Lapatinib in Treating Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: lapatinib ditosylate


Participation Criteria
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Eligibility Criteria
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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

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

| Intervention/Treatment |
| --- |
|Drug: lapatinib ditosylate|For patients receiving enzyme inducing anti-epileptic drugs (EIAEDs): Phase I: starting dose for first cohort: 1000 mg GW572016 po b.i.d.; actual dose assigned at registration; intra patient dose escalation permitted ONCE in phase I patients ONLY if specified criteria met (see section 8.6). Phase II: Recommended phase II dose from phase I portion of the study, given po b.i.d. For patients NOT receiving enzyme inducing anti-epileptic drugs (NON-EIAEDs): • Phase II: 750 mg GW572016 po b.i.d. For all patients: • Dose reductions as required based on adverse events.|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor