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Clinical Trial
. 2012 Mar;103(3):504-9.
doi: 10.1111/j.1349-7006.2011.02179.x. Epub 2012 Jan 30.

A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors

Noboru Yamamoto  1 , Hiroshi Nokihara, Yasuhide Yamada, Yasushi Goto, Maki Tanioka, Takashi Shibata, Kazuhiko Yamada, Hajime Asahina, Toshio Kawata, Xiaojin Shi, Tomohide Tamura
Affiliations
Clinical Trial

A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors

Noboru Yamamoto et al. Cancer Sci. 2012 Mar.

Abstract

Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed.

Trial registration: ClinicalTrials.gov NCT00572364.

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Figures

Figure 1
Figure 1
Geometric mean plasma‐concentration profiles of olaparib following: (a) single dosing and (b) twice‐daily dosing for 15 days.
See this image and copyright information in PMC

References

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