Population pharmacokinetics and exposure–overall survival analysis of the transforming growth factor-β inhibitor galunisertib in patients with pancreatic cancer

• Published in: Cancer chemotherapy and pharmacology Vol. 84; no. 5; pp. 1003 - 1015
• Main Authors: Gueorguieva, Ivelina, Tabernero, Josep, Melisi, Davide, Macarulla, Teresa, Merz, Valeria, Waterhouse, Timothy H., Miles, Colin, Lahn, Michael M., Cleverly, Ann, Benhadji, Karim A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2019; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; CA-19-9 Antigen - metabolism; Cancer Research; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dosage; Female; Gemcitabine; Half-Life; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Patients; Pharmacokinetics; Pharmacology/Toxicology; Pyrazoles - administration & dosage; Quinolines - administration & dosage; Randomized Controlled Trials as Topic; Statistical analysis; Survival; Survival Analysis; Transforming growth factor; Transforming growth factor-b; Young Adult; Anticancer drugs; Pharmacodynamics; Pharmacokinetics; Randomized controlled trial
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-019-03931-1

Purpose To evaluate the exposure–overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP). Methods Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm ( n  = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS. Results The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22–84 years, weight: 39–126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5–2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure–OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer. Conclusions This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.