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Published on: October 27, 2014
A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine
Alba A Brandes1, Antoine F Carpentier1, Santosh Kesari1
1Medical Oncology Department, Bellaria-Maggiore Hospitals, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy (A.A.B.); Hôpital Avicenne, Paris 13 University, Bobigny, France (A.F.C.); University of California San Diego Health System, La Jolla, California (S.K.); Hospital Universitario 12 de Octubre, Madrid, Spain (J.M.S.-S.); Department of Oncology, Royal North Shore Hospital, St Leonards, Australia (H.R.W.); CHU Hôspital De La Timone, Rue Saint Pierre, France (O.C.); Austin Hospital, Heidelberg, Australia (L.C.); Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt, Germany (J.P.S.); Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany (D.C.); Antwerp University Hospital, Edegem, Belgium (P.S.); Medical Oncology, Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain (J.R.); Eli Lilly and Company, Erl Wood, England (A.C., C.S., I.G., C.M.); Eli Lilly and Company, Indianapolis, Indiana (S.C.G., D.D., M.M.L.); Neurology Clinic, University of Heidelberg, Heidelberg, Germany (W.W.).
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms.
Clinical Trial Registration:
NCT01582269, ClinicalTrials.gov.
