Abstract 4511: Pharmacokinetics of OTX015 in a phase Ib dose-finding study of patients with hematologic malignancies: Preliminary results of a population PK analysis
Authors: Odore Elodie , Lokiec Francois , Riveiro Maria Eugenia , Bourdel Fabrice , Kahatt Carmen , Herait Patrice , Cvitkovic Esteban , Rezai Keyvan 
Published: August 2015

Abstract
Background: OTX015 (OncoEthix SA, Switzerland) is a novel oral bromodomain and extraterminal (BET) protein family inhibitor, with in vitro and in vivo activity in a variety of hematologic and solid tumor cells. A phase Ib study with OTX015 in patients with hematologic malignancies is underway including a pharmacokinetic (PK) investigation. The PK objectives of this study were to determine the PK profile of oral OTX015 using a population approach.
Materials and Methods: A multicenter, dose escalation study in cohorts of 3 to 6 patients with acute leukemia or other hematologic malignancies was performed with a dose escalation step followed by expansion cohorts at the recommended dose. Patients received oral OTX015 from 10 to 160 mg different schedules. PK blood samples from 7 time points were collected over 24 h post-administration on Day 1 for leukemia patients (complete PK) and 4 blood samples over 8 h post-administration for patients with other hematologic malignancies (limited PK). OTX015 plasma concentrations were measured using validated ultra-performance liquid chromatography with tandem mass spectrometry detection with a concentration range 1-250ng/mL. Analyses and population PK (PPK) modeling were performed with the nonlinear mixed effect modeling software program Monolix version 4.3. The following parameters were calculated absorption constant (Ka); apparent distribution volume (V/F); apparent clearance (CL/F) and lean body mass (LBM; calculated considering patient sex, weight and height) was considered as covariate.
Results: 85 patients enrolled and treated from January 2013 to August 2014, randomized to six dose levels (10, 20, 40, 80, 120 and 160 mg) QD and 40 mg BID were evaluated. Among them, 81 patients with 630 plasma concentrations (607 + 23 BLQ) were evaluable for PK assessment. A 1-compartment open model adequately described the total OTX015 concentration-time curve. The PPK parameters obtained for the structural model were Ka = 0.74 h−1 (12%); V/F = 71.7 L (6.0%) and CL/F = 8.45 L/h (5.0%). The best correlation between OTX015 AUC values and dose was observed from 10 to 120 mg dose levels (R2 = 0.71). The absorption phase was linear and Tmax was between 1 and 4 h. Mean elimination half-life of OTX015 for all patients was 5.8 h (± 1.1). In the PPK study, the best descriptive model was obtained when LBM was considered in the analysis. A correlation between CL/F and V/F was also observed for OTX015.
Conclusions: The PK of OTX015 is best described by a one-compartment model. Preliminary PPK analysis considering only the dose escalation cohort of the Phase I trial indicates that LBM is a good predictor of the OTX015 PK profile. This model should be validated in the ongoing expansion cohorts treated at 80mg QD.
Citation Format: Elodie Odore, Francois Lokiec, Maria Eugenia Riveiro, Fabrice Bourdel, Carmen Kahatt, Patrice Herait, Esteban Cvitkovic, Keyvan Rezai. Pharmacokinetics of OTX015 in a phase Ib dose-finding study of patients with hematologic malignancies: Preliminary results of a population PK analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4511. doi:10.1158/1538-7445.AM2015-4511