O3.4 - A first-in-human study of intravenous BAL101553, a novel microtubule inhibitor, in patients with advanced solid tumors

Abstract

ABSTRACT Background: BAL101553 is the prodrug of BAL27862, a novel small-molecule microtubule-targeting agent (MTA) with potent activity in tumor models refractory to conventional MTAs. It exerts antiproliferative effects and dose-dependent vascular disruption. A NSCLC xenograft mouse model demonstrated similar BAL27862 tumor exposure (AUC) at the MTD and a sub-MTD dose, with 11-fold higher peak intratumoral levels at the lower dose. Objectives of this first-in-human clinical trial were to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and to evaluate PK, PD and anti-tumor activity. Methods: Eligible patients (pts) with advanced solid tumors received BAL101553 as 2-h IV infusion on days 1, 8 and 15 of a 28-day cycle (accelerated dose-escalation). Adverse events were assessed by CTCAEv4 grade (G); tumor response was assessed every 2 cycles by RECIST 1.1. Results: 24 pts (12 males; median age 54.5 years; range 29-80) were treated at 15, 30, 45, 60 or 80 mg/m2 of BAL101553. Dose levels of 15-30 mg/m2 were well tolerated with no G3 adverse drug reactions (ADRs). Dose- related ADRs included nausea, vomiting, diarrhea, fatigue, peripheral sensory neuropathy (G1-2) and transient G3 hypertension. At 80 mg/m2, 2 out of 6 evaluable pts experienced a DLT of G2-3 reversible gait disturbance associated with G1-2 peripheral neuropathy. 60 mg/m2 was defined as MTD with 1 DLT observed in 6 pts (G3 reduced mobility with dizziness). 1 patient had a confirmed partial response (ampullary cancer, >2 years) and 5 pts had stable disease, predominantly at sub-MTD doses. PK-exposure to BAL27862 was dose-proportional. Comparison of post- to pre-treatment tumor biopsies indicated PD effects on vascularization and tumor cell proliferation. Conclusions: The MTD for BAL101553 administered as 2-h IV infusion at days 1, 8 and 15 of 28-day cycles was 60 mg/m2. Clinical activity observed at dose levels of 15-30 mg/m2 together with preclinical evidence of reduced tumour disposition at high vascular-disrupting doses indicate that a lower dose may be preferable by providing cytotoxic and intermediate anti-vascular effects without major toxicity. A randomised Phase 2a study in patients with advanced solid tumors with treatment at MTD and at 50% MTD is ongoing. (NCT01397929).