Abstract CT068: A randomized phase II, double-blind study to evaluate the efficacy and safety of galunisertib+gemcitabine (GG) or gemcitabine+placebo (GP) in patients with unresectable pancreatic cancer (PC)
Authors: Melisi Davide , Garcia-Carbonero Rocio , Macarulla Teresa , Pezet Denis , Deplanque Gaël , Fuchs Martin , Trojan Joerg , Oettle Helmut , Kozloff Mark , Cleverly Ann , Gueorguieva Ivelina , Desaiah Durisala , Lahn Michael M. , Blunt Al , Benhadji Karim A. , Tabernero Josep 
Published: July 2016

Abstract
Background: Transforming growth factor-beta (TGFβ) signaling pathway is active in PC. In preclinical in vivo models, TGFβ inhibitors enhanced activity of gemcitabine. In this study, patients with Stage II to IV unresectable PC were treated with GG or GP to evaluate their efficacy and safety.
Methods: Patients were randomized in a 2:1 ratio (stratified for ECOG PS, disease stage and previous gemcitabine use) to receive either GG or GP. Galunisertib was given orally, 150 mg BID, as intermittent dosing (14 days on/14 days off per cycle) and gemcitabine was administered as per product label. The primary efficacy outcome was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR per RECIST), pharmacokinetics (PK), biomarkers (CA19-9 and TGFβ1), and safety (CTCAE v 4). Using a Bayesian augmented control (BAC) design, which utilizes historical data, and assuming an OS hazard ratio (HR) = 0.7, the study provided 90% power to identify if the probability of a HR less than 1 (Pr(HR less than 1)) was greater than 0.85.
Results: 156 patients were randomized to receive GG (N = 104) or GP (N = 52). Baseline characteristics were balanced between the two treatment groups. The unadjusted HR based on BAC was 0.8 with 95% credible interval (0.60, 1.09) and the Pr(HR less than 1) = 0.92, indicating a positive study. The median (95% CI) OS (months) was 9.10 (7.43, 12.2) and 7.59 (4.04, 9.92) for GG and GP, respectively. Median PFS (months) was 3.65 (2.86, 5.39) and 2.79 (1.81, 3.68) for GG and GP, respectively (logrank p = 0.084). ORR (95% CI) based on central readers’ assessments was 8.7% (4.0, 15.8) and 1.9% (0.1, 10.3) for GG and GP, respectively. For the subgroup of patients with baseline TGFβ1 levels ?4224pg/ml (n = 117), OS was 10.9 vs 7.2 mo for GG vs GP, respectively (unadjusted HR (95%CI) = 0.68 (0.44, 1.04), logrank p = 0 .076). The median PFS in this subgroup was 3.9 vs 2.8 for GG vs GP, respectively (unadjusted HR (95%CI) = 0.64 (0.42, 0.96), logrank p = 0.033). The most frequent adverse events (CTC grade 3/4), possibly related to study treatment were: anemia (7.8% GG vs 13.5% GP), neutropenia (32.0% GG vs 26.9% GP) and thrombocytopenia (7.8% GG vs 9.6% GP). The PK profile of galunisertib was not altered when combined with gemcitabine.
Conclusion: The combination therapy (GG) resulted in an improved OS and PFS in patients with PC, with a manageable toxicity profile as compared to GP. Patients with lower TGFβ1 levels may benefit to a greater extent from treatment with galunisertib.
Citation Format: Davide Melisi, Rocio Garcia-Carbonero, Teresa Macarulla, Denis Pezet, Gaël Deplanque, Martin Fuchs, Joerg Trojan, Helmut Oettle, Mark Kozloff, Ann Cleverly, Ivelina Gueorguieva, Durisala Desaiah, Michael M. Lahn, Al Blunt, Karim A. Benhadji, Josep Tabernero. A randomized phase II, double-blind study to evaluate the efficacy and safety of galunisertib+gemcitabine (GG) or gemcitabine+placebo (GP) in patients with unresectable pancreatic cancer (PC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT068.