Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers.

BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available. AIMS: Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions. METHODS: Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males. RESULTS/OUTCOMES: No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. CONCLUSIONS/INTERPRETATION: BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies.

AIMS: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. METHODS: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. RESULTS: In rats, BI 474121 was associated with a dose-dependent increase (71% at the highest dose tested [3.0 mg kg-1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum-measured concentration CSF-to-plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose-adjusted geometric mean: 8.96% overall). BI 474121 2.5-40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure-related change from baseline ratio, BI 474121: 1.44-2.20 vs. placebo: 1.26). The most common treatment-emergent adverse event (AE) was mild-to-moderate post-lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. CONCLUSIONS: BI 474121 crosses the blood-brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. CLINICALTRIALS: gov number (NCT04672954).

Predictors of mortality in subjects with progressive fibrosing interstitial lung diseases.

BACKGROUND AND OBJECTIVE: Demographic and clinical variables, measured at baseline or over time, have been associated with mortality in subjects with progressive fibrosing interstitial lung diseases (ILDs). We used data from the INPULSIS trials in subjects with idiopathic pulmonary fibrosis (IPF) and the INBUILD trial in subjects with other progressive fibrosing ILDs to assess relationships between demographic/clinical variables and mortality. METHODS: The relationships between baseline variables and time-varying covariates and time to death over 52 weeks were analysed using pooled data from the INPULSIS trials and, separately, the INBUILD trial using a Cox proportional hazards model. RESULTS: Over 52 weeks, 68/1061 (6.4%) and 33/663 (5.0%) subjects died in the INPULSIS and INBUILD trials, respectively. In the INPULSIS trials, a relative decline in forced vital capacity (FVC) >10% predicted within 12 months (hazard ratio [HR] 3.77) and age (HR 1.03 per 1-year increase) were associated with increased risk of mortality, while baseline FVC % predicted (HR 0.97 per 1-unit increase) and diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (HR 0.77 per 1-unit increase) were associated with lower risk. In the INBUILD trial, a relative decline in FVC >10% predicted within 12 months (HR 2.60) and a usual interstitial pneumonia-like fibrotic pattern on HRCT (HR 2.98) were associated with increased risk of mortality, while baseline DLCO % predicted (HR 0.95 per 1-unit increase) was associated with lower risk. CONCLUSION: These data support similarity in the course of lung injury between IPF and other progressive fibrosing ILDs and the value of FVC decline as a predictor of mortality.

Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial.

BACKGROUND: The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial. METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean±sd exposure to trial medication was 15.6±7.2 and 16.8±5.8 months in the nintedanib and placebo groups, respectively. RESULTS: In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (hazard ratio (HR) 0.66, 95% CI 0.53-0.83; p=0.0003) and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69, 95% CI 0.53-0.91; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67, 95% CI 0.46-0.98; p=0.04) and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62, 95% CI 0.39-0.97; p=0.03). CONCLUSION: Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.

Effects of nintedanib by inclusion criteria for progression of interstitial lung disease.

BACKGROUND: The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated the decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression. METHODS: Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met the following criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5-<10% predicted with worsened respiratory symptoms and/or increased extent of fibrosis on high-resolution computed tomography (HRCT); Group C, worsened respiratory symptoms and increased extent of fibrosis on HRCT only. RESULTS: In the placebo group, the rates of FVC decline over 52 weeks in Groups A, B and C, respectively, were -241.9, -133.1 and -115.3 mL per year in the overall population (p=0.0002 for subgroup-by-time interaction) and -288.9, -156.2 and -100.1 mL per year among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on HRCT (p=0.0005 for subgroup-by-time interaction). Nintedanib had a greater absolute effect on reducing the rate of FVC decline in Group A than in Group B or C. However, the relative effect of nintedanib versus placebo was consistent across the subgroups (p>0.05 for heterogeneity). CONCLUSIONS: The inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression.

Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. METHODS: The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. FINDINGS: Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. INTERPRETATION: The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. FUNDING: Boehringer Ingelheim.

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.

BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. CLINICAL TRIAL REGISTRATION: NCT01403974; NCT01317420.

The natural history of progressive fibrosing interstitial lung diseases.

