Efficacy and safety of lipegfilgrastim compared with placebo in patients with non-small cell lung cancer receiving chemotherapy: post hoc analysis of elderly versus younger patients

Purpose Lipegfilgrastim, a glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF), reduces neutropenia duration and febrile neutropenia (FN) incidence in patients with cancer receiving myelosuppressive chemotherapy. A phase 3 trial of lipegfilgrastim was conducted in patients with advanced non-small cell lung cancer (NSCLC) receiving cisplatin/etoposide (which produces mild-to-moderate myelosuppression). Because patients aged >65 years are at higher risk for FN versus younger patients, this post hoc analysis compared outcomes in elderly (>65 years) versus younger participants in this trial. Methods Patients were randomized 2:1 to receive a once-percycle single subcutaneous injection of lipegfilgrastim 6 mg or placebo, with up to 4 cycles of every-3-week cisplatin (day 1) and etoposide (days 1–3). The primary end point was FN incidence during cycle 1. Outcomes were compared across treatment groups and by age groups (≤65 and >65 years). Results For patients aged ≤65 years, FN incidence during cycle 1 was similar in the lipegfilgrastim and placebo groups (3.0 vs 3.2 %, respectively), whereas for elderly patients, there was a reduction in FN incidence with lipegfilgrastim (0 vs 13.3 %, respectively). In both age subgroups, lipegfilgrastim showed a propensity to reduce the incidence and duration of severe neutropenia, time to absolute neutrophil count (ANC) recovery, and depth of ANC nadir. Adverse events were generally similar between groups. Conclusions This analysis suggests that in patients with a higher FN risk, such as the elderly patients of this study, lipegfilgrastim reduces not only the duration of severe neutropenia but also the incidence of FN

A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib–pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population

A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer

Abstract An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P = 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther; 15(9); 2251–8. ©2016 AACR.</jats:p

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) þ IFNa versus IFN in metastatic renal cell carcinoma (RCC). Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 mg/ kg i. v. in three cycles of four once-daily injections) + IFN (9 MU s. c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS). Results: This phase II/III study did notmeetits primary endpoint. Median OS/PFS for Nap + IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P = 0.56; HR, 1.08/P = 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of antiSEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n = 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap þ IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P = 0.02; HR, 0.59/P = 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile. Conclusions: The study did not meet its primary endpoint. Nap + IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup

Theta rhythm-like bidirectional cycling dynamics of living neuronal networks in vitro.

The phenomena of synchronization, rhythmogenesis and coherence observed in brain networks are believed to be a dynamic substrate for cognitive functions such as learning and memory. However, researchers are still debating whether the rhythmic activity emerges from the network morphology that developed during neurogenesis or as a result of neuronal dynamics achieved under certain conditions. In the present study, we observed self-organized spiking activity that converged to long, complex and rhythmically repeated superbursts in neural networks formed by mature hippocampal cultures with a high cellular density. The superburst lasted for tens of seconds and consisted of hundreds of short (50-100 ms) small bursts with a high spiking rate of 139.0 ± 78.6 Hz that is associated with high-frequency oscillations in the hippocampus. In turn, the bursting frequency represents a theta rhythm (11.2 ± 1.5 Hz). The distribution of spikes within the bursts was non-random, representing a set of well-defined spatio-temporal base patterns or motifs. The long superburst was classified into two types. Each type was associated with a unique direction of spike propagation and, hence, was encoded by a binary sequence with random switching between the two "functional" states. The precisely structured bidirectional rhythmic activity that developed in self-organizing cultured networks was quite similar to the activity observed in the in vivo experiments

Clustering of the spiking patterns of small bursts in the long superburst.

<p>(A) K-means clustering of the activation patterns revealed two motifs (green and blue dots) plotted by principal component analysis (PCA) coefficients. (B) Dynamic patterns represent the average activation patterns of two motifs identified using K-means clustering. The colour represents the average first spike timing of the bursts. (C) Dependence of the DB index on the number of clusters estimated using the K-means analysis. (D) Clustering of the same spiking patterns using EM clustering applied to the two principal components. (E) Dynamic patterns of motifs identified using EM clustering. (F) Dependence of the DB index on the number of clusters estimated using EM clustering and its average (G) (mean±s.d., n = 6 cultures). (H) EM clustering of the spiking patterns applied to the 6 motifs estimated from the three principal components. (I) Dynamic patterns of the 6 motifs estimated by EM using 3 principal components. (J) Dependence of the DB index on the number of clusters estimated using EM clustering with 3 principal components and its average (K) (mean±s.d., n = 6 cultures).</p

The sequence of small bursts in a long superburst displayed a stable rhythmic structure.

<p>(A) Example of the long superburst activity recorded on the MEA, and a fragment of 5 detected small bursts (B). The green horizontal line represents the burst detection threshold, and the red vertical lines represent the burst initiation and end time points. (C) Distribution of burst frequencies (the instantaneous frequency (IF) corresponded to the the interburst peak interval measure (IBPI), see the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192468#sec002" target="_blank">Methods</a>) in one culture. The median IF (burst frequency) was 9.8 Hz. (D) Distribution of spiking rate frequency from the electrodes with small bursts in one culture. The mean spiking rate was 178.5 Hz. (E) Distribution of IFs (n = 6 cultures). The median burst frequency was 11.2 ± 1.5 Hz (mean ± s.d., n = 6 cultures). (F) Distribution of the spiking rate frequency from the electrodes with small bursts (n = 6 cultures). The spiking rate was 139.0 ± 78.6 Hz (mean±s.d.).</p

Theta rhythm-like bidirectional cycling dynamics of living neuronal networks <i>in vitro</i>

<div><p>The phenomena of synchronization, rhythmogenesis and coherence observed in brain networks are believed to be a dynamic substrate for cognitive functions such as learning and memory. However, researchers are still debating whether the rhythmic activity emerges from the network morphology that developed during neurogenesis or as a result of neuronal dynamics achieved under certain conditions. In the present study, we observed self-organized spiking activity that converged to long, complex and rhythmically repeated superbursts in neural networks formed by mature hippocampal cultures with a high cellular density. The superburst lasted for tens of seconds and consisted of hundreds of short (50–100 ms) small bursts with a high spiking rate of 139.0 ± 78.6 Hz that is associated with high-frequency oscillations in the hippocampus. In turn, the bursting frequency represents a theta rhythm (11.2 ± 1.5 Hz). The distribution of spikes within the bursts was non-random, representing a set of well-defined spatio-temporal base patterns or motifs. The long superburst was classified into two types. Each type was associated with a unique direction of spike propagation and, hence, was encoded by a binary sequence with random switching between the two “functional” states. The precisely structured bidirectional rhythmic activity that developed in self-organizing cultured networks was quite similar to the activity observed in the <i>in vivo</i> experiments.</p></div