Lapatinib in Treating Patients With Recurrent Glioblastoma Multiforme

A Phase I/II Study of GW572016 in Patients With Recurrent Malignant Glioma

RATIONALE: Lapatinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of lapatinib and to see how well it works in treating patients with recurrent glioblastoma multiforme.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: lapatinib ditosylate

Detailed Description

OBJECTIVES:

Phase I

• Determine the maximum tolerated dose and recommended phase II dose of lapatinib in patients with recurrent malignant glioblastoma multiforme who are taking CYP3A4 enzyme-inducing anti-epileptic drugs (EIAEDs).
• Determine the toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.

Phase II

• Determine the efficacy of this drug, in terms of objective tumor response rate, in patients who are taking EIAEDs and in those who are not taking EIAEDs.
• Correlate immunohistochemical measures of cellular proteins and receptors from tumor samples with anti-tumor activity of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.

OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study followed by a phase II study.

• Phase I: Patients receive oral lapatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients receive escalating doses of lapatinib 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.

• Phase II: Patients receive lapatinib as in phase I at the MTD. Patients are followed at 1 month and then periodically for survival. Patients with stable or responding disease who go off therapy are followed every 3 months for up to one year and then periodically thereafter for survival.

PROJECTED ACCRUAL: A total of 3-24 patients will be accrued for the phase I portion of this study within 18 months. A total of 15-30 patients will be accrued for the phase II portion of this study within 18 months.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre - Calgary
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • British Columbia Cancer Agency - Centre for the Southern Interior
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • British Columbia Cancer Agency - Vancouver Cancer Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Margaret and Charles Juravinski Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L-4M1
      • Centre Hospitalier de l'Universite de Montreal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant glioblastoma multiforme
• Recurrent or progressive disease after prior primary treatment with radiotherapy with or without adjuvant chemotherapy
• Bidimensionally measurable disease on CT scan or MRI with at least one lesion ≥ 1 cm x 1 cm
• Paraffin embedded tumor sample available

• Concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) required for phase I of the study

  • Patients in phase II of the study may or may not be receiving EIAEDs

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• LVEF ≥ 50% by echocardiogram or MUGA
• No myocardial infarction within the past 6 months
• No congestive heart failure
• No unstable angina
• No active cardiomyopathy
• No cardiac arrhythmia
• No uncontrolled hypertension

Pulmonary

• No pulmonary disease requiring oxygen

Neurologic

• No preexisting peripheral neuropathy ≥ grade 3
• No history of significant neurologic disorder that would preclude study compliance or ability to give informed consent

Gastrointestinal

• No upper gastrointestinal or other conditions that would preclude compliance with oral medication
• No active peptic ulcer disease

Other

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumor
• No immune deficiency
• No history of significant psychiatric disorder (e.g., uncontrolled psychotic disorders) that would preclude study compliance or ability to give informed consent
• No other serious illness or medical condition that would preclude study participation
• No known hypersensitivity to compounds of similar chemical or biological composition to lapatinib
• No active uncontrolled or serious infection
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent prophylactic filgrastim (G-CSF), sargramostim (GM-CSF), or other hematopoietic growth factors

  • Concurrent hematopoietic growth factors allowed for treatment of acute toxicity (e.g., febrile neutropenia)

Chemotherapy

• See Disease Characteristics
• No prior chemotherapy for recurrent disease

• No more than one prior chemotherapy regimen in the adjuvant setting

  • At least 6 months since prior adjuvant chemotherapy

Endocrine therapy

• Concurrent steroids allowed provided the dose is stable for at least 14 days before study entry

Radiotherapy

• See Disease Characteristics
• At least 6 weeks since prior radiotherapy

Surgery

• At least 2 weeks since prior major surgery

Other

• H2 blockers and proton pump inhibitors allowed, unless they are CYP3A4 inducers or inhibitors

• At least 7 days since prior and no concurrent administration of any of the following CYP3A4 inhibitors:

  • Clarithromycin
  • Erythromycin
  • Troleandomycin
  • Telithromycin
  • Ciprofloxacin
  • Norfloxacin
  • Itraconazole
  • Ketoconazole
  • Voriconazole
  • Fluconazole (≤150 mg/day allowed)
  • Nefazodone
  • Fluovoxamine
  • Delavirdine
  • Nelfinavir
  • Amprenavir
  • Ritonavir
  • Indinavir
  • Saquinavir
  • Lopinavir
  • Verapamil
  • Diltiazem
  • Aprepitant
  • Grapefruit or grapefruit juice
  • Bitter orange

• At least 14 days since prior and no concurrent administration of any of the following CYP3A4 inducers:

  • Rifampin
  • Rifabutin
  • Rifapentine
  • Efavirenz
  • Nevirapine
  • Hypericum perforatum (St. John's wort)
  • Modafinil
• At least 6 months since prior and no concurrent administration of amiodarone
• Antacids (e.g., mylanta, maalox, tums, rennies) must be administered ≥ 1 hour before and ≥ 1 hour after study drug
• At least 2 days since prior and no concurrent cimetidine
• No other concurrent anti-cancer agents
• No other concurrent investigational therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Toxicity for phase I assessed by CTCAE v.3.0 MacDonald criteria	7 years
Response for phase II	7 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlative studies on archival tissue	7 years
Pharmacokinetics	7 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: NCIC Clinical Trials Group
• Investigators: Study Chair: Brian A. Thiessen, MD, British Columbia Cancer Agency

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: December 8, 2004
• First Submitted That Met QC Criteria: December 8, 2004
• First Posted (Estimate): December 9, 2004

Study Record Updates

• Last Update Posted (Estimate): January 27, 2014
• Last Update Submitted That Met QC Criteria: January 24, 2014
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Lapatinib
• Other Study ID Numbers: I170; CAN-NCIC-IND170; CDR0000389155 (Other Identifier: PDQ)