We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs).Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year-1) and mortality over 52 weeks in the INBUILD trial with pooled data from the INPULSIS trials.The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (-192.9 mL·year-1 and -221.0 mL·year-1, respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52 weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95).These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality.

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.

BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).

Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer.

BACKGROUND: Trastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer. MATERIALS AND METHODS: This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer. RESULTS: Of the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit. CONCLUSIONS: Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial.

BACKGROUND: Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. METHODS: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m(2) per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. FINDINGS: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). INTERPRETATION: Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. FUNDING: Boehringer Ingelheim.

A phase I study of two dosing schedules of oral BI 847325 in patients with advanced solid tumors.

PURPOSE: This study determined the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of BI 847325, an oral dual MEK and Aurora kinase inhibitor, in patients with refractory solid tumors. METHODS: This trial recruited patients with an advanced non-resectable and/or metastatic solid tumor following failure of conventional treatment (NCT01324830; 1287.1). BI 847325 was administered orally, once daily (starting at 6 mg in the first cohort) using two dosing schedules: Schedule A (2 weeks on, 1 week off) and Schedule B (three periods of 5 days on, 2 days off). The primary objective was to identify the MTD of BI 847325 for both dosing schedules. RESULTS: Sixty-nine patients (Schedule A, n = 47; Schedule B, n = 22) were treated. The MTD was 120 mg per day for Schedule A (cumulative dose of 1680 mg per 3-week cycle) and 150 mg per day for Schedule B (cumulative dose of 2250 mg per 3-week cycle). Reversible hematologic and gastrointestinal toxicities were the most common dose-limiting toxicities. One patient with esophageal cancer (receiving 160 mg BI 847325, Schedule A) experienced a partial response for 67 days, and 21 patients (n = 11 [23.4%], Schedule A; n = 10 [45.5%], Schedule B) had stable disease. Pharmacokinetic analyses showed at least bi-exponential disposition, with high inter-subject variability. There was no obvious relationship between markers of MEK or Aurora kinase inhibition and exposure to BI 847325 (exploratory analysis). CONCLUSIONS: This first-in-human trial suggests that BI 847325 has an acceptable safety profile. However, due to insufficient drug exposure at the MTD to achieve relevant MEK inhibition, a decision was taken to halt the development of BI 847325.

A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors.

Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.

Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment.

PURPOSE: Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib. METHODS: This was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib C max and AUC0-∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of afatinib. RESULTS: Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC0-∞ was 92.6% (90% CI 68.0-126.3%) and Cmax was 109.5% (90% CI 82.7-144.9%) for subjects with mild hepatic impairment, and 94.9% (90% CI 72.3-124.5%) and 126.9% (90% CI 86.0-187.2%), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90% CI included 100%. Afatinib was generally well tolerated with no serious adverse events reported. CONCLUSION: Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.

Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours.

BACKGROUND AND OBJECTIVE: Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of a variety of solid tumours. This study evaluated the pharmacokinetics of afatinib (10-100 mg once daily) in cancer patients. METHODS: Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods. RESULTS: Within each dose group, the shape of the geometric mean plasma concentration-time profiles after single and multiple doses were comparable. Maximum plasma concentration (C(max)) values were achieved 2-5 h after dosing and thereafter declined at least bi-exponentially. Steady-state plasma concentrations were attained within 8 days after the start of dosing. The geometric mean terminal elimination half-life at steady state was about 37 h. Repeated dosing resulted in a 2.77-fold accumulation based on the area under the plasma concentration-time curve (AUC), and 2.11-fold accumulation based on C(max) values. A slightly more than dose-proportional increase in afatinib exposure was observed. There was moderate intra-individual variability in afatinib trough concentration values (the geometric coefficient of variation (gCV) ranged from 22.2 to 67.5 %). The inter-patient variability in plasma concentrations was moderate to high (e.g. at the 40 mg dose, the gCVs ranged from 35.6 to 221 %). The exposure to afatinib (as measured by AUC and C(max)) correlated with the severity of the most common adverse events of afatinib--diarrhoea and rash. CONCLUSION: The pharmacokinetic profile of afatinib supports a once-daily dosage regimen. As expected for this patient population, the pharmacokinetic parameters of afatinib showed moderate to high inter-patient variability. Afatinib exhibits non-linear pharmacokinetics.