ABSTRACT
BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.
Subject(s)
Benzimidazoles/administration & dosage , Neoplasms/drug therapy , Oxadiazoles/administration & dosage , Adult , Aged , Aged, 80 and over , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Disease Progression , Female , Humans , Infusions, Intravenous , M Phase Cell Cycle Checkpoints/drug effects , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Oxadiazoles/adverse effects , Oxadiazoles/pharmacokinetics , Prodrugs/administration & dosage , Prodrugs/adverse effects , Prodrugs/pharmacokinetics , Spindle Apparatus/drug effects , United KingdomABSTRACT
Liquid chromatography-tandem mass spectrometry (LC/MS/MS) has become the technology of choice for bioanalysis, due to its high selectivity and high sample throughput. However, concerns have grown that this technique may be subject to errors due to "invisible" interferences, in particular ion-suppression. Investigations on ion-suppression from formulation agents have only been published to a limited extent. Such effects can be of particular importance in pre-clinical discovery studies where drugs may be formulated with large amount of solubilisers and bioanalysis may use fast generic methods. In a preliminary pharmacokinetic study we observed strong ion-suppression from a polysorbate co-solvent, which, if undetected, would have given highly erroneous pharmacokinetic results and possibly could have led to the inappropriate elimination of a promising drug candidate. Different chromatographic methods were tested indicating that the separation step was essential in controlling these effects. A method based on matrix dilution is proposed to check for these effects during the use of discovery support methods, where full validation is not practical. Some excipients commonly used in formulations are polydispersed polymers, for which very limited pharmacokinetic information is available. Further investigation is needed to better understand the mechanisms of ion-suppression and the kinetics of the suppressing species to allow the development of new LC/MS/MS based analytical strategies, which will not be subject to such ionisation interferences.
