1.Phase I Study of ABT-751 in Combination with CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients with Advanced Colorectal Cancer.
Rudek MA1, Dasari A2, Laheru D1, He P1, Jin R1, Walker R1, Taylor GE1, Jimeno A1,2, Donehower RC1, Hidalgo M1,3, Messersmith WA1,2, Purcell WT1,2. J Clin Pharmacol. 2015 Dec 3. doi: 10.1002/jcph.681. [Epub ahead of print]
ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A non-randomized phase I dose-escalation study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT-751 daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751 daily and capecitabine twice daily for 14 days, irinotecan on day 1 intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1 after the first two dose levels. Due to intolerance of the regimen, a reduced dose of ABT-751 was also explored with reduced dose and full dose CAPIRI with bevacizumab. ABT-751 and irinotecan pharmacokinetics, ABT-751 glucuronidation, and protein binding were explored. Twenty-four patients were treated over 5 dose levels. The maximum tolerated dose was ABT-751 125 mg combined with full dose CAPIRI and bevacizumab 7.
2.Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.
Innocenti F1, Ramírez J, Obel J, Xiong J, Mirkov S, Chiu YL, Katz DA, Carr RA, Zhang W, Das S, Adjei A, Moyer AM, Chen PX, Krivoshik A, Medina D, Gordon GB, Ratain MJ, Sahelijo L, Weinshilboum RM, Fleming GF, Bhathena A. Pharmacogenet Genomics. 2013 Jul;23(7):374-81. doi: 10.1097/FPC.0b013e3283623e81.
OBJECTIVE: ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751.
3.A phase I trial and in vitro studies combining ABT-751 with carboplatin in previously treated non-small cell lung cancer patients.
Ma T1, Fuld AD, Rigas JR, Hagey AE, Gordon GB, Dmitrovsky E, Dragnev KH. Chemotherapy. 2012;58(4):321-9. doi: 10.1159/000343165. Epub 2012 Nov 12.
BACKGROUND: ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs.
4.Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children's Oncology Group (ANBL0621).
Fox E1, Mosse' YP, Meany HM, Gurney JG, Khanna G, Jackson HA, Gordon G, Shusterman S, Park JR, Cohn SL, Adamson PC, London WB, Maris JM, Balis FM. Pediatr Blood Cancer. 2014 Jun;61(6):990-6. doi: 10.1002/pbc.24900. Epub 2013 Dec 18.
BACKGROUND: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population.PROCEDURE: Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease.