Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer.

BACKGROUND: This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: Patients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20 µg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20 µg/ml was above the prespecified non-inferiority margin of - 12.5%. RESULTS: For PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20 µg/ml; the lower limit of the 95% confidence interval (- 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (- 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%. CONCLUSIONS: PF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug-Drug and Drug-Disease Interactions.

Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of bosutinib; 2) verify and refine the PBPK models based on clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration. Results showed that the PBPK models adequately predicted bosutinib oral exposures in patients after single- and multiple-dose administrations. The PBPK models also reasonably predicted changes in bosutinib exposures in the single-dose DDI and DDZI results, suggesting that the PBPK models were sufficiently developed and verified based on the currently available data. Finally, the PBPK models predicted 2- to 4-fold increases in bosutinib exposures by moderate CYP3A inhibitors, as well as comparable increases in bosutinib exposures in renally and hepatically impaired patients between single- and multiple-dose administrations. Given the challenges in conducting numerous DDI and DDZI studies of anticancer drugs in patients, we believe that the PBPK models verified in our study would be valuable to reasonably predict bosutinib exposures under various scenarios that have not been tested clinically.

Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.

Population pharmacokinetic and pharmacodynamic analysis of bosutinib.

Bosutinib is an orally active, competitive inhibitor of Src/Abl tyrosine kinases. A population pharmacokinetic model was developed using data pooled from 3 studies of patients (n = 870) with solid tumors or Philadelphia chromosome-positive leukemia. Patients (aged 18-91 y, weighing 35-221 kg) who received bosutinib 50 to 600 mg orally with food each contributed 6-9 pharmacokinetic samples. The final pharmacokinetic model was a linear two-compartment model with first-order absorption, an absorption lag-time, and dose-dependent bioavailability. Oral absorption was relatively slow, with a half-time of 1.14 h and a lag-time of 0.87 h; time to peak concentration was 5-6 h. Apparent clearance was 120 L/h. The apparent volume of the peripheral compartment was large with a slow turnover; alpha and beta half-lives were 19 h and 290 days, respectively. All parameters were estimated with acceptable precision (standard error <30%). No tested covariate (protocol, baseline demographic/clinical characteristics, or laboratory results) explained the high inter-individual variability of bosutinib pharmacokinetics. Therefore, adjusting bosutinib dose for body size (weight, surface area) would not provide benefit over fixed dosing. Using this exposure model in pharmacodynamic assessment of one study, adverse event incidence was shown to be similar in overall and bosutinib-responsive populations.

Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors.

PURPOSE: Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses. RESULTS: Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway. CONCLUSION: The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.

A clinical study to examine the potential effect of lansoprazole on the pharmacokinetics of bosutinib when administered concomitantly to healthy subjects.

BACKGROUND: Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect bosutinib absorption. OBJECTIVES: The objectives of this study were to evaluate the effect of lansoprazole, a gastric proton pump inhibitor, on the pharmacokinetics and safety of bosutinib. METHODS: This open-label, non-randomized, phase I study involved inpatients and outpatients at a single site. The study participants were healthy men or women of non-childbearing potential aged 18-50 years. Each subject received bosutinib 400 mg on Day 1, lansoprazole 60 mg on Day 14, and bosutinib 400 mg co-administered with lansoprazole 60 mg on Day 15 under fasting conditions. The main outcome measure was the effect of multiple doses of lansoprazole on the pharmacokinetic profile of a single oral dose of bosutinib. RESULTS: A total of 24 healthy male subjects were enrolled. Co-administration with lansoprazole decreased the mean maximum plasma concentration (C(max)) of bosutinib from 70.2 to 42.9 ng/mL, and the total area under the plasma concentration-time curve (AUC) from 1,940 to 1,470 ng·h/mL. Log-transformed bosutinib pharmacokinetic parameters indicated significant between-treatment differences; the least squares geometric mean ratio for C(max) was 54 % (95 % CI 42-70) and for AUC was 74 % (95 % CI 60-90). Mean apparent total body clearance from plasma after oral administration increased from 237 to 330 L/h, and the median time to reach Cmax increased from 5 to 6 h, although this change may be related to decreased bosutinib absorption when combined with lansoprazole. When co-administered with lansoprazole, bosutinib maintained an acceptable safety profile, which was primarily characterized by diarrhea (33 %), headache (21 %), and nausea (13 %). One subject experienced serious adverse events of diverticulitis, gastritis, and duodenitis after co-administration; however, no participant withdrew because of toxicity. CONCLUSIONS: This study demonstrated that bosutinib absorption may be reduced when co-administered with lansoprazole or other proton pump inhibitors. Caution should be used with such drug combinations, as subtherapeutic exposure of bosutinib may limit its clinical antitumor activity; short-acting antacids are recommended instead.

Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.

PURPOSE: Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. METHODS: Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast. RESULTS: Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2). CONCLUSIONS: A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.

Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects.

BACKGROUND: Bosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of bosutinib, allowing for the study of bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. OBJECTIVE: This study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of bosutinib can be achieved with ketoconazole. METHODS: This was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days -1 and 1 through 4. RESULTS: Forty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18-50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for C(max) and 2980 (802) to 23,000 (4020) ng·h/mL for AUC(0-∞); mean AUC(0-24) and AUC(0-last) ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. C(max) and AUC were linear and dose proportional. Mean C(max) at 600 mg was 2.1-fold higher than the steady-state C(max) previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. CONCLUSIONS: Single doses of bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.

A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor.

PURPOSE: Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects. METHODS: A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5-7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7. RESULTS: No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28-72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52-90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea. CONCLUSIONS: Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects.

PURPOSE: Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, is in clinical development for the treatment of patients with chronic myelogenous leukemia (CML). To support clinical development, we conducted a dose-escalation and food-effect evaluation of safety, tolerability, and pharmacokinetics (PK) of bosutinib in healthy adults. METHODS: This was a randomized, double-blind, placebo-controlled, single-ascending dose, sequential-group study of oral bosutinib. Subjects randomly received bosutinib 200, 400, 600, and 800 mg with food; 200 and 400 mg without food; or placebo. Plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry assay. Non-compartmental PK analyses were performed, and power models assessed dose linearity. RESULTS: Of 55 enrolled subjects, 33 (81%) subjects had adverse events (AEs) after receiving bosutinib. Common AEs included diarrhea (39%), nausea (29%), and headache (22%). Bosutinib 200-600 mg with food was safe and well tolerated. Bosutinib exposures (C (max) and AUC) were linear and dose proportional from 200 to 800 mg with food. Absorption was relatively slow; median time to C (max) was 6 h. Apparent volume of distribution (V (z)/F) was 131-214 L/kg, mean apparent clearance (CL/F) was 2.25-3.81 L/h/kg, and mean terminal elimination half-life (t (1/2)) was 32-39 h. Preliminary food effect assessment showed that exposure to bosutinib increased by ~2.52-fold (P = 0.002) for C (max) and ~2.28-fold (P = 0.002) for AUC when 200 mg bosutinib was administered with food compared with administration under fasting conditions; administration of 400 mg bosutinib with food increased AUC by ~1.5-fold (P = 0.037). Approximately 1% of administered dose was excreted in urine. CONCLUSIONS: Bosutinib 200-600 mg with food was safe and well tolerated. Under fed conditions, bosutinib exposures were linear and dose proportional, and C (max) increased by ~1.5-fold. The t (1/2) supported a once-daily dosing regimen.

Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors.

PURPOSE: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. PATIENTS AND METHODS: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas). RESULTS: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. CONCLUSIONS: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.

A randomized, crossover, placebo- and moxifloxacin-controlled study to evaluate the effects of bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects.

