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© 2001 American Society for Clinical Oncology Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid MalignanciesByFrom the Institute for Drug Development, Cancer Therapy and Research Center, and the University of Texas Health Science Center at San Antonio, San Antonio, TX; U.S. Oncology, and Baylor University Medical Center, Dallas, TX; and Pfizer Pharmaceuticals, Inc, Groton, CT. Address reprint requests to Manuel Hidalgo, MD, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, Mail Code 7884, San Antonio, TX 78229; email: manuelh{at}oncology.uthscsa.edu
PURPOSE: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. RESULTS: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 µg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 µg/h/mL). CONCLUSION: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.
THE EPIDERMAL GROWTH factor receptor (EGFR), a type I receptor tyrosine kinase (TK) involved in the regulation of cellular differentiation and proliferation, is highly expressed by many types of human cancer and is a rational strategic target for anticancer therapeutic development.1-3 The receptor is composed of three major domains: an extracellular ligand-binding domain, a transmembrane lipophilic segment, and a cytoplasmic protein TK domain.1 After binding of epidermal growth factor (EGF), transforming growth factor alpha, and other activating ligands, the EGFR undergoes dimerization, which, in turn, activates the intrinsic protein TK via intermolecular autophosphorylation within its cytoplasmic domain. The tyrosine autophosphorylated region functions as a binding site for cytoplasmic messenger proteins, which thereby initiate a series of signals from the cytoplasm to the nucleus that culminate in DNA synthesis and cell division.2 The notion of targeting EGFR TK as a therapeutic strategy against cancer is supported by experimental evidence indicating that the dysregulation of the EGFR-mediated signal transduction pathways plays a role in tumorigenesis and cancer cell proliferation.3 The clinical relevance of this strategy is further substantiated by the overexpression of EGFR in head and neck, breast, brain, lung, cervical, bladder, gastrointestinal, renal, and other epithelial malignancies and the evidence indicating that EGFR overexpression is a determinant of tumor aggressiveness.3 EGFR activation can be inhibited by anti-EGFR antibodies, which block binding of endogenous ligands, as well as small molecules, which results in the inhibition of downstream components of the EGFR pathway.4 Because the activity and function of EGFR TK are necessary for receptor signaling, the development of specific small molecules that inhibit EGFR TK represents a logical therapeutic approach.5,6 Recently several classes of agents have been shown to be highly selective for EGFR TK and possess impressive preclinical activity against tumors that express EGFR.5,6 Nanomolar concentrations of the quinazoline OSI-774 ([6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl]-[3-ethylphenyl]amine; OSI Pharmaceuticals, Uniondale, NY; formerly known as CP-358,774; Pfizer Pharmaceuticals, Inc, Groton, CT) (Fig 1) inhibit the activity of purified EGFR TK and EGFR autophosphorylation in intact tumor cells, with 50% inhibitory concentration values of 2 and 20 nmol/L, respectively.6 OSI-774 is 1,000-fold more potent against EGFR TK than most other human kinases, including c-src and insulin receptor TK.6 In studies of Fisher rat embryo fibroblasts, nanomolar concentrations of OSI-774 inhibited cell division induced by EGF, whereas 1,000-fold higher drug concentrations were required to block cell division stimulated by other growth factors. Nanomolar concentrations of OSI-774 also were demonstrated to inhibit growth of various EGFR-expressing cancers in vitro, which is associated with cell cycle arrest in G1 and apoptosis.6 In addition, treatment of mice that bear human HN5 head and neck carcinoma xenografts with OSI-774 profoundly inhibited tumor growth, with a 50% effective dose of 9.2 mg/kg/d.7 In HN5 xenografts, OSI-774 inhibited intratumoral EGFR autophosphorylation with 50% effective doses of 9.2 and 9.9 mg/kg after intraperitoneal and oral administration, respectively. Maximum (90%) inhibition of EGFR autophosphorylation was evident 1 hour after administration of 100 mg/kg orally, EGFR autophosphorylation was reduced by 75% to 85% for at least 12 hours, and complete recovery was noted by 24 hours after treatment.7
Toxicology studies in both rodents and dogs revealed negligible toxicity after protracted daily administration of OSI-774 doses up to 15 mg/kg/d. At higher doses, emesis, gastric distention, and transient elevations in serum bilirubin occurred. Two of eight dogs treated with protracted daily OSI-774 doses in excess of 50 mg/kg/d developed edema, ulceration, and perforation of the cornea, and three developed azotemia. In preclinical pharmacology studies, OSI-774 was highly bioavailable (approximately 80%), and peak plasma concentrations were achieved within 2 hours after oral treatment. The agent also was demonstrated to be highly bound to plasma proteins (90% to 95%) and predominantly metabolized by the P450 microsomal isoenzyme CYP1C to an O-demethylated active metabolite (OSI-420). Dose-dependent pharmacokinetics were noted at OSI-774 doses that ranged from 2 to 50 mg/kg/d, but nonlinear pharmacokinetics were observed at higher doses.8 OSI-774 also was administered to healthy human volunteers before