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

• ClinicalTrials.gov Identifier: NCT00390117
• Recruitment Status: Completed
• First Posted: October 19, 2006
• Last Update Posted: April 8, 2020
• Sponsor: NCIC Clinical Trials Group
• Information provided by (Responsible Party): Canadian Cancer Trials Group ( NCIC Clinical Trials Group )

Tracking Information

• First Submitted Date: October 18, 2006
• First Posted Date: October 19, 2006
• Last Update Posted Date: April 8, 2020
• Actual Study Start Date: August 22, 2006
• Actual Primary Completion Date: March 13, 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2011)

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

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: September 21, 2011)

• Preliminary antitumor activity of treatment in patients with measurable disease [ Time Frame: Every 60 days ]
  after every second cycle
• Overall response (complete and partial response) rate [ Time Frame: Every 60 days ]
  after every second cycle
• Response duration (median and range) [ Time Frame: after progression ]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Lymphoma
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

• Drug: CDKI AT7519
  AT7519M (1 hour IV) on days 1, 4, 8 and 11 every 5 weeks.
• Other: laboratory biomarker analysis
  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.

Study Arms

Experimental: CDKI AT7519

AT7519M (1 hour IV) on days 1, 4, 8 and 11 every 5 weeks.

Interventions:

• Drug: CDKI AT7519
• Other: laboratory biomarker analysis

Publications *

• 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.
• 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. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 2, 2012): 34
• Original Enrollment: Not Provided
• Actual Study Completion Date: January 10, 2013
• Actual Primary Completion Date: March 13, 2012 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT00390117
• Other Study ID Numbers: I177; CAN-NCIC-IND177 ( Registry Identifier: NCI US - Physician Data Query ); CDR0000507621 ( Other Identifier: PDQ )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Canadian Cancer Trials Group ( NCIC Clinical Trials Group )
• Study Sponsor: NCIC Clinical Trials Group
• Collaborators: Not Provided

Investigators

• Study Chair: Sebastien Hotte, MD; Margaret and Charles Juravinski Cancer Centre
• Study Chair: Eric X. Chen, MD, PhD; Princess Margaret Hospital, Canada

• PRS Account: Canadian Cancer Trials Group
• Verification Date: April 2020