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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]

PMID: 20938713

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Project description:BackgroundCGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525).MethodsFifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics.ResultsNo dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined.ConclusionsDespite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors.Translational relevanceHaematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.

Dataset Information

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

Publications

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

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