evaluations in cancer patients.8 Administration of a wide range of single oral doses of OSI-774 (10 to 1,000 mg) resulted in mild to moderate toxicities, including headache and a mild, diffuse, erythematous rash at the highest dose. However, all patients treated continuously with OSI-774 400 mg/d, in two divided daily doses, developed a severe papulopustular dermatitis that involved the face, scalp, chest, back, and arms. As a result, treatment was discontinued in all patients after a maximum of nine doses. The rash resolved slowly thereafter. Other, less profound effects included diarrhea, mucositis, and transient elevation of hepatic transaminases. Pharmacokinetic studies revealed drug accumulation with protracted daily treatment, which was not predicted from single-dose studies. The novel mechanism of action of OSI-774 as an EGFR TK inhibitor, and its impressive preclinical antitumor activity, served as the impetus for its clinical development. This phase I and pharmacokinetic study sought to evaluate the feasibility of oral OSI-774 administration on a protracted, continuous daily schedule to patients with advanced solid malignancies. The principal objectives of the study were to (1) determine the principal toxicities of OSI-774 administered on a protracted, continuous daily schedule, (2) determine the maximum tolerated dose (MTD) and recommend a dose for subsequent disease-specific evaluations, (3) characterize the pharmacokinetic behavior of OSI-774, and (4) seek preliminary evidence of antitumor activity.
Eligibility Patients with histologically documented advanced solid malignancies refractory to conventional therapy or for whom no effective therapy existed were candidates for this study. Eligibility criteria also included the following: (a) age 18 years or older; (b) Karnofsky performance status higher than 70% (capable of self-care); (c) life expectancy greater than 12 weeks; (d) no previous chemotherapy, radiation therapy, or major surgical procedures within 4 weeks of entry onto the study; (e) adequate hematopoietic (absolute neutrophil count  1,500/µL, hemoglobin level 9.0 g/dL, and platelet count 100,000/µL), hepatic (total bilirubin concentration  1.5 mg/dL; AST and ALT levels two times the upper normal limit [ five times the upper normal limit for patients with liver metastases]), and renal (creatinine concentration 1.5 mg/dL or creatinine clearance 50 mL/min) functions; (f) no active infection or other coexisting medical problems of sufficient severity to limit compliance with the study; and (g) no malabsorption syndrome or any other disorder that would affect gastrointestinal absorption. All patients gave written informed consent in accordance with federal and institutional guidelines before treatment.
Drug Administration In the first part of the study (part A), OSI-774 was administered daily for 3 days each week for 3 weeks. Courses were repeated every 4 weeks. The starting dose of OSI-774 was 25 mg, which was equivalent to one third of the toxic dose low of a single dose of the agent in healthy volunteers. At least three new patients each were treated successively with OSI-744 at dose levels of 25 mg/d, 50 mg/d, and 100 mg/d. In part B of the study, patients were treated with OSI-774 daily for 3 weeks every 4 weeks. In course 1 only, patients received a single dose of the agent on day 1, which was followed by a 2-day washout period for pharmacokinetic studies. Patients resumed treatment on day 4. The starting dose of OSI-744 in part B was to be 50 mg, provided that 100 mg was determined to be safe in part A. Dose escalation was to proceed in cohorts of at least three patients each in increments of 100%, spanning doses levels of 50 mg/d, 100 mg/d, and 200 mg/d. Thereafter, dose escalation was to be in increments of 200 mg/d in separate cohorts of new patients. Intermediate dose levels could be established to more precisely define the MTD. Once the MTD was established in part B, patients were treated with OSI-774 at this dose on a continuous, uninterrupted schedule (part C), and each 28-day period was considered one course of treatment. There was to be no further dose escalation in part C. Successive cohorts of at least three patients were treated at each dose level in parts A, B, and C. If any patient experienced dose-limiting toxicity (DLT) during course 1, as many as three additional patients were treated. The MTD was defined as the highest dose level at which less than two of six new patients experienced DLT in course 1. DLT was defined as any grade 3 or 4 hematologic or nonhematologic toxicity, because the principal study objective was to evaluate the feasibility of protracted daily administration. Nausea, vomiting, and diarrhea of grade 3 severity were considered DLT, provided that patients had received optimal antiemetics and antidiarrheal premedication and management, and elevations of hepatic transaminases were a DLT if grade 3 toxicity lasted longer than 7 days. Toxicities were graded according to the National Cancer Institute common toxicity criteria (version 1.0). Patients who developed DLT could continue to receive treatment at a reduced dose-schedule level after recovery. Intraindividual escalation of the dose-schedule level was allowed, provided that the patient had completed at least two courses of treatment with either no or grade 1 toxicity, the patient did not experience disease progression, and the next higher dose level had previously been determined to be safe in accordance with the aforementioned criteria.
