Clinical trial NCT00390117: AT7519M in Treating Patients With Advanced or Metastatic Solid Tumors or Refractory Non-Hodgkin's Lymphoma
Official title: A Phase I Study of AT7519M Given Twice Weekly in Patients With Advanced Incurable Malignancy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
First posted: 2006-10-19
Enrollment: 34
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: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose as assessed by NCI CTCAE v.30
timeFrame: from time of 1st dose
measure: Safety, tolerability, toxicity profile, and dose-limiting toxicities as assessed by NCI CTCAE v.30
timeFrame: from time of 1st dose
measure: Pharmacokinetic profile as measured on days 1, 2, and 4 in course 1
timeFrame: one month
measure: Correlation of toxicity profile with pharmacokinetics
timeFrame: after completion of each dose level
Secondary outcomes:
measure: Preliminary antitumor activity of treatment in patients with measurable disease
timeFrame: Every 60 days
measure: Overall response (complete and partial response) rate
timeFrame: Every 60 days
measure: Response duration (median and range)
timeFrame: after progression
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: Margaret and Charles Juravinski Cancer Centre
name: Sebastien Hotte, MD
role: STUDY_CHAIR
affiliation: Princess Margaret Hospital, Canada
name: Eric X. Chen, MD, PhD
role: STUDY_CHAIR
References:
citation: Chen EX, Hotte S, Hirte H, Siu LL, Lyons J, Squires M, Lovell S, Turner S, McIntosh L, Seymour L. A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177. Br J Cancer. 2014 Dec 9;111(12):2262-7. doi: 10.1038/bjc.2014.565. Epub 2014 Nov 13.
citation: Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009 Mar;9(3):153-66. doi: 10.1038/nrc2602.