Open AccessA Phase I, dose‐finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors *,†
Author(s) -
Yamamoto Noboru,
Nokihara Hiroshi,
Yamada Yasuhide,
Goto Yasushi,
Tanioka Maki,
Shibata Takashi,
Yamada Kazuhiko,
Asahina Hajime,
Kawata Toshio,
Shi Xiaojin,
Tamura Tomohide
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02179.x
Subject(s) - olaparib , medicine , tolerability , pharmacokinetics , parp inhibitor , leukopenia , dosing , adverse effect , pharmacology , gastroenterology , toxicity , poly adp ribose polymerase , chemistry , biochemistry , polymerase , gene
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. ( Cancer Sci 2012; 103: 504–509)