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A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors

Journal Paper/Review - Aug 30, 2019

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Joerger M, Sessa C, Stuedeli S, Levy N, Hafner P, Lane H, Larger P, Engelhardt M, Kaindl T, Volden M, Mark M, Mantiero M, Hess D, Metaxas Y, Stathis A, von Moos R. A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors. Invest New Drugs 2019
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Journal Paper/Review (English)
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Invest New Drugs 2019
Publication Date
Aug 30, 2019
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1573-0646
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Purpose 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/m. Three grade 3 DLTs occurred: hypotension (70 mg/m), hyponatremia and neutropenia (both 90 mg/m). The MTD for 48-h IV BAL101553 was 70 mg/m. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the C 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.