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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Non-Hodgkins Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: Aurora kinase inhibitor AT9283


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AT9283<br> | Drug: Aurora kinase inhibitor AT9283<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 1 year | 
| Recommended phase II dose of AT9283 | RPTD defined as one dose lower than MTD. | 1 year | 
| Safety, tolerability, toxicity profile, and dose-limiting toxicity of AT9283 | Adverse events graded using NCI CTCAE V3.0 | every 3 weeks | 
| Pharmacokinetic profile of AT9283 | PK samples collected on all patients during cycle 1 as described in protocol section 17.2. | cycle one only | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of AT9283 | All patients with measurable disease were assessed for response using RECIST criteria as described in protocol section 10. | every 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific, recurrent adult Burkitt lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, recurrent grade 2 follicular lymphoma, stage III grade 2 follicular lymphoma, stage IV grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 3 follicular lymphoma, recurrent mantle cell lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, recurrent adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage IV adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, stage III adult lymphoblastic lymphoma, stage IV adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, stage III grade 1 follicular lymphoma, stage IV grade 1 follicular lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, recurrent marginal zone lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, recurrent small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, recurrent adult grade III lymphomatoid granulomatosis, adult grade III lymphomatoid granulomatosis, Waldenstrom macroglobulinemia