lapatinib in treating patients with recurrent glioblastoma multiforme

Conditions: Brain and Central Nervous System Tumors

Summary: 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.

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.

Eligibility criteria:
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

Keywords: adult giant cell glioblastoma adult gliosarcoma recurrent adult brain tumor