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Title: A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.
Austin Authors: Brandes, Alba A;Carpentier, Antoine F;Kesari, Santosh;Sepulveda-Sanchez, Juan M;Wheeler, Helen R;Chinot, Olivier;Cher, Lawrence M ;Steinbach, Joachim P;Capper, David;Specenier, Pol;Rodon, Jordi;Cleverly, Ann;Smith, Claire;Gueorguieva, Ivelina;Miles, Colin;Guba, Susan C;Desaiah, Durisala;Lahn, Michael M;Wick, Wolfgang
Affiliation: Department of Oncology, Royal North Shore Hospital, St Leonards, Australia
Hospital Universitario 12 de Octubre, Madrid, Spain
University of California San Diego Health System, La Jolla, California, USA
Hôpital Avicenne, Paris 13 University, Bobigny, France
Medical Oncology Department, Bellaria-Maggiore Hospitals, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy
Austin Health, Heidelberg, Victoria, Australia
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
Antwerp University Hospital, Edegem, Belgium
Medical Oncology, Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain
Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt, Germany
Eli Lilly and Company, Indianapolis, Indiana
Eli Lilly and Company, Erl Wood, England
CHU Hôspital De La Timone, Rue Saint Pierre, France
Neurology Clinic, University of Heidelberg, Heidelberg, Germany
Issue Date: Aug-2016 2016-02-21
Publication information: Neuro-oncology 2016; 18(8): 1146-1456
Abstract: The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma. Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity. One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS. Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms. NCT01582269,
DOI: 10.1093/neuonc/now009
PubMed URL: 26902851
Type: Journal Article
Subjects: Bayesian design
Phase II randomized study
antitumor activity
galunisertib monohydrate (LY2157299)
Appears in Collections:Journal articles

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