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The starting dose of AT9283 will be 1.5 mg/m2 given as a 24 hour IV infusion on Days 1 and 8 every three weeks.

Aurora kinase inhibitor AT9283

Karen A. Gelmon, MD

Susan F. Dent, MD

RATIONALE: Aurora kinase inhibitor AT9283 (AT9283) may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of AT9283 in treating patients with advanced or metastatic solid tumors or non-Hodgkin's lymphoma.

OBJECTIVES:

* 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 patients.
* 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 toxicity.

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.

Aurora Kinase Inhibitor AT9283 in Treating Patients With Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma

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

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).

Adverse events graded using NCI CTCAE V3.0

PK samples collected on all patients during cycle 1 as described in protocol section 17.2.

All patients with measurable disease were assessed for response using RECIST criteria as described in protocol section 10.

Astex Pharmaceuticals, Inc.

NCIC Clinical Trials Group

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