Phase I study of E7010

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

Section: Discussionmentioning

confidence: 98%

“…It has a broad spectrum of antitumor activity that is not affected by P-glycoprotein overexpression and has good absorption after oral administration. (11,12,42).…”

Section: Discussionmentioning

confidence: 99%

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

Yee

Hagey

Verstovšek

et al. 2005

“…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 2 for the single dose and 240 mg/m 2 for the 5-day dose schedule. The toxicities reported included peripheral neuropathy and intestinal paralysis.…”

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confidence: 99%

The Pharmacokinetics and Safety of ABT-751, a Novel, Orally Bioavailable Sulfonamide Antimitotic Agent: Results of a Phase 1 Study

Hande

Hagey

Berlin

et al. 2006

Purpose: Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on h-tubulin that leads to a block in the cell cycle at the G 2 M 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 urine ABT-751and metabolite pharmacokinetics were determined. Results:The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1were abdominal pain, constipation, and fatigue.The MTD on the b.i.d. schedule was 150 mg. Cycle 1of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 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 T max of about 2 hours. The pharmacokinetics of ABT-751were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after 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-751 were 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.

“…An alternative microtubule-interacting compound currently under development is ABT-751, which has shown promising efficacy both in vitro and in vivo (17 -19). However, this compound has shown little efficacy in clinical trials to date (20,21). This may be due to the rapid conjugation and inactivation of ABT-751 upon oral dosing (21,22).…”

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confidence: 97%

“…However, this compound has shown little efficacy in clinical trials to date (20,21). This may be due to the rapid conjugation and inactivation of ABT-751 upon oral dosing (21,22). A natural metabolite of estrogen, 2-MeOE2, which interacts with microtubules, has been extensively studied in phase I and phase II trials.…”

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confidence: 99%

STX140 Is Efficacious In vitro and In vivo in Taxane-Resistant Breast Carcinoma Cells

Newman

Foster

Stengel

et al. 2008

Purpose:The aim of these studies was to characterize the action of STX140 in a P-glycoproteinô verexpressing tumor cell line both in vitro and in vivo. In addition, its efficacy was determined against xenografts derived from patients who failed docetaxel therapy. Experimental Design:The effects of STX140,Taxol, and 2-methoxyestradiol (2-MeOE2) on cell proliferation, cell cycle, and apoptosis were assessed in vitro in drug-resistant cells (MCF-7 DOX ) and the parental cell line (MCF-7 WT ). Mice bearing an MCF-7 DOX tumor on one flank and an MCF-7 WT tumor on the other flank were used to assess the in vivo efficacy. Furthermore, the responses to STX140 of three xenografts, derived from drug-resistant patients, were assessed. Results: In this study, STX140 caused cell cycle arrest, cyclin B1 induction, and subsequent apoptosis of both MCF-7 DOX and MCF-7 WT cells. Taxol and 2-MeOE2 were only active in the MCF-7 WT parental cell line. Although both STX140 and Taxol inhibited the growth of xenografts derived from MCF-7 WT cells, only STX140 inhibited the growth of tumors derived from MCF-7 DOX cells. 2-MeOE2 was ineffective at the dose tested against both tumor types. Two out of the three newly derived docetaxel-resistant xenografts, including a metastatic triple-negative tumor, responded to STX140 but not to docetaxel treatment. Conclusions: STX140 shows excellent efficacy in both MCF-7 WT and MCF-7 DOX breast cancer xenograft models, in contrast toTaxol and 2-MeOE2. The clinical potential of STX140 was further highlighted by the efficacy seen in xenografts recently derived from patients who had failed on taxane therapy.