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

Michels, Jorg; Ellard, Susan L.; Le, Lyly; Kollmannsberger, Christian; Murray, Nevin; Guns, Emma S. Tomlinson; Carr, Robert; N., Kim

doi:10.1093/annonc/mdp311

Cited by 21 publications

(14 citation statements)

References 17 publications

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“…Patients with DLT had higher dose-normalized ABT-751 AUC (mean±SD=0.21±0.05 h/l, n =7) than patients who did not experience DLT (0.16±0.05, n =40; P =0.03). At the dose intervals tested in this study, the pharmacokinetics of ABT-751 (Table 4) is linear, consistent with previous reports [8,25]. …”

Section: Resultssupporting

confidence: 92%

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

Innocenti

Ramı́rez²,

Obel³

et al. 2013

Pharmacogenetics and Genomics

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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. Methods UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. Results UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (> 2) was associated with an average 34% increase in ABT-751 clearance (P= 0.044), an 18% reduction in ABT-751 AUC (P = 0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P =0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 Ctrough (P = 0.009). Conclusion These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.

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Section: Resultssupporting

confidence: 92%

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

Innocenti

Ramı́rez²,

Obel³

et al. 2013

Pharmacogenetics and Genomics

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“…A phase IB study of ABT-751 and docetaxel in patients with castrate-resistant prostate cancer had DLTs of febrile neutropenia, diarrhea and nausea [28]. Interestingly, ABT-751 demonstrated limited myelosuppression, thus it may be safely combined with myelosuppressing chemotherapies [23–25].…”

Section: Introductionmentioning

confidence: 99%

A Phase I Trial and in vitro Studies Combining ABT-751 with Carboplatin in Previously Treated Non-Small Cell Lung Cancer Patients

Ma¹,

Fuld²,

Rigas³

et al. 2012

Chemotherapy

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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. Methods: Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs. Results: Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9–27.0). Time to tumor progression was 2.8 months (95% CI 2.0–2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs. Conclusion: Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.

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“…The ability of ixabepilone to circumvent these multidrug resistance (MDR) mechanisms has provided a unique chemotherapeutic approach for patients with anthracyclines or taxanes resistant tumors. An orally bioavailable sulfonamide (ABT-751) that inhibits tubulin polymerization and maintains activity in cells expressing P-glycoprotein is currently being evaluated in phase I trials (9, 10), but is not yet available for routine clinical use. Despite the widespread use of the vinca alkaloids for the treatment of cancer and their susceptibility to these same MDR mechanisms, an anticancer agent that destabilizes microtubules and effectively circumvents P-gp-mediated drug resistance is not yet approved for clinical use.…”

Section: Introductionmentioning

confidence: 99%

Biological Activity of 4-Substituted Methoxybenzoyl- Aryl-Thiazole: An Active Microtubule Inhibitor

Wang

Lü

et al. 2011

Cancer Research

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Formation of microtubules is a dynamic process that involves polymerization and depolymerization of ab-tubulin heterodimers. Drugs that enhance or inhibit tubulin polymerization can destroy this dynamic process, arresting cells in the G 2 /M phase of the cell cycle. Although drugs that target tubulin generally demonstrate cytotoxic potency in the subnanomolar range, resistance due to drug efflux is a common phenomenon among the antitubulin agents. We recently reported a class of 4-substituted methoxybenzoylaryl-thiazoles (SMART) that exhibited great in vitro potency and broad spectrum cellular cytotoxicity.

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

Cited by 21 publications

References 17 publications

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

A Phase I Trial and in vitro Studies Combining ABT-751 with Carboplatin in Previously Treated Non-Small Cell Lung Cancer Patients

Biological Activity of 4-Substituted Methoxybenzoyl- Aryl-Thiazole: An Active Microtubule Inhibitor

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