Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: phase 1 dose-escalation study.

Abstract

BACKGROUND:

This phase 1b study evaluated an enteric-coated tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237).

METHODS:

Patients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 d BID followed by 14 d treatment-free (21-day cycles; 3 + 3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib.

RESULTS:

24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1-12). The RP2D was determined as 50 mg BID for 7 d (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50%). At doses ≥ 40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10-60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored).

CONCLUSIONS:

Alisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 d and is being evaluated in ongoing phase 2 studies.

• Authors: Gerald Falchook, Razelle Kurzrock, Launce Gouw, David Hong, Kimberly A McGregor, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Sunil Sharma
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 6 Pg. 1181-7 (Dec 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24879333 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Aurora Kinase A (antagonists & inhibitors)
• Azepines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• 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)
• Response Evaluation Criteria in Solid Tumors
• Tablets