Effects of therapeutic and supratherapeutic concentrations of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, on the corrected QT interval (QTc) in 60 healthy adults were assessed, according to ICH-E14 guidelines, in this 2-part, randomized, single-dose, double-blind, crossover, placebo- and open-label moxifloxacin-controlled study. Subjects received placebo, moxifloxacin and bosutinib 500 mg with food (therapeutic) in Part 1. In Part 2, subjects received placebo and bosutinib 500 mg plus ketoconazole (supratherapeutic). ANOVA compared baseline-adjusted QTc for bosutinib with placebo; and bosutinib plus ketoconazole with placebo plus ketoconazole. Primary endpoint was population-specific QT correction (QTcN). Secondary endpoints were Bazett QT correction (QTcB), Fridericia's formula QT correction (QTcF) and individual QT correction (QTcI). Upper bounds for 90% confidence intervals were <10 msec for the mean change in QTcN from placebo at all postdose time points, suggesting that mean therapeutic exposures (C(max) , 114 ng/mL; AUC, 2,330 ng · h/mL) and mean supratherapeutic exposures (C(max) , 326 ng/mL; AUC, 15,200 ng · h/mL) were not associated with QTc changes. Similar results were obtained for QTcB, QTcF and QTcI. No clinically relevant pharmacokinetic/pharmacodynamic relationship was observed between bosutinib concentrations and QTc. No subjects had QTcB, QTcF, QTcI or QTcN >450 msec or change from baseline >30 msec. In summary, therapeutic and supratherapeutic bosutinib exposures are not associated with QTc prolongation in healthy adults.

Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib.

Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects.

Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open-label, randomized, 2-period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once-daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of C(max(bosutinib+ketoconazole))/C(max(bosutinib alone)), AUC(T(bosutinib+ketoconazole))/AUC(T(bosutinib alone)), and AUC((bosutinib+ketoconazole))/AUC((bosutinib alone)) were assessed. Compared with bosutinib administered alone, coadministration with ketoconazole increased bosutinib C(max) 5.2-fold, AUC(T) 7.6-fold, and AUC 8.6-fold. Ketoconazole coadministration decreased the mean apparent clearance of bosutinib approximately 9-fold and increased the mean (SD) terminal half-life from 46.2 (16.4) hours to 69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between the 2 treatments. The most common AEs were headache, nausea, and increased blood creatinine. No safety-related discontinuations or serious AEs occurred. These PK results indicate that bosutinib is susceptible to interaction with potent CYP3A4 inhibitors.

A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects.

PURPOSE: Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance. EXPERIMENTAL DESIGN: This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo. RESULTS: Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were 450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P < 0.05). CONCLUSIONS: Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects.

Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer.

PURPOSE: Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. PATIENTS AND METHODS: Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. RESULTS: The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. CONCLUSION: Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.

A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.

PURPOSE: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. RESULTS: Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients. CONCLUSION: The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.

Disposition of desipramine, a sensitive cytochrome P450 2D6 substrate, when coadministered with intravenous temsirolimus.

PURPOSE: Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin (mTOR), is approved for treatment of renal cell carcinoma. In vitro studies with pooled human liver microsomes showed that temsirolimus and its principal metabolite, sirolimus, inhibit the CYP2D6 isozyme (K(i) = 1.5 and 5 microM, respectively), indicating potential for pharmacokinetic interaction with agents that are substrates of CYP2D6. METHODS: This 2-period study in healthy subjects investigated the pharmacokinetics of a single oral 50-mg dose of the CYP2D6 substrate desipramine, first without and subsequently with a single coadministered i.v. 25-mg dose of temsirolimus. RESULTS: The study population consisted of 25 males and 1 female; 10 were black, 12 were white, and 4 were of other races. Plasma and whole blood samples were available from all 26 subjects in period 1 following oral desipramine and from 23 subjects in period 2 following oral desipramine and i.v. temsirolimus coadministration. The 90% confidence intervals for least squares geometric mean ratios of desipramine and 2-hydroxy-desipramine C(max), AUC(T), and AUC were within 80-125%, indicating that parameter differences did not manifest into clinically relevant exposure changes. A single i.v. 25-mg dose of temsirolimus, alone or with desipramine, was well tolerated in healthy subjects. CONCLUSIONS: A single i.v. 25-mg dose of temsirolimus did not alter disposition of desipramine. Temsirolimus i.v. 25 mg may be safely administered with agents metabolized through the CYP2D6 pathway, but vigilance for drug interaction is warranted in patients with advanced malignancies.

A phase I study of EKB-569 in combination with capecitabine in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. EXPERIMENTAL DESIGN: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. RESULTS: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037). CONCLUSION: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.

Phase I pharmacokinetic/pharmacodynamic study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in first-line treatment of patients with metastatic colorectal cancer.

PURPOSE: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. RESULTS: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin. CONCLUSION: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.