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01.08.2015 | PHASE I STUDIES | Ausgabe 4/2015

Investigational New Drugs 4/2015

Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose

Zeitschrift:
Investigational New Drugs > Ausgabe 4/2015
Autoren:
Karthik Venkatakrishnan, Tae Min Kim, Chia-Chi Lin, Lim Soon Thye, Wee Joo Chng, Brigette Ma, Ming Huang Chen, Xiaofei Zhou, Hua Liu, Virginia Kelly, Won Seog Kim
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10637-015-0258-y) contains supplementary material, which is available to authorized users.

Summary

Purpose This phase 1 study assessed the pharmacokinetics (PK), maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the investigational Aurora A kinase inhibitor, alisertib, in East Asian patients with advanced solid tumors or lymphomas. Patients and Methods Patients received alisertib twice-daily (BID) for 7 days in 21-day cycles. Doses were escalated (3 + 3) from 30 mg BID based on cycle 1 dose-limiting toxicities (DLTs) until the MTD, followed by expansion for PK/safety characterization. Results Thirty-six patients (61 % Chinese, 36 % Korean, 3 % Malay) received alisertib (30 mg BID, n = 30; 40 mg BID, n = 6; median, 2.5 cycles). Alisertib exposures increased approximately dose proportionally, and mean half-life was 16 h. Geometric mean apparent oral clearance (2.65 L/h) was 40 % lower than previous estimates in Western patients, resulting in approximately 70 % higher mean dose-normalized, steady-state exposures (735 nM*h/mg) in East Asian patients. Two patients experienced DLTs at 40 mg BID (grade 3 stomatitis; grade 4 neutropenia); the MTD/RP2D was 30 mg BID. Common toxicities (grade ≥3 at RP2D) were neutropenia (50 %), diarrhea (13 %), and stomatitis (10 %). One patient with extranodal T-/NK-cell lymphoma (nasal type) achieved a partial response and 18 (51 %) had stable disease. Conclusion The MTD/RP2D of alisertib in East Asian patients (30 mg BID) was lower than in Western patients (50 mg BID), consistent with higher systemic exposures in the East Asian population. Alisertib was generally well tolerated and showed signs of antitumor activity in East Asian cancer patients.

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Zusatzmaterial
Supplementary Tables S1 Most frequent treatment-emergent AEs (any grade) in ≥15 % of patients by alisertib dose and East Asian race (safety population) (DOCX 13 kb)
10637_2015_258_MOESM1_ESM.docx
Literatur
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