Sven Wind

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

BACKGROUND This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). METHODS Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m(2)/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m(2) for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. RESULTS Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. CONCLUSIONS Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.

A Phase I dose-escalation study of afatinib combined with nintedanib in patients with advanced solid tumors

AIMS To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. MATERIALS & METHODS Patients received afatinib 10-20 mg daily plus nintedanib 150-200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. RESULTS Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. CONCLUSION The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose‐dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose‐dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg. The peak plasma concentration (Cmax) of BI 425809 was achieved earlier in plasma than in CSF (tmax 3–5 vs. 5–8 hours, respectively). Generally, BI 425809 was safe and well tolerated. These data provide evidence of functional target engagement of GlyT1 by BI 425809.

P1.45: Impact of Dose Adjustment on Afatinib Safety and Efficacy in EGFR Mutation-Positive NSCLC: Post-Hoc Analyses of LUX-Lung 3/6: Track: Advanced NSCLC

Background Afatinib 40 mg/day is approved for the first-line treatment of pts with EGFR mutation-positive NSCLC. The dose can be adjusted based on individual tolerability. Post-hoc analyses assessed the impact of afatinib dose adjustment on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in LL3 and LL6. Methods All afatinib-treated pts in LL3 (n = 229) and LL6 (n= 239) were included. In case of drug-related grade 3 or selected prolonged grade 2 AEs with afatinib 40 mg, the dose could be reduced by 10 mg decrements to a minimum of 20 mg. We analysed the incidence and severity of common AEs before and after dose reduction and compared PK data collected as part of the standard visit schedule on Day 43 in pts who reduced to 30 mg vs those remaining at 40 mg. PFS in pts who dose reduced within the first 6 months of treatment was compared with those who remained on afatinib 40 mg/day. Results Dose reductions occurred in 53% (122/229) and 28% (67/239) of pts in LL3 and LL6, respectively; the majority (86% and 82%, respectively) within the first 6 months of treatment. Dose reduction led to decreases in the incidence and severity of EGFR-mediated drug-related AEs (table). Combined PK analysis of LL3 and LL6 suggested that dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who had dose reduced to 30 mg (n = 59) had geometric mean plasma afatinib concentrations of 23.3 ng/mL, vs 22.8 ng/mL in pts who remained on the 40 mg dose (n = 284). Median PFS was similar in pts who dose reduced during the first 6 months of treatment vs those who did not in LL3 (11.3 vs 11.0 months [HR = 1.25; 95% CI, 0.91–1.72]) and LL6 (12.3 vs 11.0 months [HR = 1.00; 95% CI, 0.69–1.46]). Conclusions Tolerability-guided dose adjustment of afatinib reduced treatment-related AEs without adversely affecting efficacy.

PHARMACOKINETICS OF SINGLE AND MULTIPLE RISING DOSES OF BI 425809, A NEW GLYT1 INHIBITOR, IN YOUNG AND ELDERLY HEALTHY VOLUNTEERS

Background:Omega-3 fatty acids (O-3 FAs) are highly vulnerable to oxidative damage. This study investigated whether pre-treatment oxidative stress, measured by the lipid peroxidation marker 4-hydroxynoneal (4-HNE), predicted efficacy of O-3 FA supplementation for improving immediate recall in patients with stable coronary artery disease (CAD). Methods: Immediate recall was measured by the mean of Z-scores from the immediate recall sections of the California Verbal Learning Test II and Brief Visuospatial Memory Test-Revised. Patients were then randomized (1:1) to receive 1.9 g/day O-3 FA supplements or a placebo for 12 weeks as part of the CAROTID trial (NCT00981383). Immediate recall was reassessed at week 12. Baseline serum 4-HNE concentrations were analysed from fasting blood. Repeated measures linear models were used to investigate the interaction between 4-HNE and O-3 FA efficacy. Results:86 CAD patients (age1⁄461.468.5, 77% male, n1⁄440 O-3 FA, n1⁄446 placebo) were included. Baseline immediate recall performance (F1,851⁄40.74, p1⁄4.39) and serum 4-HNE concentrations (F1,851⁄40.02, p1⁄4.90) were not different between the treatment groups. O-3 FA treatment did not increase immediate recall performance over 12 weeks compared to placebo (treatment x time interaction: F1,851⁄40.34, p1⁄4.56). Higher baseline 4-HNE concentrations predicted greater improvements in immediate recall over 12 weeks in the O-3 FA group (F1,391⁄45.34, p1⁄4.03), but not in the placebo (F1,451⁄40.21, p1⁄4.65). Conclusions: These findings suggest that greater pre-treatment oxidative stress might predict greater improvements in immediate recall with O-3 FA treatment. Future work may clarify the relationship between oxidative stress and O-3 FAmetabolism as it pertains to potential cognitive efficacy.