Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study.

PURPOSE: Previous studies established the safety of continuous gefitinib 250 or 500 mg daily. It was postulated that a higher dose may have increased efficacy by inhibiting signaling in both the mitogen-activated protein kinase and AKT pathways. This study investigated the tolerability, pharmacokinetics, and antitumor activity of high-dose gefitinib in patients with refractory solid malignancies. METHODS: Sequential cohorts received oral gefitinib once or twice-weekly, with dose escalation from 1,500 to 3,500 mg. RESULTS: Twenty-three patients received gefitinib at seven dose levels (1,500, 2,000, 2,500, 3,000, and 3,500 mg once-weekly; 1,500 and 2,000 mg twice-weekly). Gefitinib was well tolerated, with no dose-limiting toxicities. The maximum tolerated dose was not reached. The most common gefitinib-related adverse events were nausea and diarrhea, vomiting, and rash. Pharmacokinetic data demonstrated no consistent increase in exposure to gefitinib with increasing dose across cohorts. Consequently, the study was stopped early and gefitinib 2,000 mg twice-weekly was the highest dose administered. One of eight patients with non-small-cell lung cancer achieved a partial response. CONCLUSIONS: Exposure to gefitinib did not increase consistently with increasing dose beyond gefitinib 1,500 mg once-weekly or twice-weekly. These data do not support further evaluation of gefitinib at high-dose schedules.

The effect of different etiologies of hepatic impairment on the pharmacokinetics of gefitinib.

PURPOSE: We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies. METHODS: In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days. RESULTS: In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts. CONCLUSIONS: We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.

Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors.

PURPOSE: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. EXPERIMENTAL DESIGN: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. RESULTS: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and C(max) of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. CONCLUSIONS: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d.

Effects of the Src inhibitor saracatinib (AZD0530) on renal function in healthy subjects.

BACKGROUND: Saracatinib (AZD0530), a potent Src inhibitor, is a subject of current evaluation as an anticancer therapy. Increased plasma creatinine levels have previously been observed after saracatinib administration in healthy subjects and this study was undertaken to characterize the underlying mechanism of this increase. SUBJECTS AND METHODS: 56 healthy male subjects were assigned to either single- (n=28; randomised to placebo or saracatinib 500 mg) or multiple-dose oral treatment (n=28; randomised to placebo or saracatinib 125 mg for 14 days). Renal function variables assessed included inulin clearance and tubular secretion of creatinine. RESULTS: Saracatinib led to a reduction in mean creatinine fractional excretion ratio, which was due to a reduction in tubular secretion of creatinine. Increased plasma creatinine was not associated with decreased glomerular filtration rate or increased creatinine production. CONCLUSION: The observed increase in plasma creatinine after saracatinib administration was due to reduced tubular secretion of creatinine, but was not considered to be clinically relevant in the context of this study.

Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial.

Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis.

Gefitinib-phenytoin interaction is not correlated with the C-erythromycin breath test in healthy male volunteers.

AIMS: We aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. METHODS: An open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg(-1) daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the (14)C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. RESULTS: Following treatment with phenytoin, mean gefitinib C(max) and AUC(0-infinity) decreased by 26 +/- 44% [95% confidence interval (CI) for the difference 5-48%, P= 0.005] and 47 +/- 26% (95% CI for the difference 34-60%, P= 0.001), respectively, and apparent oral clearance increased by 126 +/- 93% (95% CI for the difference 80-172%, P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 +/- 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase. CONCLUSIONS: The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.

Epidermal growth factor receptor tyrosine kinase inhibitors: similar but different?

Two small-molecule epidermal growth factor receptor tyrosine kinase inhibitors, gefitinib and erlotinib, have been approved for the treatment of non-small-cell lung cancer. Here, we compare the pharmacology and pharmacokinetics of these agents, and reflect on how these properties may affect important clinical questions including the clinical efficacy, optimum dose, and whether there is a relationship between skin rash and clinical outcome for each of these agents. Gefitinib and erlotinib have similar mechanisms of action and pharmacological profiles; however, different molecular structures confer pharmacokinetic differences that may have important clinical implications. Although gefitinib 250 mg/day produces lower mean plasma concentrations and area under the plasma concentration versus time curve compared with erlotinib 150 mg/day, published data suggest that gefitinib significantly accumulates in tumour tissue. This difference may partly explain why it seems possible to achieve maximum clinical efficacy with gefitinib at doses significantly lower than its maximum tolerated dose and, hence, use of an optimal biological dose approach with this agent. We hypothesize that gefitinib is used and is effective at a dose below the maximum tolerated dose as it accumulates in tumour tissue, thus providing the concentration needed at its target to achieve effective epidermal growth factor receptor inhibition in the tumour while causing less skin toxicity than erlotinib; therefore, skin rash is not a useful predictive factor for efficacy with gefitinib.

Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected].

PURPOSE: To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with gefitinib 250 or 500 mg/day or standard methotrexate. PATIENTS AND METHODS: Four hundred eighty-six patients with recurrent SCCHN were randomly assigned to oral gefitinib 250 mg/day, gefitinib 500 mg/day, or methotrexate 40 mg/m(2) intravenously weekly. Primary end point was overall survival, secondary end points were objective response rate (ORR), safety, symptom improvement, and quality of life (QOL). Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers. RESULTS: Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate (hazard ratio [HR], 1.22; 95% CI, 0.95 to 1.57; P = .12; and HR, 1.12; 95% CI, 0.87 to 1.43; P = .39, respectively). In the gefitinib 250 mg/day, 500 mg/day, and methotrexate groups, respectively, median overall survival was 5.6, 6.0, and 6.7 months; ORRs (Response Evaluation Criteria in Solid Tumors) were 2.7%, 7.6% and 3.9%, with no statistically significant difference between either gefitinib arm and methotrexate. No unexpected adverse events were observed, except for tumor hemorrhage-type events with gefitinib (8.9%, gefitinib 250 mg/day; 11.4%, gefitinib 500 mg/day; 1.9%, methotrexate). QOL improvement rates (Functional Assessment of Cancer Therapy-Head & Neck total score) were 13.4%, 18.0%, and 6.0% for gefitinib 250 mg/day, 500 mg/day, and methotrexate, respectively. CONCLUSION: In patients with recurrent or metastatic SCCHN, while responses with gefitinib were seen, neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate. With the exception of tumor hemorrhage-type events with gefitinib, the adverse event profiles were generally consistent with those previously observed.

Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. PATIENTS AND METHODS: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. RESULTS: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. CONCLUSION: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.