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.