Clinical trial NCT00443976: Aurora Kinase Inhibitor AT9283 in Treating Patients With Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Hodgkins Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: Astex Pharmaceuticals, Inc.
First posted: 2007-03-07
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose of Aurora kinase inhibitor AT9283 (AT9283)
timeFrame: 1 year
measure: Recommended phase II dose of AT9283
timeFrame: 1 year
measure: Safety, tolerability, toxicity profile, and dose-limiting toxicity of AT9283
timeFrame: every 3 weeks
measure: Pharmacokinetic profile of AT9283
timeFrame: cycle one only
Secondary outcomes:
measure: Efficacy of AT9283
timeFrame: every 6 weeks
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - General Division
state: Ontario
Study officials:
affiliation: British Columbia Cancer Agency
name: Karen A. Gelmon, MD
role: STUDY_CHAIR
affiliation: Ottawa Regional Cancer Centre
name: Susan F. Dent, MD
role: STUDY_CHAIR
References:
citation: Dent SF, Gelmon KA, Chi KN, Jonker DJ, Wainman N, Capier CA, Chen EX, Lyons JF, Seymour L. NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies. Invest New Drugs. 2013 Dec;31(6):1522-9. doi: 10.1007/s10637-013-0018-9. Epub 2013 Sep 27.