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.

ABT-751 associated toxicity was acceptable. The median time to progression and overall survival as demonstrated for ABT-751 were comparable to other agents considered active in this patient population and to current treatments approved for second-line NSCLC. The novel antimitotic targeting of ABT-751 in combination with the compound's acceptable nonmyelosuppressive toxicity profile and efficacy similar to agents currently in use in this setting, warrant further evaluation of this compound in combination with other cytotoxic agents in advanced NSCLC.

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

Purpose: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population. Experimental Design: Patients who were V18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m 2 /d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m 2 /d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle. Results: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m 2 /d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor. ABT-751 (Abbott Laboratories, Abbott Park, IL) is an orally bioavailable sulfonamide that binds to the colchicine binding site on h-tubulin and inhibits the polymerization of microtubules (1, 2). ABT-751 had antitumor activity in a panel of 30 tumor cell lines in vitro including cell lines resistant to Vinca alkaloids and taxanes due to P-glycoprotein overexpression (3). In pediatric solid tumor cell lines, the ABT-751 IC 50 was <3 Amol/L in neuroblastoma cell lines and <6 Amol/L in other pediatric solid tumor cell lines (4). ABT-751 was active as a single agent in xenograft models of human tumors including gastric, colorectal, lung, and breast cancer models (3), and in combination, ABT-751 enhanced the efficacy of radiation, cisplatin, and fluorouracil (5). In childhood cancer murine models, ABT-751 resulted in the regression of rhabdomyosarcoma and Wilms tumor models and prolonged time to tumor progression in neuroblastoma xenografts (6).In adults with refractory solid tumors, a dose escalation study of ABT-751 administered once daily or twice daily for 7 days every 3 weeks has been previously completed. The maximum tolerated dose (MTD) on the once daily schedule was 250 mg/d (%140 mg/m 2 /d). Dose-limiting toxicities (DLT) were abdominal pain, constipation, and fatigue. On the twice daily for 7 days schedule, the MTD was 150 mg/dose (%85 mg/m 2 / dose), and the DLTs were grade 3 ileus, constipation, abdominal pain, or fatigue during cycles 2 or 3 in seven of eight patients receiving the 175 mg/dose twice daily. No complete or partial tumor responses were observed, but four patients had stable disease for z6 months (7). In adults with hematologic malignancies, ABT-751 was administe...

Purpose: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751administered orally once daily for 7 days, repeated every 21days. Experimental Design: Patients who were V18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m 2 /d (n = 3) and was escalated to 130 mg/m 2 /d (n = 6), 165 mg/m 2 /d (n = 6), 200 mg/m 2 /d (n = 6), and 250 mg/m 2 /d (n = 2) in cohorts of three to six patients.The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle. Results: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m 2 /d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m 2 /d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed. Conclusion: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m 2 /d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.ABT-751 (Abbott Laboratories, Abbott Park, IL) is an orally bioavailable sulfonamide that binds to the colchicine binding site on h-tubulin and inhibits polymerization of microtubules (1, 2). ABT-751 had a broad spectrum of antitumor activity in a panel of 30 tumor cell lines in vitro and in xenograft models of human tumors in vivo, including gastric, colorectal, lung, and breast cancer models. ABT-751 is not a substrate for P-glycoprotein and is active against HC-15, a human colon carcinoma model that is resistant to the tubulin inhibitors, paclitaxel and vincristine, due to overexpression of P-glycoprotein (3). By oligonucleotide microarray analysis, ABT-751 exposure down-regulated a-tubulin transcripts in HC116 human colon carcinoma cells (4, 5). Similar to other agents that bind the colchicine binding site of tubulin, ABT-751 has shown antivascular effects in animal models (6). More than 450 adults with cancer have been enrolled in clinical trials of ABT-751 and a variety of oral dosing schedules have been studied. Based on pharmacokinetics and tolerability, the daily for 7 days and daily for 21 days schedules have entered phase 2 clinical trials in adults. Reversible peripheral neuropathy, ileus, parti...