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Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid
Rebecca Kristeleit1,2, Jeffry Evans3,4, L Rhoda Molife5
1Department of Oncology, Guys and St Thomas' NHS Foundation Trust, London, UK. rebecca.kristeleit@gstt.nhs.uk.
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.
Insights
BAL101553 (lisavanbulin) showed anti-proliferative activity in cancer. The recommended dose of 30 mg/m² was well tolerated, with dose-limiting neurological and myocardial toxicities observed.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BAL101553 (lisavanbulin) is a prodrug of avanbulin with broad anti-proliferative activity.
- It is effective in cancer models resistant to standard microtubule-targeting agents.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of BAL101553 via 2-hour infusion.
- To characterize safety, efficacy, and establish the recommended phase 2 dose (RP2D) for advanced or recurrent solid tumors.
Main Methods:
- A two-part, open-label, phase 1/2a study.
- Modified accelerated titration design in phase 1 to determine MTD.
- Phase 2a expansion at MTD and lower doses to assess safety, efficacy, and RP2D.
Main Results:
- The MTD of BAL101553 was 60 mg/m².
- DLTs included reversible gait disturbance and peripheral sensory neuropathy at doses ≥60 mg/m².
- Asymptomatic myocardial injury occurred at doses ≥45 mg/m²; the RP2D was 30 mg/m².
- Overall disease control rate was 26.3%.
Conclusions:
- The RP2D of 30 mg/m² for BAL101553 (lisavanbulin) via 2-hour infusion was well tolerated.
- Observed dose-limiting toxicities were consistent with the drug's vascular-disrupting properties.
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