The Pharmacokinetics and Safety of ABT-751 , a Novel , Orally Bioavailable SulfonamideAntimitotic Agent : Results of a Phase 1 Study
Purpose: Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751is a novel sulfonamide antimitotic that binds to the colchicine site on h-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics. Experimental Design: ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urineABT-751and metabolite pharmacokinetics were determined. Results:The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle1were abdominal pain, constipation, and fatigue.The MTDon the b.i.d. schedule was150 mg. Cycle1of therapy with the 175 mgb.i.d. schedulewas toleratedwithout DLT. However, six of sevenpatients reportedgrade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean Tmax of about 2 hours. The pharmacokinetics of ABT-751were dose-proportional and time-independent. There was minimal accumulation of ABT-751after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 Ag/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months. Conclusions: The MTD and recommended phase 2 doses for ABT-751were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing.Toxicities were abdominal pain, constipation, and neuropathy. Microtubules play a critical role in determining cell shape and polarity, facilitating cellular movement and intracellular transport, and segregating chromosomes during mitosis. In mitosis, interphase microtubules disappear and are replaced with a new network of microtubules that interact with the mitotic spindle to distribute chromatids equally between the two daughter cells (1). Disruption of microtubules arrests the cell division cycle at the G2M checkpoint, preventing cell division and triggering apoptosis. Thus, these important and highly labile microtubules are a principal target of several effective anticancer agents. Known antimitotic agents fall into three classes, Vinca alkaloids (vincristine, vinblastine, and vinorelbine), taxanes (paclitaxel and docetaxel), and colchicine site binders or colchicines. The Vinca alkaloids and colchicines are potent inhibitors of microtubule polymerization that block cell proliferation at metaphase during mitosis (2). The taxanes stabilize microtubules and block microtubulin depolymerization (3). Each antimitotic class has a distinct binding site on tubulin h-subunits (4, 5). The consequences of disruption of tubulin and microtubule dynamics with these three drug classes seems to be the same: a block in the cell cycle that ultimately induces cellular apoptosis. The Vinca alkaloids and the taxanes have shown antineoplastic activity in a wide variety of human cancers. No colchicine-site binders are currently approved for cancer chemotherapy. ABT-751 is a novel sulfonamide molecule (Fig. 1), that has shown significant preclinical tumor activity in a variety of syngeneic and human xenograft models (colon, lung, stomach, breast, pancreas, prostate, nasopharyngeal; refs. 6–10). ABT751 binds to the colchicine binding site on h-tubulin (11) and is distinct from the current clinically approved tubulin binding agents, the Vinca alkaloids and the taxanes. ABT-751 is not a substrate for the multiple drug resistance (MDR) transporter Cancer Therapy: Clinical Authors’Affiliations: Vanderbilt/Ingram Cancer Center, Nashville,Tennessee and Abbott Laboratories, Abbott Park, Illinois Received10/4/05; revised1/23/06; accepted 3/2/06. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Kenneth R. Hande, 777 Preston Research Building, Vanderbilt University School of Medicine, Nashville,TN 37232. Phone: 615-3224967; Fax: 615-343-7602; E-mail: kenneth.r.hande@vanderbilt.edu. F2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-2159 www.aacrjournals.org Clin Cancer Res 2006;12(9) May 1, 2006 2834 Research. on May 1, 2017. © 2006 American Association for Cancer clincancerres.aacrjournals.org Downloaded from and is active against cell lines resistant to vincristine, doxorubicin, and cisplatin (11). ABT-751 has been previously evaluated in a phase 1 study in Japan using both a single dose (80-480 mg/m) and a 5-day repeated dose (30-240 mg/m q.d.) oral administration. The study design was unconventional in that no additional subjects were added to confirm the maximum allowable dose, nor were additional cycles of drug administered after the first cycle. The estimated maximal allowable dose in this study, based on Japanese toxicity criteria (12), was 480 mg/m for the single dose and 240 mg/m for the 5-day dose schedule. The toxicities reported included peripheral neuropathy and intestinal paralysis. Antitumor activity was noted in 3 of 41 patients studied in this clinical trial. Because of the novel site of tubulin binding of this antimitotic agent and the preclinical and clinical activity shown in other studies, this phase 1 trial was designed to determine the maximum tolerated dose, toxicities, and pharmacokinetics of ABT-751 given to cancer patients with solid tumors on a fixed (i.e., non–body surface area adjusted) q.d. and b.i.d. oral dosing schedule for 7 days every 3 weeks.