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NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies
S F Dent1, K A Gelmon, K N Chi
1Division of Medical Oncology, Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, 501 Smyth Rd, Ottawa, ON, Canada, K1H 8L6, sdent@ottawahospital.on.ca.
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.
Insights
The novel cancer drug AT9283, an inhibitor of Aurora-kinases A and B, demonstrated good tolerability in patients with advanced cancers. The recommended phase II dose was established, paving the way for further efficacy studies.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- AT9283 is a potent inhibitor of Aurora-kinases A and B.
- It has demonstrated anti-tumor activity in solid and hematological malignancies.
Purpose of the Study:
- To assess the safety and tolerability of AT9283 in patients with advanced cancers.
- To determine the pharmacokinetic and pharmacodynamic properties of AT9283.
Main Methods:
- A Phase I, 3+3 dose escalation study was conducted.
- Patients received AT9283 via continuous 24-hour infusion on days 1 and 8 of a 21-day cycle.
- Pharmacokinetic and pharmacodynamic samples were collected.
Main Results:
- AT9283 was well tolerated, with dose-limiting toxicities including febrile neutropenia and neutropenia with infection at 47 mg/m(2)/day.
- The maximum tolerated dose was 47 mg/m(2)/day, and the recommended phase II dose (RP2D) was 40 mg/m(2)/day.
- Pharmacokinetic analysis indicated linear kinetics with a mean half-life of 8.2 hours. One partial response and four instances of stable disease were observed.
Conclusions:
- AT9283 is well tolerated in patients with advanced cancers.
- The recommended phase II dose is 40 mg/m(2)/day.
- Ongoing trials will further evaluate AT9283's efficacy and safety in various cancers.
