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Article: Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors

TitlePhase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors
Authors
Issue Date2013
Citation
Clinical Cancer Research, 2013, v. 19, n. 1, p. 236-246 How to Cite?
AbstractPurpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. Experimental Design: Sorafenib dose was escalated from 90 to 110mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course. Results: Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m2at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019). Conclusion: The recommended phase II doses are sorafenib, 90mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation. ©2012 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/294459
ISSN
2020 Impact Factor: 12.531
2020 SCImago Journal Rankings: 5.427
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNavid, Fariba-
dc.contributor.authorBaker, Sharyn D.-
dc.contributor.authorMcCarville, M. Beth-
dc.contributor.authorStewart, Clinton F.-
dc.contributor.authorBillups, Catherine A.-
dc.contributor.authorWu, Jianrong-
dc.contributor.authorDavidoff, Andrew M.-
dc.contributor.authorSpunt, Sheri L.-
dc.contributor.authorFurman, Wayne L.-
dc.contributor.authorMcGregor, Lisa M.-
dc.contributor.authorHu, Shuiying-
dc.contributor.authorPanetta, John C.-
dc.contributor.authorTurner, David-
dc.contributor.authorFofana, Demba-
dc.contributor.authorReddick, Wilburn E.-
dc.contributor.authorLeung, Wing-
dc.contributor.authorSantana, Victor M.-
dc.date.accessioned2020-12-03T08:22:47Z-
dc.date.available2020-12-03T08:22:47Z-
dc.date.issued2013-
dc.identifier.citationClinical Cancer Research, 2013, v. 19, n. 1, p. 236-246-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10722/294459-
dc.description.abstractPurpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. Experimental Design: Sorafenib dose was escalated from 90 to 110mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course. Results: Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m2at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019). Conclusion: The recommended phase II doses are sorafenib, 90mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation. ©2012 AACR.-
dc.languageeng-
dc.relation.ispartofClinical Cancer Research-
dc.titlePhase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-12-1897-
dc.identifier.pmid23143218-
dc.identifier.pmcidPMC3537913-
dc.identifier.scopuseid_2-s2.0-84871979382-
dc.identifier.volume19-
dc.identifier.issue1-
dc.identifier.spage236-
dc.identifier.epage246-
dc.identifier.eissn1557-3265-
dc.identifier.isiWOS:000313051100025-
dc.identifier.issnl1078-0432-

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