Pretreatment and Follow-Up Studies Evaluations of measurable and assessable disease by appropriate radiologic studies, as well as an assessment of relevant tumor markers, were performed before treatment and after every other course. Patients were able to continue treatment in the absence of progressive disease. A complete response was scored if there was disappearance of all active disease on two measurements separated by a minimum period of 4 weeks, and a partial response required at least a 50% reduction in the sum of the products of the bidimensional measurements of all lesions documented by two measurements at least 4 weeks apart. A concurrent increase in the size of any lesion by 25% or more, or the appearance of new lesions, was considered disease progression.
Pharmacokinetic Sampling and Assay Separation of the plasma samples for quantification of both OSI-774 and OSI-420 was accomplished by reverse-phase high-performance liquid chromatography (HPLC) after extraction in our laboratory. After plasma samples were thawed to room temperature and vortexed, 100 µL of internal standard (OSI-597) solution was added to a 200-µL aliquot of sample in a 15-mL polypropylene extraction tube, and 5.0 mL of methyl t-butyl ether was added to each tube. The samples were then rotated for 10 minutes and centrifuged at 3,000 rpm for 5 minutes. The supernatant was transferred to a clean 5-mL polypropylene tube and evaporated to dryness under a gentle stream of nitrogen at room temperature. The extracts were reconstituted with 200 µL of the mobile phase, filtered through an Alltech Microspin Nylon 66 microcentrifuge filter (Alltech Associates, Deerfield, IL), centrifuged at 6,000 rpm for 3 minutes, and transferred to glass microinserts; 75 µL were then injected into the HPLC system. The HPLC system was equipped with a Waters model no. 515 isocratic solvent delivery pump (Waters Corporation, Milford, PA), a Waters model no. 717 refrigerated autosampler, a Waters model no. 2487 dual wavelength absorbance detector, and a Waters Symmetry (4.9 mm x 150 mm, 5 µm) C18 column. The flow rate was 1.0 mL/min, and an aliquot of 75 µL was injected for sample analysis. Detection of the compounds of interest was at 345 nm, and the data were collected by use of the Waters Millennium chromatography data collection software. OSI-774, OSI-420, and the internal standard were separated on a Waters Symmetry (4.9 mm x 150 mm, 5 µm) C18 column. Samples were eluted isocratically at a flow rate of 1.0 mL/min with a mobile phase that consisted of acetonitrile and water (vol/vol, 30/70; pH 2.40). Under these conditions, the retention times for OSI-774, OSI-420, and the internal standard were 3.2, 2.1, and 5.0 minutes, respectively. Standard curves for OSI-774 and OSI-420 were prepared over a concentration range of 10.0 to 2,500 ng/mL by the addition of known amounts of OSI-774, OSI-420, and internal standard to appropriate volumes of human plasma. Plasma concentrations were determined by plotting the plasma OSI-774 and OSI-420 peak areas to that of the internal standard versus known concentrations. The lower limit of assay quantification, which was based on the extraction of 200-µL plasma samples, was 10 ng/mL for both OSI-774 and OSI-420. The performance of the assay was monitored using quality control (QC) samples at 20, 200, and 2,000 ng/mL. On each day of analysis, duplicate QC samples at each concentration were extracted and quantified along with patient samples. Each separate analysis was considered acceptable if two thirds of all QC samples were within 15% of the nominal concentration and at least one QC sample was acceptable at each concentration analyzed.
Pharmacokinetic Analysis Pharmacokinetic parameters were characterized by use of descriptive statistics. The nonparametric statistical test for several unrelated (Kruskal-Wallis one-way analysis of variance [ANOVA]) or related (Wilcoxon matched-pairs signed-rank test) parameters was used to determine whether the pharmacokinetics of OSI-774 were dose or time dependent. Relationships between drug dose and indices that reflect drug exposure (Cmax, AUC, and Css,min) were evaluated with the Kruskal-Wallis one-way ANOVA test. The extent of drug exposure as determined by Cmax, AUC, and Css,min was compared among patients with various grades of toxicity with the use of nonparametric statistical tests for two (Mann-Whitney U test) or several (Kruskal-Wallis one-way ANOVA) independent samples.
Immunohistochemistry
General Forty patients, whose pertinent characteristics are listed in Table 1, received a total of 123 28-day courses of OSI-774. The median number of courses administered per patient was two (range, 1 to 20+), and a single patient was in treatment at the time of this report. One patient, who was taken off study as a result of the development of pneumonia after 7 days of treatment with OSI-774 150 mg/d in study part C, was not considered fully assessable. Thirty-seven patients had received cytotoxic therapy previously, including 29 patients who had been treated with chemotherapy alone and eight patients who had been treated with both chemotherapy and radiation. The numbers of patients and courses administered as a function of the dose-schedule levels are listed in Table 2. Dose reduction and escalation were performed in five patients each, and four patients were treated with OSI-774 in two study parts.
In study part A (OSI-774 once daily for 3 days each week, for 3 weeks every 4 weeks), no DLT occurred among three groups of new patients treated with doses of 25, 50, and 100 mg/d. In study part B (OSI-774 once daily for 3 weeks every 4 weeks), four groups of new patients were treated with 50, 100, 150, and 200 mg/d of OSI-774. Because one of three patients treated at the 200-mg/d dose level experienced DLT during course 1, three additional patients were treated. Overall, three patients experienced DLT during course 1, including grade 3 diarrhea (one patient) and grade 4 diarrhea (one patient), and another patient developed a grade 2 but clinically intolerable acneiform rash. To evaluate whether the administration of the agent on a divided daily dose schedule would permit further dose escalation, the next group of patients was treated with OSI-774 at a dose of 100 mg twice daily for 3 weeks every 4 weeks. This strategy was not successful, however, as one of three new patients in course 1 developed a grade 2 but clinically intolerable acneiform rash, which was considered dose limiting. Three additional patients were then treated with OSI-774 at the dose level of 150 mg once daily, and they experienced no DLT. In the final part of the study (part C), one of 12 new patients developed DLT (grade 3 mucositis) after treatment with OSI-774 150 mg/d on a continuous once-daily dose schedule, which was considered the MTD.
Toxicity
Diarrhea Both the incidence and severity of diarrhea generally seemed related to the schedule and dose of OSI-774. Although there were no episodes of diarrhea among nine patients treated with 20 courses of OSI-774 on the intermittent schedule evaluated in part A, 18 patients experienced 38 episodes of diarrhea during treatment on the protracted schedules evaluated in parts B and C. In part B, in which patients were treated with OSI-774 doses that ranged from 50 to 200 mg/d for 3 weeks every 4 weeks, the incidence of patients who experienced diarrhea increased with higher doses of OSI-774. Diarrhea was not noted among five patients who received nine courses at the 50-mg/d dose level (part B); however, 25%, 86%, and 67% of patients treated with OSI-774 at doses of 100, 150, and 200 mg/d, respectively, experienced diarrhea. Most episodes of diarrhea were mild to moderate (grade 1 to 2) in severity. In general, the onset of this toxicity occurred during weeks 3 to 4 of course 1, and symptoms were either self limited or managed successfully with nonspecific, symptomatic measures such as loperamide. OSI-774 was not discontinued for mild to moderate diarrhea, which usually did not worsen with cumulative treatment. Severe (grade 3 to 4) diarrhea occurred in only two patients; they were treated with OSI-774 200 mg/d in study part B. The first patient, a 69-year-old woman with breast cancer and liver metastases, developed grade 4 diarrhea and abdominal discomfort on day 18 of her first course. The event was characterized by eight to 10 watery stools daily, which resulted in dehydration that required treatment with parenteral fluids. This toxicity resolved 3 days after OSI-774 was discontinued. The second patient, a 49-year-old woman with ovarian carcinoma, developed grade 3 diarrhea on day 8 of course 1, which worsened to a grade 4 event on day 13 despite treatment with loperamide. At peak toxicity, the patient had 10 to 12 watery bowel movements daily and developed dehydration, hypokalemia, and hypotension. The episode resolved 2 to 3 days after drug discontinuation and treatment with parenteral fluids and octreotide. The study protocol was amended subsequently to allow treatment with loperamide (4 mg orally followed by 2 mg orally every 2 hours until resolution of diarrhea), which was initiated consistently at the earliest onset of diarrhea. Thereafter, severe diarrhea was not noted among additional new patients treated with OSI-774 doses of 150 and 200 mg/d in study parts B and C, nor in the two patients who initially experienced grade 3 to 4 diarrhea at the 200-mg/d dose level in part B after dose reduction and protracted treatment at the 150-mg/d dose level.
