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

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.

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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 4 Pg. 942-53 (Aug 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 26084989 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Azepines
• MLN 8237
• Protein Kinase Inhibitors
• Pyrimidines
• Aurora Kinase A

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Asian People
• Aurora Kinase A (antagonists & inhibitors)
• Azepines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Young Adult