A Randomized Phase 2a Study To Assess Pharmacodynamics, Antitumor Activity And Safety Of Intravenous Bal101553, A Novel Microtubule Inhibitor, At Two Dose Levels In Adult Patients With Selected Advanced Solid Tumors.

TPS2611 Background: BAL101553 is the pro-drug of BAL27862, a novel small-molecule microtubule-targeting agent with potent activity in drug-refractory tumor models. It exerts antiproliferative effects and dose-dependent vascular disruption, acting as a tumor checkpoint controller by modulating the spindle assembly checkpoint (SAC). In a Phase 1 dose escalation study pharmacodynamic (PD) effects were observed in post-treatment tumor biopsies1. The maximum tolerated dose (MTD) was determined at 60 mg/m2 IV (intravenous), however clinical activity was observed at dose levels of 15-30 mg/m2. A non small cell lung cancer (NSCLC) xenograft mouse model showed similar BAL27862 tumor exposure (AUC) at the MTD and a sub-MTD dose, with 11-fold higher peak intratumoral levels at the lower dose. Thus, enhanced vascular disruption at high BAL101553 doses may be associated with lower intratumoral drug disposition. The goal of this Phase 2a study is to assess the pattern of antivascular and antiproliferative effects and antitumor activity at two BAL101553 dose levels. Methods: This is an ongoing multicenter randomized, open-label Phase 2a study (NCT01397929) to assess PD, antitumor activity and safety of BAL101553. Eligible patients (pts) with advanced colorectal, gastric, pancreatic, ovarian, NSCLC or triple negative breast cancers are randomized to either 60 (MTD) or 30 mg/m2 BAL101553 as a 2-h IV infusion on day(d) 1, 8 and 15 q28d. PD evaluations include serial collection of circulating tumor cells (CTCs), circulating endothelial cells and circulating endothelial progenitor cells. Pts with lesions amenable to biopsy will be asked to undergo pre- and post-dose biopsies. Biomarkers analyzed in CTCs and tumor biopsies include BubR1, a protein kinase involved in the SAC and a potential biomarker for BAL101553 activity. Antivascular effects will be quantified by dynamic-contrast enhanced MRI in a subset of pts. Tumor response will be assessed every 2 cycles using RECIST 1.1. Forty pts will be enrolled into this Phase 2a study, which started in June 2014. 1Molife LR et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 2562) Clinical trial information: NCT01397929.