A Phase I Study of AT9283 Given As a 24 Hour Infusion on Days 1 and 8 Every Three Weeks in Patients With Advanced Incurable Malignancy
- Determine the maximum tolerated dose and recommended phase II dose of Aurora kinase
inhibitor AT9283 (AT9283) in patients with incurable advanced or metastatic solid
tumors or non-Hodgkin's lymphoma.
- Determine the safety, tolerability, toxicity profile, dose-limiting toxicity, and
pharmacokinetic profile of this drug in these patients.
- Correlate the toxicity profile with the pharmacokinetics of this drug in these
- Assess, preliminarily, evidence of antitumor activity of this drug in these patients.
- Determine the pharmacodynamic activity of this drug in these patients and correlate
with biological endpoints.
OUTLINE: This is an open-label, dose-escalation, multicenter study.
Patients receive Aurora kinase inhibitor AT9283 (AT9283) IV over 24 hours on days 1 and 8 .
Treatment repeats every 3 weeks in the absence of disease progression or unacceptable
Cohorts of 3-6 patients receive escalating doses of AT9283 until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose at which at least 2 of 3 or 2 of 6
patients experience dose-limiting toxicity. The dose preceding the MTD is the recommended
phase II dose (RPTD). Up to 8 additional patients are treated at the RPTD.
Patients treated at the RPTD undergo skin and tumor tissue biopsy and blood collection at
baseline and on days 2 and/or 3. Samples are examined by pharmacokinetic and pharmacodynamic
analysis, including immunohistochemistry, immunocytochemistry, western blotting,
immunoenzyme techniques, flow cytometry, and reverse transcriptase-polymerase chain
reaction, for biological markers.
After completion of study treatment, patients are followed at 4 weeks and then every 3
months until disease progression.
PROJECTED ACCRUAL: Up to 30 patients will be accrued for this study.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of Aurora kinase inhibitor AT9283 (AT9283)
Doses escalated as described in protocol section 4.3. MTD defined as that dose at which ≥ 2/6 or ≥ 2/3 patients experience DLT (as defined in protocol section 4.4).
Karen A. Gelmon, MD
British Columbia Cancer Agency
Canada: Health Canada