 to 24 h; Cmax, maximum plasma concentration; CR, complete response; DLT, dose-limiting toxicity; EGFR, epidermal growth factor receptor; EIAED, enzyme-inducing antiepileptic drug; GBM, glioblastoma multiforme; HER1, human epidermal growth factor receptor type 1; MTD, maximum tolerated dose; NABTC, North American Brain Tumor Consortium; NSCLC, non-small-cell lung cancer; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; SD, stable disease; Tmax, time to the maximum plasma drug concentration.

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