A Phase 1 Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 7 Days Every 21 Days in Pediatric Patients with Solid Tumors

Purpose: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects.Experimental Design: BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker.Results: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m 2 ). The recommended dose level was 16 mg/m 2 and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects.Conclusions: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m 2 and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced. Clin Cancer Res; 17(15); 5152-60. Ó2011 AACR.

Section: Discussionmentioning

confidence: 99%

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

Rischin

Bibby

Chong

et al. 2011

“…days, a schedule that has been shown to be well tolerated for up to 50 cycles in children (9). Even at the lowest dose level, administration of ABT-751 daily for 21 days was not well tolerated in subsequent cycles.…”

Section: Resultsmentioning

confidence: 99%

“…Monitoring for treatment-related toxicity included weekly physical examination and serum chemistries as well as twice weekly complete blood counts. Clinical and laboratory adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 2, 5 except for peripheral and sensory neuropathy, which were evaluated using pediatric-specific grading scales for sensory and motor neuropathy, as previously reported (9).…”

Section: Methodsmentioning

confidence: 99%

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A Phase I Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 21 Days Every 28 Days in Pediatric Patients with Solid Tumors

Fox

Maris

Widemann

et al. 2008

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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...

“…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).…”

mentioning

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.