Abstract A72: A first-in-man Phase I study of the galectin-1 (gal-1) inhibitor OTX008 given subcutaneously as a single agent to patients with advanced solid tumors.
Authors: Delord Jean-Pierre , Awada Ahmad , Raymond Eric , Lokiec François , Herait Patrice , Rezai Keyvan , Lachaux Nicolas , Rabinovich Gabriel A. , Gomez-Roca Carlos , Aftimos Philippe , Faivre Sandrine , Stupirski Juan Carlos 
Published: August 2014

Abstract
Background: Gal-1 is a lectin with multiple biological functions including tumor progression, migration, and angiogenesis. OTX008, a small molecule downregulating gal-1 protein level, displays direct antiproliferative and anti-invasive effects in human cancer cells.
Objectives: Determine the maximum tolerated dose (MTD) of single agent OTX008 using a subcutaneous (SC) daily dosing based on dose-limiting toxicities (DLTs). Secondary objectives were safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
Patients and Methods: Patients (pts) with solid tumors having failed standard therapies, and given a written consent were enrolled. OTX008 was delivered as daily SC injection. In case of DLT, treatment was interrupted until recovery and resumed at the dose level (DL) below. Dose was escalated according to a 3+3 design. The MTD was defined as the highest DL, in which ≤1/6 pt experiences a DLT.
Results: 22 pts (50% with colorectal carcinoma) were treated from March 2012 to March 2013. Six were enrolled at DL1 (65mg-flat dose) without DLT. Among the 7 pts enrolled at DL2 (120-130mg), 2 experienced DLT. DL2 was therefore deemed to exceed the MTD and 9 additional pts were enrolled at DL1. No DLT was observed among the 15 patients treated at DL1. The most frequent related adverse event (AE) was G1-2 injection site reaction in 20 patients. Two pts experienced skin ulcerations, resulting in subcutaneous abscess and treatment discontinuation in one and consent withdrawal in another. Transient and fully reversible neurological AEs were observed in 12 pts (55%), and were more frequent (100% vs 33%) and more severe (G3 in 29% vs 0%) at DL2 compared to DL1 respectively. G 1-2 tremor was observed in 8 pts, perioral paresthesia in 5, dizziness in 4 and myoclonia in 2. Two patients experienced G3 ataxia (DLT), and one patient with past history of post-traumatic epilepsy experienced G3 seizure. Gastrointestinal (GI) AEs were reported by 12 pts (55%); G3 vomiting/abdominal pain and G3 diarrhea were reported in 1 pt each; 12 patients developed asymptomatic abnormal lab values (10 hypomagnesemia and 8 transient elevation of CPK without rhabdomyolysis or cardiac ischemia). OTX008 plasma concentrations were &gt;1µM over 12h after administration. PK of OTX008 is best described by a two compartment open model and showed less than proportional exposure increase, possibly due to wide inter-patient variability. The main covariate effect was related to body weight. Plasma gal-1 levels decreased proportionally with increasing OTX008 plasma concentrations. Serial tumor biopsies in 6 patients did not conclude on a PD effect. No objective response was reported.
Conclusions: OTX008 recommended flat daily sc dose is 65mg, which achieves significant systemic plasma concentrations based on in vitro models. Weight adapted dosing may optimize systemic exposure. Local tolerance of SC injection is poor.Reversible ataxia was a dose-limiting toxicity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A72.
Citation Format: Jean-Pierre Delord, Ahmad Awada, Eric Raymond, François Lokiec, Patrice Herait, Keyvan Rezai, Nicolas Lachaux, Gabriel A. Rabinovich, Carlos Gomez-Roca, Philippe Aftimos, Sandrine Faivre, Juan Carlos Stupirski. A first-in-man Phase I study of the galectin-1 (gal-1) inhibitor OTX008 given subcutaneously as a single agent to patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A72.