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Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose.
- Source :
-
Investigational new drugs [Invest New Drugs] 2015 Aug; Vol. 33 (4), pp. 942-53. Date of Electronic Publication: 2015 Jun 19. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Aged
Asian People
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms metabolism
Treatment Outcome
Young Adult
Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents therapeutic use
Aurora Kinase A antagonists & inhibitors
Azepines administration & dosage
Azepines adverse effects
Azepines pharmacokinetics
Azepines therapeutic use
Neoplasms drug therapy
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors adverse effects
Protein Kinase Inhibitors pharmacokinetics
Protein Kinase Inhibitors therapeutic use
Pyrimidines administration & dosage
Pyrimidines adverse effects
Pyrimidines pharmacokinetics
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 33
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 26084989
- Full Text :
- https://doi.org/10.1007/s10637-015-0258-y