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A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors.


ABSTRACT: Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors.Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies.Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1-24). Total doses ranged from 40 to 105 mg/m(2). The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 ?M. Area under the concentration-versus-time curve ([Formula: see text]) ranged from 4.31 to 32.2 ?M[Symbol: see text]hr with an overall mean of 13.6 ± 7.0 ?M[Symbol: see text]hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes.The maximum-tolerated dose of flavopiridol is 20 mg/m(2) bolus followed by 20 mg/m(2) infusion over 4 h given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.

SUBMITTER: Ramaswamy B 

PROVIDER: S-EPMC3486515 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors.

Ramaswamy Bhuvaneswari B   Phelps Mitch A MA   Baiocchi Robert R   Bekaii-Saab Tanios T   Ni Wenjun W   Lai Ju-Ping JP   Wolfson Anna A   Lustberg Mark E ME   Wei Lai L   Wilkins Deidre D   Campbell Angela A   Arbogast Daria D   Doyle Austin A   Byrd John C JC   Grever Michael R MR   Shah Manisha H MH  

Investigational new drugs 20101012 2


<h4>Purpose</h4>Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors.<h4>Experimental design</h4>Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase  ...[more]

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