AT7519M in Treating Patients With Advanced or Metastatic Solid Tumors or Refractory Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: AT7519M 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 AT7519M in treating patients with advanced or metastatic solid tumors or refractory non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the recommended phase II dose of AT7519M in patients with advanced or metastatic solid tumors or refractory non-Hodgkin's lymphoma. Determine the safety, tolerability, toxicity profile, and dose-limiting toxicities of this drug in these patients. Determine the pharmacokinetic profile of this drug in these patients. Correlate the toxicity profile with pharmacokinetics of this drug in these patients. Secondary Assess, preliminarily, the antitumor activity of this drug in these patients. OUTLINE: This is an open-label, dose-escalation, multicenter study. Patients receive AT7519M IV over 1-3 hours on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of AT7519M until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity during course 1. Once the MTD has been determined, up to 8 additional patients are treated at the MTD. Patients undergo blood collection periodically for pharmacokinetic studies. Patients treated at the MTD also undergo tumor tissue biopsies or aspirates and blood collection periodically for additional pharmacodynamic and correlative biomarker studies. After completion of study therapy, patients are followed at 4 weeks. Patients with complete response, partial response, or stable disease are followed every 3 months thereafter until relapse. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Official Title
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A Phase I Study of AT7519M Given Twice Weekly in Patients With Advanced Incurable Malignancy

Conditions
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Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: CDKI AT7519
* Other: laboratory biomarker analysis


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 No more than 3 prior regimens for metastatic disease Refractory non-Hodgkin's lymphoma Clinically or radiologically documented disease Patients whose only evidence of disease is tumor marker elevation are not eligible No untreated brain or meningeal metastases Patients with radiologic or clinical evidence of stable, treated brain metastases are eligible provided they are asymptomatic AND have no requirement for corticosteroids 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 patient has documented liver metastases) Potassium normal Calcium normal Creatine kinase (CK or CPK) ≤ 2 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No pre-existing cardiovascular conditions and/or symptomatic cardiac dysfunction, including any of the following: Significant cardiac event (including symptomatic heart failure or angina) within the past 3 months or any cardiac disease that, in the opinion of the investigator, increases the risk for ventricular arrhythmia Any history of ventricular arrhythmia, which was symptomatic or required treatment (CTC grade 3), including multifocal PVCs, bigeminy, trigeminy, or ventricular tachycardia Uncontrolled hypertension Previous history of QT prolongation with other medication Congenital long QT syndrome QT and QTc, with Bazett's correction, unmeasurable or ≥ 460 msec on screening ECG LVEF < 45 % by MUGA for patients with significant cardiac history (i.e., myocardial infarction, severe hypertension, or arrhythmia) or prior doxorubicin (> 450 mg/m²) No active or uncontrolled infections No serious illness or medical condition that would preclude study compliance No peripheral neuropathy > grade 1 PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 21 days since prior cytotoxic chemotherapy and recovered (solid tumors) At least 21 days since prior palliative radiotherapy and recovered Exceptions may be made for low-dose, nonmyelosuppressive radiotherapy Prior hormonal, immunologic, biologic, or signal transduction inhibitor therapy allowed At least 14 days since prior major surgery and recovered (no nonhealing wounds) At least 4 weeks since prior steroids No other concurrent medications which affect QT/QTc and cannot be discontinued No other concurrent experimental drugs or 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: CDKI AT7519<br>AT7519M (1 hour IV) on days 1, 4, 8 and 11 every 5 weeks. | Drug: CDKI AT7519<br>* AT7519M (1 hour IV) on days 1, 4, 8 and 11 every 5 weeks.<br>Other: laboratory biomarker analysis<br>* Pharmacokinetic bioanalysis of the AT7519 plasma concentration data will be performed by BioDynamics Northhampton, U.K. The pharmacokinetic parameters for AT7519 will be determined by Astex Therapeutics as data permits.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose as assessed by NCI CTCAE v.30 |  | from time of 1st dose | 
| Safety, tolerability, toxicity profile, and dose-limiting toxicities as assessed by NCI CTCAE v.30 |  | from time of 1st dose | 
| Pharmacokinetic profile as measured on days 1, 2, and 4 in course 1 | during cycle 1 | one month | 
| Correlation of toxicity profile with pharmacokinetics |  | after completion of each dose level | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary antitumor activity of treatment in patients with measurable disease | after every second cycle | Every 60 days | 
| Overall response (complete and partial response) rate | after every second cycle | Every 60 days | 
| Response duration (median and range) |  | after progression | 

 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, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, Waldenstrom macroglobulinemia, recurrent adult grade III lymphomatoid granulomatosis, adult nasal type extranodal NK/T-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma