Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors

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.

Indibulin dampens microtubule dynamics and produces synergistic antiproliferative effect with vinblastine in MCF-7 cells: Implications in cancer chemotherapy

“…In human patients, the concentration of orally administered indibulin peaks in plasma after ~4 h of administration and remains above the lower limit of quantitation for about 96 h 3 , indicating its good bioavailability. The orally administered indibulin has been found to be well tolerated in human patients 4 , 5 , though further improvement in the formulation was needed. The most interesting and unique advantage of indibulin was shown to be its comparatively low neuronal toxicity.…”

Design and Synthesis of Aminostilbene–Arylpropenones as Tubulin Polymerization Inhibitors

“…[19] 6-Methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole (BPR0L075, Figure 1), a microtubule depolymerizing agent, exhibits antiangiogenic activities. [23,24] In continuation of our earlier efforts and on the basis of literature findings, we linked amino-substituted combretastatin with arylamino-2-propenones to generate aminostilbene-arylpropenone hybrids. [22] Thus, it is clear from the background presented above that the pharmacophores represented by aminostilbene 1 c and ar-ylpropenones 2 a offer excellent possibilities for hybridization towards the design of improved tubulin polymerization inhibitors.…”

“…We have been previously involved in the development of new heterocyclic scaffolds such as combretastatinamidobenzothiazole conjugates, and benzofurans were shown to be potential inhibitors of tubulin polymerization with significant cytotoxic activity. [23,24] In continuation of our earlier efforts and on the basis of literature findings, we linked amino-substituted combretastatin with arylamino-2-propenones to generate aminostilbene-arylpropenone hybrids. The 3,4,5-trimethoxyphenyl unit constitutes the A ring, which is utilized without any structural modification in view of its pharmacophoric importance.…”

Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer

“…None of the colchicine-binding agents is approved for routine clinical use yet. However, some of them, such as ABT-751 (sulfonamide) (11–13), indibulin (14,15), and STX140 (16,17), are in preclinical or clinical development. These agents have shown the potential to be orally available and to circumvent P-glycoprotein-mediated drug resistance.…”