NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies.

Abstract

PURPOSE:

AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283.

PATIENTS AND METHODS:

Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D).

RESULTS:

35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months).

CONCLUSION:

In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

• Authors: S F Dent, K A Gelmon, K N Chi, D J Jonker, N Wainman, C A Capier, E X Chen, J F Lyons, L Seymour
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 6 Pg. 1522-9 (Dec 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 24072436 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
• Antineoplastic Agents
• Benzimidazoles
• Histones
• Ki-67 Antigen
• Proliferating Cell Nuclear Antigen
• Protein Kinase Inhibitors
• Tumor Suppressor Protein p53
• Urea

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Drug Administration Schedule
• Female
• Histones (metabolism)
• Humans
• Infusions, Intravenous
• Ki-67 Antigen (metabolism)
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Proliferating Cell Nuclear Antigen (metabolism)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Skin (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Urea (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)