Abstract 2046: Exposure - response (overall survival [OS]) analyses of patients with unresectable pancreatic cancer (PC) treated with galunisertib+gemcitabine (GG) or gemcitabine+placebo (GP) in a randomized phase 2, double-blind study
Authors: Gueorguieva Ivelina , Tabernero Josep , Melisi Davide , Waterhouse Timothy H. , Miles Colin , Desaiah Durisala , Lahn Michael M. , Cleverly Ann , Benhadji Karim A. 
Published: July 2016

Abstract
Background: Transforming growth factor-beta (TGF-β) signaling pathway is active in PC. A pharmacokinetic/pharmacodynamic (PK/PD) approach integrated preclinical biomarkers and toxicity and allowed for prospective definition of therapeutic window (Gueorguieva et al. Br J Clin Pharmacol 2014;77:796-807). Here, we evaluate the observed exposure-OS relationship in patients with unresectable PC treated with either GG or GP with median (95% CI) OS (months) of 9.10 (7.43, 12.2) and 7.59 (4.04, 9.92), respectively.
Methods: A therapeutic exposure window for galunisertib between 3730 and 8380 ng*hr/mL was targeted in patients as described in Gueorguieva et al. 2014. Galunisertib 150 mg BID was given orally as intermittent dosing (14 days on/14 days off per cycle) and gemcitabine was administered as approved. Using nonlinear mixed effects modeling, data from six studies (n = 297, 3097 observations) were combined; galunisertib population PK model was developed. Galunisertib exposure metrics were calculated for each patient in the phase 2 PC study (n = 100 GG arm). Parametric survival models were used to identify influential covariates on OS such as dose, plasma exposure at steady state (AUC0-24,ss), Cmax,ss, ECOG, pre-treatment with gemcitabine, age, biomarkers (CA19-9 and TGFβ) and liver metastasis.
Results: PK profile of galunisertib was not altered when combined with gemcitabine. The population PK dataset included data from 297 patients/healthy subjects whose ages ranged from 22 to 84 years and who weighed between 39 and 126 kg. The PK of galunisertib was best described by a 2-compartment model with first order absorption and elimination. Galunisertib was rapidly absorbed with peak concentrations within 1-3 h and elimination half-life of 8 h. The mean (% SEE) population apparent clearance and volume of distribution of galunisertib was 35 (3%) L/hr and the steady state was 190 (11%) L. Between-patient variance was estimated to be 47% on the population apparent clearance. There was a small, but statistically significant effect of age on apparent clearance. None of the other investigated demographic patient characteristics were found to be significant. Galunisertib median (25th-75th percentile) AUC0-24,ss for PC patients was 5.56 (3.82-7.91) mg*h/L with Cmax and tmax of 904 (668-1194) ng/mL and 1.5 (1-2.5) h, respectively. A Weibull parametric survival model provided best fit to the OS data. There was a flat exposure-OS relationship within the observed exposure range, once all significant covariates (namely ECOG, pre-treatment with gemcitabine, age, CA19-9, and liver metastasis) were included.
Conclusion: This investigation confirms that 300 mg galunisertib administered as 150 mg BID for 14 days followed by 14 days off treatment is an appropriate dosing regimen for patients with PC.
Citation Format: Ivelina Gueorguieva, Josep Tabernero, Davide Melisi, Timothy H. Waterhouse, Colin Miles, Durisala Desaiah, Michael M. Lahn, Ann Cleverly, Karim A. Benhadji. Exposure - response (overall survival [OS]) analyses of patients with unresectable pancreatic cancer (PC) treated with galunisertib+gemcitabine (GG) or gemcitabine+placebo (GP) in a randomized phase 2, double-blind study. [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 2046.