Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Abstract

Purpose: ABT-751is anoral antimitotic agent that binds to the colchicine site on h-tubulin. A phase 1study was conducted to determine the maximum tolerated dose and toxicities of ABT-751in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Study Design: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m 2 (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m 2 (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). Results: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m 2 , with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala 185

Clinical, Pharmacodynamic, and Pharmacokinetic Evaluation of BNC105P: A Phase I Trial of a Novel Vascular Disrupting Agent and Inhibitor of Cancer Cell Proliferation

“…No other cases of drug-related liver dysfunction were observed in the study. Other tubulin modulating agents have also shown clinical elevations in transaminases, e.g., paclitaxel (7) and the tubulin-targeting VDA, ABT-751 (8,9).…”

ELR510444, A Novel Microtubule Disruptor with Multiple Mechanisms of Action

“…Based on the structural similarity of ELR510444 to ABT-751, which has been shown to bind to the colchicine site on tubulin (Yee et al, 2005), we evaluated whether ELR510444 also binds to the colchicine site. An assay that takes advantage of the fact that colchicine binding to tubulin can be monitored fluorometrically was used (Bhattacharyya and Wolff, 1974).…”

A phase IB study of ABT-751 in combination with docetaxel in patients with advanced castration-resistant prostate cancer

“…Broad-spectrum preclinical activity results included activity against paclitaxel-and vincristineresistant tumors [6]. In addition, ABT-751 appears to work as a vascular disrupting agent (VDA) thereby reducing tumor blood flow to enhance the cytotoxic effect [7,8]. This action is pertinent for patients with CRPC since targeting tumor vasculature appears an attractive treatment strategy.…”

“…Combination of docetaxel and ABT-751 therapy had at least additive activity in xenograft models including the androgeninsensitive PC-3 prostate cancer model [10]. In phase I trials, the dose-limiting toxicities (DLTs) observed with ABT-751 were peripheral neuropathy, ileus and fatigue [8,11,12]. The recommended single-agent phase II dose was 200 mg daily on a 21/28-day schedule and is currently being evaluated in a number of phase II trials.…”