Cutaneous Toxicity
Symptoms attributable to the cutaneous effects of OSI-774 were generally minimal as compared with the intensity of the cutaneous manifestations. In the majority of affected individuals, although the cutaneous effects were prominent, the rash was either asymptomatic or minimally symptomatic. Three patients, however, including one each treated with OSI-774 at the 100-mg bid and 200-mg once-daily dose levels in part B and one patient treated with OSI-774 150 mg/d in part C, developed clinically intolerable rash that was considered dose limiting, although it was grade 2 in severity as defined by the National Cancer Institute common toxicity criteria. These patients considered the overall cosmetic appearance of the cutaneous lesions to be intolerable. To determine whether OSI-774 dose schedules associated with lower peak plasma concentrations resulted in less cutaneous toxicity, three patients were treated with OSI-774 100 mg/d on a twice-daily divided daily dose schedule, but the intensity, onset, and qualitative features of the cutaneous toxicity were similar in these patients. At the OSI-774 150-mg/d dose level in study part C, which was ultimately determined to be the MTD and the dose recommended for phase II studies, seven (50%) of 14 assessable patients experienced cutaneous toxicity during 51 courses, but only one required termination of treatment because of unacceptable cutaneous effects.
Miscellaneous Toxicities After concurrent chronic toxicology studies revealed possible corneal toxicity in dogs treated with high doses of OSI-774, the final 16 patients enrolled onto the study underwent serial ophthalmologic examinations, including slit lamp assessments, to evaluate potential corneal effects. Only one patient, who wore contact lenses and had a normal examination immediately before treatment, was noted to have corneal edema, subepithelial infiltrates, and a minimal decrement in visual acuity after a single 28-day course of OSI-774 150 mg/d (part C). These effects, considered typical manifestation of keratitis punctata probably related to contact lenses, resolved shortly after both OSI-774 treatment and contact lens use were discontinued. These corneal effects did not recur after administration of an additional course of OSI-774 and permanent discontinuation of contact lenses.
Antitumor Activity
Pharmacokinetic Studies Complete plasma sampling for pharmacokinetic studies was performed after treatment on day 1 in all 40 patients enrolled onto the study. Plasma sampling also was performed in all nine patients in study part A, 16 of 18 new patients in part B, and 10 of 13 new patients in part C on days 3, 24, and 28, respectively. Trough (pretreatment) plasma samples were collected on days 11, 18, and 24 of course 1 in 17, 16, and 16 of 18 patients enrolled onto study part B and in 12, 11, and 10, of 13 new patients enrolled onto study part C on days 8, 15, 22, and 29, respectively. Plasma concentration-time curves of OSI-774 and its principal metabolite, OSI-420, on days 1 and 24 in a representative patient are shown in Fig 4. The pertinent pharmacokinetic parameters of OSI-774 derived by use of noncompartmental methods are listed in Table 4. After oral ingestion, the OSI-774 Cmax values (Tmax) were achieved at a median of 3 hours (range, 2 to 12 hours). Both Cmax and AUC0-24 values were roughly proportional to the OSI-774 dose in the range of 25 to 200 mg/d (R2 = 0.33 and 0.46, respectively, on day 1). Intersubject variability was moderate at the 150-mg/d dose level, as indicated by coefficient of variation values of 64% for day 1 AUC0-24 and Cmax.
