PHASE I STUDIES

Investigational New Drugs

, Volume 25, Issue 5, pp 445-451

First online:

Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC)

  • Charles J. RyanAffiliated withUrologic Oncology Program, UCSF Comprehensive Cancer Center Email author 
  • , Walter M. StadlerAffiliated withUniversity of Chicago
  • , Bruce RothAffiliated withVanderbilt University Medical Center
  • , Douglass HutcheonAffiliated withUrologic Oncology Program, UCSF Comprehensive Cancer Center
  • , Shauna ConryAffiliated withUrologic Oncology Program, UCSF Comprehensive Cancer Center
  • , Thomas PuchalskiAffiliated withAstraZeneca
  • , Charles MorrisAffiliated withAstraZeneca
  • , Eric J. SmallAffiliated withUrologic Oncology Program, UCSF Comprehensive Cancer Center

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Summary

To explore the pharmacokinetics and tolerability of AZD2171, an inhibitor of vascular endothelial growth factor receptors 1 and 2, in patients with hormone refractory prostate cancer. Twenty-six patients received oral daily dosing of AZD2171 at 1, 2.5, 5, 10, 20, 30 mg. The maximum tolerated dose (MTD) was defined as the dose below that at which ≥33% of patients experienced a dose-limiting toxicity (DLT) within 21 days of initiating therapy. Pharmacokinetic analysis was performed. DLTs occurred at the 30 mg dose and included grade 3 events in three patients: fatigue (n = 3) and muscle weakness (n = 2). The pharmacokinetic profile revealed an effective half-life of approximately 27 h. At steady state, the unbound drug concentration was 4.4 times above the concentration required to inhibit endothelial cell proliferation in vitro. Four patients experienced PSA reductions within 30 days following drug discontinuation (one on 2.5 mg, two on 20 mg and 1 on 30 mg). In two patients treated with 20 mg, post therapy PSA declines persisted for >17 months, despite a PSA increase on therapy. Resolution of adenopathy occurred in one patient persisting for >17 months. Plasma concentrations were maximum 2–8 h post dosing with an overall median value of 2 h. The dose of 20 mg daily was declared as the MTD. One objective response and several PSA declines following the discontinuation of therapy for toxicity suggest that evidence of clinical efficacy may be delayed. While further study is indicated, careful attention must be paid to the novel toxicities of this agent with prolonged dosing.

Keywords

Prostate cancer Hormone refractory prostate cancer Angiogenesis inhibitors Pharmacokinetics