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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.2046-2046
• Main Authors: Gueorguieva, Ivelina, Tabernero, Josep, Melisi, Davide, Waterhouse, Timothy H., Miles, Colin, Desaiah, Durisala, Lahn, Michael M., Cleverly, Ann, Benhadji, Karim A.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-2046

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