The plasma sampling scheme used in study part B, in which extensive plasma collections were performed after treatment on days 1 and 24, permitted characterization of the disposition of OSI-774. In these patients, the values for Cl/F, elimination t1/2, and volume of distribution averaged 6.3 ± 6.4 L/h, 24.4 ± 14.6 hours, and 136 ± 93 L, respectively, on day 1 and 5.2 ± 3.5 L/h, 31.4 ± 39.8 hours, and 93.9 ± 97.7 L, respectively, on day 24. At doses that ranged from 50 to 200 mg/d, there were no differences in Cl/F values among dosage groups on day 1 (P = .1, Kruskal Wallis nonparametric test) and day 24 (P = .7, Kruskal Wallis nonparametric test), which further supports dose-independent pharmacokinetics. In addition, Cl/F values were not significantly different for paired intraindividual assessments performed on days 1 and 24 (6.3 ± 6.4 L/h v 5.2 ± 3.5 L/h [P = .5, Wilcoxon signed rank test]), and day 24–day 1 AUC ratios averaged 1.01 (range, 0.4 to 2.2), which indicates time-independent pharmacokinetics. In patients treated in study parts B and C, mean Css,min values increased from 0.28 ± 0.10 µg/mL to 1.36 ± 0.46 µg/mL as the dose of OSI-774 was increased from 50 to 200 mg/d, as shown in Fig 5. At the MTD of OSI-774 (150 mg/d), Css,min values ranged from 0.33 to 2.64 µg/mL (median, 1.2 ± 0.62 µg/mL), and interpatient variability was moderate (coefficient of variation, 51%).
The principal metabolite, OSI-420, was reliably measured in patients treated with OSI-774 doses of at least 50 mg/d. At the OSI-774 dose level of 150 mg/d, mean Cmax and AUC0-24 values on day 1 were 0.085 ± 0.038 µg/mL and 1.69 ± 1.42 µg·h/L, respectively, and Tmax averaged 6.00 ± 5.83 hours (range, 2 to 24 hours). The results indicated that exposure to OSI-420 relative to that of the parent compound was low. On day 1, the OSI-420–OSI-774 AUC0-24 ratio averaged 0.121 (range, 0.002 to 0.58), and the ratio was nearly identical on subsequent days of treatment.
Pharmacodynamics
The transduction of proliferative signals mediated by extracellular growth factor receptors, such as the EGFR, is an attractive target for therapeutic development in cancer. The notion that EGFR may be a strategic target is supported by preclinical studies, which have demonstrated that the EGFR is expressed, overexpressed, or mutated in the majority of human cancers, and receptor expression has been demonstrated to be a negative prognostic determinant in some malignancies.3 EGF-dependent cell proliferation can be inhibited in vitro by antibodies against the extracellular domain of the EGFR, antisense oligonucleotides, which elicit expression of dominant negative mutants, and small molecule inhibitors of the EGFR TK.4-7,9-10 Clinical evaluation is underway for several strategies, and the preliminary results of these efforts are exciting.11-15 OSI-774, a low-molecular weight quinazoline inhibitor of EGFR tyrosine phosphorylation, blocks transduction of proliferative signals mediated by the EGFR in a concentration-dependent manner. The agent was selected for development in part because of its extraordinarily high specificity as an inhibitor of the EGFR TK, with negligible activity against other receptor and nonreceptor TKs.6 In preclinical studies, OSI-774 demonstrated notable antitumor activity against neoplasms that express the EGFR with a predictable and tolerable toxicologic profile.7 This phase I and pharmacologic study was designed to evaluate the feasibility of oral administration of OSI-774 on a protracted, continuous daily dose schedule, which was associated with prominent activity in preclinical studies, presumably because it results in prolonged exposure to biologically relevant concentrations.8 The toxicities associated with OSI-774 at the MTD and recommended phase II dose of 150 mg/d were tolerable. At this dose level, DLT occurred in one of 12 new patients, and there was adequate safety experience with protracted daily administration over multiple courses. In contrast, there was an unacceptably high rate of early DLT in patients treated at the next higher dose of OSI-774 200 mg/d administered for 3 weeks every 4 weeks. The principal toxicities of OSI-774 were cutaneous effects and diarrhea. Similar toxicities have been observed with monoclonal antibodies and other small-molecule inhibitors of EGFR in early clinical evaluations, which suggests that these adverse effects are related to similar underlying mechanisms of action. This hypothesis is supported by studies in mice, in which complete or partial knock out of the EGFR gene results in significantly altered and thinned epidermis and abnormal colonic mucosa.11,12,14-16 These results suggested that the EGFR and/or its downstream signaling effects are important for the proper development of these EGFR-rich tissues. Although the rash and diarrhea seemed to be caused by inhibition of the EGFR, the precise pathogenic mechanisms for these toxic effects are unknown. Despite the acneiform appearance of the cutaneous lesions, the histologic characteristics of affected cutaneous tissues were dissimilar to those of a typical acneiform drug eruption. The principal