Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN™), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors
- 233 Downloads
To evaluate safety and tolerability of cediranib, a highly potent and selective vascular endothelial growth factor signaling inhibitor, in Japanese patients with advanced solid tumors refractory to standard therapies.
In part A (n = 16), patients received once-daily oral cediranib (10–45 mg) to identify the maximum tolerated dose (MTD). In part B (n = 24), patients with non-small-cell lung cancer or colorectal cancer received multiple daily doses at the MTD.
Cediranib 30 mg/day was considered the MTD since 50% of evaluable patients receiving 45 mg/day experienced dose-limiting toxicities in part A (proteinuria and diarrhea n = 1, proteinuria n = 1, thrombocytopenia n = 1). The most common adverse events were diarrhea (n = 34) and hypertension (n = 32). Pharmacokinetic analysis confirmed cediranib as suitable for once-daily oral dosing. Of 32 evaluable patients, two had partial RECIST responses and 24 had stable disease ≥8 weeks.
Cediranib was generally well tolerated at ≤30 mg/day in these Japanese patients and showed encouraging antitumor activity.
KeywordsAZD2171 Cediranib Phase I study Tolerability Vascular endothelial growth factor receptor
- 15.Johnson DH, Fehrenbacher L, Novotny WF et al (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184–2191PubMedCrossRefGoogle Scholar
- 18.Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
- 19.Langenberg M, van Herpen CM, de Bono JS et al (2008) Optimal management of emergent hypertension during treatment with a VEGF signaling inhibitor: a randomized phase II study of cediranib. J Clin Oncol 26(15S):abst 3555Google Scholar
- 20.Curwen JO, Musgrove HL, Kendrew J et al (2008) Inhibition of vascular endothelial growth factor-A signaling induces hypertension: examining the effect of cediranib (Recentin; AZD2171) treatment on blood pressure in rat and the use of concomitant antihypertensive therapy. Clin Cancer Res 14:3124–3131PubMedCrossRefGoogle Scholar
- 22.Raymond E, Faivre S, Vera K et al (2003) Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. Proc Am Soc Clin Oncol 22:abst 769Google Scholar
- 23.Veronese ML, Flaherty KT, Townsend R et al (2004) Pharmacodynamic study of the raf kinase inhibitor BAY 43-9006: mechanisms of hypertension. J Clin Oncol 22(suppl):abst 2035Google Scholar
- 26.Ramalingam SS, Mack PC, Vokes EE et al (2008) Cediranib (AZD2171) for the treatment of recurrent small cell lung cancer (SCLC): a California Consortium phase II study (NCI # 7097). J Clin Oncol 26(15S):abst 8078Google Scholar
- 27.Hirte HW, Vidal L, Fleming GF et al (2008) A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial. J Clin Oncol 26(15S):abst 5521Google Scholar