Abstract 33: OTX008 pharmacokinetics (PK) during the first-in-man phase I study in patients with advanced solid tumors .
Authors: Rezai Keyvan , Durand Sylvere , Lachaux Nicolas , Raymond Eric , Herait Patrice , Lokiec Francois 
Published: August 2014

Abstract
Background: Galectin-1, a multifunctional lectin, modulates cancer cell proliferation and tumor angiogenesis. OTX-008, a synthetic calixarene molecule, binds directly to galectin-1 and induces a conformation change in reduces galectin-1 binding to carbohydrates. In vitro pharmacodynamic studies showed that OTX008, at micromolar concentrations, inhibited agglutination, proliferation, and invasion of cultured cancer cells. Objectives of the ongoing OTX008 phase I study are: determine the recommended dose, pharmacokinetics (PK), pharmacodynamics (PD) and a PK/PD modeling of OTX008 given subcutaneously (SC) in humans.
Materials and Methods: This is a multicenter, dose escalation, open label, phase I study in successive cohorts of 3 to 6 evaluable patients treated with OTX008. Nine time point blood samples were collected on D1 of cycle 1 and two blood samples, just before and 1 hour after OTX008 administration (Cmin/Cmax) were collected on D2 and D22. Urine samples were collected during the first 24 hours after D1 administration. At the first DL (65 mg OTX008 sq qd), tumor samples also were obtained from a patient with advanced, heavily pre-treated cutaneous angiosarcoma of the scalp at baseline and at D22.
Plasma, urine and tumor concentrations of OTX008 were measured using a validated Ultra Performance Liquid Chromatography with tandem Mass Spectrometry detection (UPLC-MS/MS) with range of 5 - 250 ng/mL. Pharmacokinetic analyses were carried out using the nonlinear mixed effect modeling software program Monolix version 4.1.
Results: PK profiles of 7 patients treated at DL1 (65 mg) are reported. A 2-compartment open model adequately described the total OTX008 time-concentration curve with linear elimination. Following D1 administration, mean + SD Cmax was 4666 + 2012 ng/ml; and Tmax ranged from 0.5 h to 2 h; mean + SD AUC was 48.9 + 36.8 mg.h/l and mean + SD T1/2 was T1/2=5.5 + 0.9 h. Prior to D2 dosing, all patients had OTX008 plasma concentrations ≥1 μM. No accumulation was observed, steady state was reached around D22 after drug administration; 8-10 % of dose was recovered in urine during the first 24 hours. In one patient assessed, the intra-tumor concentration of OTX008 at D22 was 0.002 nM/mg of tumor. DL2 130mg sq qd ongoing (ongoing) and 65 mg bid schedule (planned) will be assessed and also presented.
Conclusions: Our DL1 results show that OTX008 is rapidly absorbed and distributed after single SC administration. The PK of OTX008 is best described by a two compartment open model. The influence of BMI will be studied with further DL cohorts and larger number of patients. Urinary excretion seems to be the major route of unchanged drug elimination. High plasma concentrations, close to the active dose in vitro were achieved from DL1.
Citation Format: Keyvan Rezai, Sylvere Durand, Nicolas Lachaux, Eric Raymond, Patrice Herait, Francois Lokiec. OTX008 pharmacokinetics (PK) during the first-in-man phase I study in patients with advanced solid tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 33. doi:10.1158/1538-7445.AM2013-33