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.

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.

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