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Published on: January 29, 2019
Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid
R L Oostendorp1, P O Witteveen, B Schwartz
1Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. r.oostendorp@nki.nl
Abstract:
Indibulin (ZIO-301/D-24851) is an orally applied small molecule with antitumor activity based upon destabilization of microtubule polymerization. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) as well as the dose limiting toxicity (DLT), the pharmacokinetics, safety and tolerability of orally administered indibulin as capsule formulation in patients with advanced solid tumors. Patients received a single dose of indibulin. Seven dose-levels were evaluated: 100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part). A total of 28 patients entered the study. Indibulin administered as capsules was generally well tolerated. The MTD was not reached. There was a disproportionate increase of the area under the plasma concentration-time curve (AUC) with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. There was no significant difference in AUC of indibulin after multiple dosing (day 1-14) compared to single administration (day-4). Inter-patient variability in AUC (102% CV) was high. A plateau in drug exposure was observed prior to reaching the MTD. Continued dose-escalation was unlikely to yield any increase in exposure of indibulin. The formulation needs optimization to increase the systemic exposure upon oral administration.
Insights
Indibulin, an oral antitumor drug, showed good tolerability in a Phase I trial. However, dose escalation did not increase drug exposure, indicating a need for formulation optimization.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Indibulin (ZIO-301/D-24851) is an oral small molecule antitumor agent targeting microtubule polymerization.
- Advanced solid tumors represent a significant unmet medical need, driving research into novel therapeutic agents.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of oral indibulin capsules.
- To evaluate the pharmacokinetics, safety, and tolerability of indibulin in patients with advanced solid tumors.
Main Methods:
- Phase I clinical trial involving 28 patients with advanced solid tumors.
- Dose escalation of oral indibulin capsules across seven dose levels (100-600 mg QD and 450-600 mg BID).
- Single and multiple dose administration with pharmacokinetic assessments (AUC).
Main Results:
- Indibulin capsules were generally well tolerated; the MTD was not reached.
- A plateau in drug exposure (AUC) was observed before the MTD, with disproportionate increases and declining AUC corrected for dose above 250 mg.
- High inter-patient variability in AUC (102% CV) and no significant difference in AUC between single and multiple doses.
Conclusions:
- Oral indibulin capsules are generally safe and well-tolerated, but dose escalation beyond a certain level does not increase systemic exposure.
- The current capsule formulation requires optimization to enhance oral bioavailability and achieve higher systemic drug exposure.
- Further development should focus on improving indibulin's pharmacokinetic profile for potential therapeutic benefit.