pathologic finding was a neutrophilic infiltrate in a perifollicular distribution, presumably caused by the release of cytokines by the follicular cells or keratinocytes. Of interest, the maximum intensity of the dermatologic toxicity occurred during week 2, and it then resolved gradually despite uninterrupted daily treatment with OSI-774. In some cases, the rash resolved completely by week 4 of treatment, but the majority of affected patients had scattered active acneiform lesions in various stages of progression and regression for the duration of therapy. It is important to recognize that the National Cancer Institute common toxicity grading scale did not permit accurate classification of the dermatologic effects of OSI-774 in accordance with the degree of functional impairment. This inadequacy is illustrated by the fact that three patients considered their cutaneous manifestations clinically intolerable and therefore dose limiting despite classification as grade 2 toxicity. Although these patients considered the cosmetic appearance of their cutaneous lesions intolerable, which led to dose modification and/or treatment delay, other individuals with cutaneous toxicity of similar quality and intensity did not consider the toxic effects intolerable. This demonstrates the need to develop a grading scale for cutaneous toxicity that takes into account patients’ subjective views of the cosmetic appearance of the skin manifestations and functional impairment. The pharmacokinetic results in the present study confirm the biologic relevance of the recommended phase II dose. The antiproliferative activity of OSI-774 against human tumor xenografts has been related to the inhibition of the EGFR, as would be expected with a true rationally designed target-based therapeutic modality.7 Furthermore, it has been demonstrated that the magnitude of EGFR inhibition achieved after OSI-774 treatment of human tumors grown in vitro and xenografts is concentration dependent.6,7 In mice treated with a single oral dose of OSI-774, maximum inhibition of the EGFR is observed approximately 1 hour after treatment, and complete recovery generally occurs within 24 hours, which further supports the rationale for development of a protracted daily administration schedule.7 Based on the results of pharmacodynamic studies in animals, corrected for interspecies differences in protein binding, OSI-774 plasma concentrations of approximately 0.5 µg/mL have been estimated to provide a level of EGFR inhibition associated with a relevant degree of antiproliferative activity. As shown in Fig 5, the Css,min values in the majority of patients treated at the 150-mg/d dose level exceeded 0.5 µg/mL, whereas Css,min values of this magnitude were achieved much less frequently in patients treated with 50 and 100 mg/d. Nonetheless, cutaneous toxicity, presumed to be attributable to EGFR inhibition, also was common in patients treated with 50 and 100 mg/d of OSI-774. Although it would be reasonable to perform phase II screening studies of OSI-774 at 150 mg/d, further evaluations of the effects of OSI-774 dose and concentration on EGFR inhibition in tumors and suitable surrogate tissues are necessary to provide information regarding the relative merits of various dose levels in inhibition of EGFR activation. Similar information also can be obtained by assessment of whether relevant clinical outcomes are truly different in patients treated with low- versus high-dose OSI-774 in randomized clinical trials. Skin and other accessible tissues potentially can be used as pharmacodynamic markers to assess and serially observe relevant pathologic and biologic effects of OSI-774. Assays of this type may facilitate the optimal development of OSI-774 doses and schedules. More important, relation of histopathologic and biologic effects in skin to inhibition of the EGFR and antiproliferative activity in tumors may lead to the development of assays to predict the likelihood of a benefit from treatment. Although skin toxicity was not related to time to treatment failure in the present study, however, such relationships cannot be studied adequately in the context of a phase I trial to evaluate the toxicologic effects of a wide range of doses in patients with a variety of tumor types, previous therapy, performance status, and EGFR status, as well as largely inaccessible tumor sites. The histopathologic and biologic effects of OSI-774 in both skin and tumor currently are being studied for clinical benefit in a disease-directed evaluation of the agent in patients with head and neck cancer. This study incorporates prospective, serial, and concurrent assessments of antitumor activity, dermatopathology, EGFR phosphorylation, and downstream signaling in both cutaneous and tumor tissues.17 The development of OSI-774 and other EGFR-directed therapeutics presents many unique challenges with regard to clinical trial design. One dilemma encountered in the present study, which undoubtedly will be revisited in evaluations of other inhibitors of growth factor receptor activation, is whether to restrict eligibility to patients whose malignancies