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ABSTRACT The orally administered tubulin-binding agent 1069C85 was developed with the hope of overcoming the multidrug resistance associated with existing anti-tubulin agents, such as the

vinca alkaloids. A phase I study was performed using a single oral dose every 3 weeks, administered as a suspension reconstituted in 0.1% Tween 80 and 0.9% saline. The starting dose was 2.8

mg m-2, and dose doubling was permitted until the area under curve (AUC) was > or = 40% of that at the mouse LD10; thereafter, a modified Fibonacci scheme was used. The formulation proved

to be unsatisfactory, resulting in inconsistent absorption. The terminal elimination half-life was prolonged (range 18-73.5 h). Sporadic central neurotoxicity was observed, which was grade

3 in one patient treated at 200 mg m-2. A revised formulation with micronized drug was more easily suspended and appeared to increase the bioavailability by a factor of 2-4. Severe central

neurotoxicity, up to grade 4, was then observed at doses of 50-100 mg m-2. Unfortunately, toxicity was not predictable and one patient, with a previous history of partial intestinal

obstruction, treated at 50 mg m-2, cleared the drug very slowly, possibly because of prolonged, delayed absorption. This patient died from pancytopenia and severe gastrointestinal damage. It

was concluded that such unpredictable behaviour would be incompatible with safe evaluation in phase II studies; the trial was closed and further clinical development abandoned. Access

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access 23 December 2022 PHASE 1 DOSE-ESCALATION STUDY EVALUATING THE SAFETY, PHARMACOKINETICS, AND CLINICAL ACTIVITY OF OBI-3424 IN PATIENTS WITH ADVANCED OR METASTATIC SOLID TUMORS Article

Open access 12 May 2023 AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK I Judson

Authors * I Judson View author publications You can also search for this author inPubMed Google Scholar * E Briasoulis View author publications You can also search for this author inPubMed 

Google Scholar * F Raynaud View author publications You can also search for this author inPubMed Google Scholar * J Hanwell View author publications You can also search for this author

inPubMed Google Scholar * C Berry View author publications You can also search for this author inPubMed Google Scholar * H Lacey View author publications You can also search for this author

inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Judson, I., Briasoulis, E., Raynaud, F. _et al._ Phase I trial and

pharmacokinetics of the tubulin inhibitor 1069C85--a synthetic agent binding at the colchicine site designed to overcome multidrug resistance. _Br J Cancer_ 75, 608–613 (1997).

https://doi.org/10.1038/bjc.1997.107 Download citation * Issue Date: 01 February 1997 * DOI: https://doi.org/10.1038/bjc.1997.107 SHARE THIS ARTICLE Anyone you share the following link with

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