Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified Recurrent High-Grade Glioma

Protocol # :
Anaplastic Astrocytoma
Anaplastic Ependymoma
Anaplastic Oligodendroglioma
Mixed Glioma
Recurrent Adult Brain Neoplasm
Recurrent Glioblastoma
Feasibility / Pilot
Disease Sites
Brain and Nervous System
Principal Investigator
Lee, Eudocia, Quant

Trial Description

This pilot phase I clinical trial studies how well lapatinib ditosylate before surgery works
in treating patients with high-grade glioma that has come back after a period of time during
which the tumor could not be detected. Lapatinib ditosylate may stop the growth of tumor
cells by blocking some of the enzymes needed for cell growth.

Eligibility Requirements

Inclusion Criteria:

- Patients must have histologically proven World Health Organization (WHO) grade IV
glioblastoma/ gliosarcoma or WHO grade III glioma (anaplastic astrocytoma, anaplastic
oligodendroglioma, mixed anaplastic oligoastrocytoma, anaplastic ependymoma) which is
progressive or recurrent following radiation therapy +/- chemotherapy

- Patients must have measurable, supratentorial contrast-enhancing progressive or
recurrent high-grade glioma by magnetic resonance imaging (MRI) imaging within 21 days
of starting treatment; patient must be able to tolerate MRIs

- Patients may have an unlimited number of prior therapy regimens

- Patients must have recovered from severe toxicity of prior therapy; the following
intervals from previous treatments are required to be eligible:

- 12 weeks from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not Food and Drug Administration
[FDA]-approved) agents

- 4 weeks from the last treatment with bevacizumab

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent other than
bevacizumab (e.g., hydroxychloroquine, etc.)

- Patients must be undergoing surgery that is clinically indicated as determined by
their care providers; patients must be eligible for surgical resection according to
the following criteria:

- Expectation that the surgeon is able to resect at least 500 mg of tumor from
enhancing tumor and 100 mg from non-enhancing tumor with low risk of inducing
neurological injury

- Patient tumor sample must have evidence of EGFR gene amplification by fluorescence in
situ hybridization (FISH) using a Clinical Laboratory Improvement Act (CLIA)-certified
laboratory assay

- Paraffin embedded tissue must be available from initial surgical resection at
diagnosis (prior to any treatment)

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal

- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60
ml/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5
x institutional upper limit of normal

- Patients must have left ventricular ejection fraction (LVEF) within normal
institutional limits within 21 days of starting treatment

- Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatment
start with corrected (QTC) =< 470 msec

- Patients must be able to provide written informed consent

- Women of childbearing potential must have a negative serum pregnancy test prior to
study entry; women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and for 4 months after completion of lapatinib administration

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must be able to swallow medication by mouth, either tablets or dispersed
tablets in solution

Exclusion Criteria:

- Patients may not be receiving any other investigational agents

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to lapatinib are ineligible

- Patients with prior therapy with EGFR inhibitors are ineligible because treatment with
EGFR kinase inhibitors or other EGFR-targeted agents has the potential to deplete the
tumor of EGFR-amplified or EGFR mutant cell populations and confound the evaluation of
lapatinib effects on EGFR phosphorylation; patients with prior EGFRvIII vaccine are
eligible if recurrent tumor is positive for EGFR gene amplification

- Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic
drugs or not be taking any anti-epileptic drugs; patients previously treated with
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the
first dose of lapatinib

- Patients must not have evidence of significant hematologic, renal, or hepatic

- Patients must not have evidence of significant intracranial hemorrhage

- Patients with uncontrolled intercurrent illness including, but not limited to,
hypertension, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements, are ineligible

- Pregnant women are excluded from this study because lapatinib has potential for
teratogenic or abortifacients effects; because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
lapatinib, breastfeeding should be discontinued if the mother is treated with

- Human immunodeficiency virus (HIV)-positive patients on strong cytochrome P450, family
3, subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors are ineligible

- Patients who have acute or currently active/requiring anti-viral therapy hepatic or
biliary disease are ineligible (with the exception of patients with Gilbert's
syndrome, asymptomatic gallstones, liver metastases from the primary brain tumor, or
stable chronic liver disease per investigator assessment)

- Patients receiving P-glycoprotein (P-gp) inhibitors are ineligible

- Patients who are receiving a drug that has a risk of QTc prolongation if QTc is >= 460
msec. are ineligible