Abstract
SummaryPurpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15–21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m2. Three grade 3 DLTs occurred: hypotension (70 mg/m2), hyponatremia and neutropenia (both 90 mg/m2). The MTD for 48-h IV BAL101553 was 70 mg/m2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the Cmax was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.
Highlights
Microtubule targeting agents (MTAs) are used therapeutically to induce either polymerization or depolymerization of Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Cantonal Hospital St
IV BAL101553 was well tolerated at doses up to and including 70 mg/m2 and no dose-limiting toxicities (DLTs) were reported following administration of doses of 30 mg/m2 and 45 mg/m2
There were six maximum tolerated dose (MTD)-evaluable patients among those treated at 70 mg/m2, one experienced a DLT of grade 3 hypotension in cycle 1 and one experienced a suspected unexpected serious adverse reaction of grade 3 peripheral neuropathy during cycle 2
Summary
CH-4005 Basel, Switzerland 5 Swiss Group for Clinical Cancer Research, Bern, Switzerland microtubules and are categorized into two groups, known as stabilizers (including taxanes and epothilones) and destabilizers (including Vinca alkaloids, halichondrins and combretastatins) [1]. Stabilizing or destabilizing the microtubule polymer results in spindle assembly poisoning, mitotic blockage, and cell death through apoptosis [1]. Despite many malignancies having a high initial sensitivity to MTAs, several mechanisms can result in drug resistance, including tumor overexpression of P-glycoprotein (Pgp), elevated levels of ß-tubulin subtype III, reduced levels of BRCA1 (the cancer susceptibility gene), elevated levels of the cell cycle inhibitory protein p21, and acquired mutations in ß-tubulin [4,5,6,7,8,9]. There is a need to identify novel tubulin-inhibiting agents that overcome these resistance factors and improve treatment effectiveness
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