Lapatinib Ditosylate Before Surgery in Treating Patients With Recurrent High-Grade Glioma

PRIMARY OBJECTIVES:

I. To achieve an intratumoral lapatinib (lapatinib ditosylate) concentration of at least 1.5
uM in at least 70% of patients 3 hours after the last dose of pulsatile lapatinib. (Group A)
II. To determine the pharmacodynamic (PD) effect of pulsatile lapatinib (at pulsatile maximum
tolerated dose [MTD]) on epidermal growth factor receptor (EGFR) phosphorylation (using
Mesoscale Discovery enzyme-linked immunosorbent assay [ELISA] assay for total and
phospho-EGFR). (Group A and Reference Group)

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of pulsatile lapatinib in pre-operative patients with EGFR
amplified recurrent high-grade glioma. (Group A and Reference Group) II. To evaluate acute
and late toxicities associated with pulsatile lapatinib. (Group A and Reference Group) III.
To determine the effect of lapatinib on tumor cell proliferation (marker of proliferation
Ki-67 [KI-67] staining). (Group A compared to Reference Group) IV. To determine the ex-vivo
sensitivity of tumor sphere cultures to lapatinib. (Group A and Reference Group) V. To assess
tumor objective response rate (ORR). (Group A and Reference Group) VI. To estimate overall
survival (OS). (Group A and Reference Group) VII. To estimate progression-free survival.
(Group A and Reference Group)

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

GROUP A: Patients receive lapatinib ditosylate orally (PO) twice daily (BID) on days -2 to 0.
Within 3-5 hours after last dose of lapatinib ditosylate, patients undergo surgical resection
of tumor on day 0. Within 30 days of surgical resection of tumor, patients receive lapatinib
ditosylate BID for 2 days every 7 days. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

REFERENCE GROUP: Patients undergo surgical resection of tumor on day 0. Within 30 days of
surgical resection of tumor, patients receive lapatinib ditosylate BID for 2 days every 7
days. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for at 30 days, every 2 months
for 2 years, and every 6 months thereafter.

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; the lapatinib
Investigator Brochure can be referenced for more information

- Patients with prior therapy with EGFR inhibitors are ineligible; 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
dysfunction

- 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; breastfeeding should be discontinued if
the mother is treated with lapatinib

- 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