Lapatinib in Treating Patients With Recurrent Glioblastoma Multiforme

National Cancer Institute (NCI)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Brain and Central Nervous System Tumors

Treatments

Drug: lapatinib ditosylate

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00099060

CAN-NCIC-IND170

CDR0000389155 (Other Identifier)

I170

Details and patient eligibility

About

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.

Full 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.

Enrollment

24 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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