Background: Based on preclinical data suggesting an additive antitumor effect of galunisertib (G), a TGF-β RI kinase inhibitor, and lomustine (L), this study evaluated the activity of G+L in patients (pts) with recurrent glioblastoma (GB). We report safety, population pharmacokinetics (PK), and efficacy final results. Methods: G (300 mg/day) was given as intermittent dosing (each cycle = 14 days on/14 days off). L was given on day 7 of cycle 1 every 6 weeks as approved. Pts received L with either G or placebo (P) thereby blinding for G; pts who received G alone were unblinded (randomization 2:1:1). Primary objective was overall survival (OS) assessed by Bayesian analysis incorporating prior clinical data for L. Secondary objectives were safety, progression-free survival (PFS), tumor response assessed by Response Assessment in Neurooncology (RANO) criteria, and population PK analysis. Results: 158 pts were randomized to treatment: G+L (N = 79), G alone (N = 39), P+L (N = 40). Study included, male (64.6%), Caucasian (75.3%); mean age 57 years, 63% had ECOG PS 1, 93.7% had primary GB. The median number of cycles for G was 2 in all 3 arms. G PK was not altered by co-administration with L. G was rapidly absorbed and had median half-life of ~8h with moderate between-patient variability on exposure (CV 41%). The median OS (95% CI) for G+L was 6.7 months (5.3-8.5), [HR (G+L):(L+P) 1.13 (0.8-1.7)], 8.0 months (5.7-11.7) for G alone, [HR (G):(L+P) 0.93 (0.6-1.5)], 7.5 months (5.6-10.3) for L+P control arm. Success criteria for superiority of G+L to L+P was not met [P (HR < 1) < 85%]. The median PFS in months (95% CI) were 1.8 (1.7-1.8) for G+L, 1.8 (1.6-3.0) for G, and 1.9 (1.7-1.9) for P+L. Best overall response according to RANO included 1 CR in G+L and 2 PR in G. 34 pts had Grade 3/4 adverse events (AEs) related to study drug, 24% G+L, 13% G, 26% L+P. The most common drug-related Grade 3/4 AEs (G+L, G, L+P) were: thrombocytopenia (8%, 0%, 13%); lymphopenia (9%, 3%, 0%); neutropenia (8%, 0%, 5%). Conclusions: The observed efficacy outcomes including OS and PFS were similar in all 3 treatment arms suggesting no efficacy improvement when adding G to L. The treatment was safe and well tolerated in all arms. Clinical trial information: NCT01582269