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

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.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following:

  • Advanced and/or metastatic solid tumor
  • Advanced or metastatic non-Hodgkin's lymphoma refractory to standard therapy

• Clinically or radiologically documented disease

  • No tumor marker elevation as only evidence of disease

• No untreated brain or meningeal metastases

  • Treated and stable brain metastases allowed provided they are asymptomatic and do not require steroids

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.25 times upper limit of normal (ULN) OR creatinine clearance ≥ 50 mL/min
• Bilirubin normal
• ALT and AST ≤ 2 times ULN (≤5 times ULN if liver metastases are present)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use two effective methods of contraception
• No untreated or uncontrolled hypertension, cardiovascular conditions, or symptomatic cardiac dysfunction
• No active or uncontrolled infections
• No serious illness or medical condition that would preclude study treatment

PRIOR CONCURRENT THERAPY:

• At least 2 weeks since prior major surgery and recovered

• At least 3 weeks since prior palliative radiotherapy and recovered

  • Low-dose, nonmyelosuppressive radiotherapy may be allowed

• At least 3 weeks since prior chemotherapy for solid tumors and recovered

  • No more than 2 prior cytotoxic chemotherapy regimens for metastatic disease

• At least 4 weeks since prior steroids

• No limitations on prior therapy for patients with non-Hodgkin's lymphoma

• Prior hormonal, immunologic, biologic or signal transduction inhibitor therapy allowed

• No other concurrent investigational agents

• No other concurrent anticancer therapy