have been documented to express the receptor target. With specific regard to patient eligibility restrictions based on EGFR status, documentation of "EGFR positivity" by use of conventional diagnostic monoclonal antibodies directed against the extracellular domain of the receptor does not ensure that the receptor is functional. In addition, EGFR mutations that give rise to truncated, albeit functional, EGF receptors, and that may not be appreciated with commercial antibodies used to assess EGFR status, have been reported.18 Furthermore, such EGFR mutations also may result in intrinsic receptor activation.18 Because most commercially available EGFR antibodies are directed against epitopes located in the extracellular domain of the EGFR, functionally positive EGFR tumors with mutations that alter the configuration of these epitopes may be incorrectly classified as EGFR-negative. These observations indicate the importance of evaluating EGFR activation status, in addition to total EGFR, in order to develop a more functionally and biologically accurate EGFR assessment strategy. It is hoped that the recent development of immunohistochemical methods to assess the functional status of EGFR, by use of antibodies targeted against the phosphorylated or activated EGFR, will increase the predictability of EGFR characterization, particularly for studies that relate EGFR status to antitumor activity and clinical outcome. It also will be important to evaluate signaling proteins downstream of EGFR, such as the mitogen-activated kinase and the phosphatidyl inositol 3-phosphate kinase, to develop an optimal strategy for selection of patients who might benefit most from treatment with EGFR-targeted therapeutics. The real-time assessment of EGFR activation and downstream signaling in skin and other accessible tissues may facilitate the development of optimal dose and schedule strategies, as well as the overall prioritization of EGFR-directed therapeutics. The results of this phase I and pharmacologic study indicate that treatment with OSI-774 on a daily, uninterrupted oral dose schedule is well tolerated, and biologically relevant plasma drug concentrations are achieved and sustained at the recommended phase II dose of 150 mg/d. The principal toxicities of OSI-774, cutaneous effects and diarrhea, probably are related to drug-induced EGFR inhibition. Preclinical studies indicate that the most likely favorable clinical manifestation of rationally designed therapeutics that target EGFR and other strategic components of growth signal transduction is a decreased rate of tumor growth, which may not be readily apparent or unequivocally attributed to the agent in phase I and nonrandomized phase II "screening" trials. Several patients with epidermoid carcinomas, the majority of which expressed EGFR, had relatively long periods of stable disease, but randomized clinical trials are required to gauge the validity and overall clinical impact of the antiproliferative effects of OSI-774. Although regression of several types of neoplasms has been observed in patients treated with OSI-774 and other low-molecular-weight inhibitors of EGFR in phase I and phase II clinical trials,13-15 it will be difficult to interpret the clinical significance of any level of tumor regression in nonrandomized clinical trials until there is sufficient experience with this class of compounds, similar to that with nonspecific cytotoxic agents.19 Nevertheless, it is clear that the optimal clinical development of OSI-774 will require the use of novel trial designs and strategies, perhaps in patients with tumors that have sufficient levels of the target. The development of biologic assays that enhance the assessment of the functional significance, and not only the presence, of the EGFR in tumors, as well as real-time pharmacodynamic assays that use skin and other accessible tissues to measure target inhibition and titrate drug effect in order to maximize the therapeutic index of OSI-774, undoubtedly will increase the therapeutic index of this unique anticancer agent.
Supported in part by a grant from Pfizer, Inc. Some patients were treated at the Frederic C. Barter General Clinical Research Unit of the Audie Murphy Veterans Administration Hospital, which is supported by NIH grant no. MO1 RR01346. M.H. is supported in part by grant no. PF 97 52273279 from the Ministerio de Educacion y Cultura, Spain, and is the recipient of a National Cancer Institute-European Organization for Research and Treatment of Cancer Fellowship Award.
OSI-774 (OSI Pharmaceuticals, Uniondale, NY) was formerly known as CP-358,774 (Pfizer Global Research and Development, Groton, CT). Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-19, 1999.
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ABSTRACT
INTRODUCTION
) by dividing the last measured concentration by the terminal rate constant (
z), which was determined from the log-linear fit of the terminal portion of the drug concentration-time curve. The oral clearance (Cl/F) was determined by dividing the dose by the AUC; the elimination half-life (t1/2) was calculated by dividing 0.693 by 
