Phase I study of LErafAON-ETU, an easy-to-use formulation of liiposome entrapped c-raf antisense oligonucleotide, in advanced cancer patients

Abstract

3214 Background: Raf kinases play key roles in integrating the K-Ras and mitogen-activated protein kinase (MAPK) intracellular signaling cascades, which are important regulators of tumor cell proliferation. LErafAON-ETU is an easy-to-use, liquid, liposomal formulation of an antisense oligonucleotide complementary to the c-raf mRNA sequence. The lipid component consists of a novel, positively charged, synthetic cardiolipin (PCL-2). Formulation with liposomes eliminates the need for extensive phosphorothioate modification; thus, only the 3’- and 5’- termini of the LErafAON-ETU oligonucleotide are modified. Methods: This Phase I dose-escalation study is designed to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of LErafAON-ETU in patients with advanced cancer. LErafAON-ETU is administered as a 60 minute intravenous infusion once weekly for 3 consecutive weeks (a treatment cycle). Patients are eligible to receive repeated treatment cycles until disease progression or unacceptable toxicity occurs. Dose levels of 7.5, 15, 30, 60, 120, 240, and 480 mg/m2 or more are planned, depending on the tolerability of LErafAON-ETU. An accelerated dosing strategy will be implemented after the safety and tolerability of the initial dose level has been established in 3 patients. In this design, a single patient will be treated at each subsequent dose level until an adverse event of Grade ≥2, a pre-infusion platelet count of <75,000/mm3, or an increase in the serum creatinine level to ≥1.5 x the upper limit of normal occurs. At such time this cohort will be expanded, and a standard dose-escalation scheme will be employed with 3–6 patients in each cohort dependent upon the occurrence of DLTs. Results: Patient enrollment has begun. Three patients have completed infusion at the initial dose of 7.5 mg/m2. Conclusions: This accelerated dose-escalation scheme should reach potentially therapeutic doses more rapidly than would a standard design. This study represents the initial clinical dosing and proof of concept for a novel, liquid, PCL-2 based liposomal formulation of an antisense oligonucleotide with minimal phosphorothioation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm NeoPharm