Concentration and Activity of Lapatinib in Vestibular Schwannomas

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder with an
incidence of approximately 1/40,000. The most common tumor type in NF2 is vestibular
schwannoma and the majority of NF2 patients develop progressive hearing loss in adolescence
or young adulthood due to bilateral vestibular schwannoma (VS). In addition to hearing loss,
VS can cause significant morbidity, and in some cases mortality, due to brain stem
compression.

Currently, the only accepted modality for treatment of VS in patients with NF2 is surgical
resection. Although surgical resection is effective at tumor reduction, it is often
associated with morbid complications such as hearing loss, facial palsy, CSF leaks, chronic
headache and infection. In addition, the tumors often recur after surgery. Radiation therapy
(RT) has been proposed as an alternative, however, its safety in the NF2 population has not
been established and there is concern about long term efficacy. For a distinct population of
NF2 patients, surgery and RT at not feasible and no additional therapy is currently
available. Hence, a systemic therapy is needed.

Sporadic VS are common with roughly 3,000 new cases per year in the United States and a
growing incidence in recent years. These tumors cause unilateral hearing loss, tinnitus, and
vertigo. The primary treatment modality for these tumors is surgical resection or
radiosurgery. Surgery is associated with the same complications listed above for NF2-related
VS. Hence, RT is often offered in place of surgery. Although considered safe in sporadic VS,
it may not have good long term efficacy and may complicate future procedures. Again, a
systemic therapy that could control tumor progression obviating the need for an invasive
procedure is needed.

As the understanding of tumor molecular biology continues to advance, there are an increasing
number of attractive targets for VS growth inhibition. EGFR and ErbB2 have been identified as
important targets for VS. In a study of 21 sporadic and 17 NF2-related VS samples, both EGFR
and ErbB2 were found to be upregulated in the majority of tumors. In addition, an anti-ErbB2
monoclonal antibody reduced schwannoma cell proliferation in vitro. Collectively, this data
suggests that abnormal signaling via EGFR and ErbB2 is a major contributor to tumor growth
and progression in both sporadic and NF2-related VS, and that inhibition of this signaling
pathway can result in decreased tumor growth. Although agents targeting these pathways are
commercially available, there is little pre-clinical data to assist in prioritizing which
agents to advance to clinical trials. Given the relative rarity of the disorder and the
enormous patient, financial and time commitments an efficacy study requires, there is a need
to carefully select agents for testing that have the best chance of success.

In this trial, we propose to assess the delivery of lapatinib, a commercially available
inhibitor of ErbB2 and EGFR, to VS via tissue sampling at the time of clinically indicated
surgery. Demonstrating that lapatinib reaches meaningful intratumoral concentrations is
important data to recommend this drug above other small molecule inhibitors for efficacy
trials for VS. The primary objective is to determine the steady state concentration of
lapatinib in VS in patients with NF2 and in patients with sporadic VS. Patient who are
planning to have surgical resection of their tumor for clinical indications will be given
lapatinib for 15 days prior to resection. At the time of resection, VS tissue will be
assessed for drug concentration and molecular markers of drug activity.

Demonstrating that lapatinib reaches meaningful concentrations within VS would support
selecting this agent for investigation in efficacy studies for VS, and tissue-based molecular
studies will provide corollary information about the behavior of VS in general and about
lapatinib specifically in VS tissue. This may further our understanding of the
pathophysiology of VS, the similarities and differences between NF2-related and sporadic VS,
and inform the design of subsequent efficacy trials.

Inclusion Criteria:

- Meet diagnostic criteria for NF2 including presence of bilateral VS or idiopathic VS
without evidence of genetic syndrome.

- VS surgery determined clinically necessary by the treating physician and scheduled
within 4 weeks.

- Normal cardiac left ventricular ejection fraction (LVEF) by multiple-gated acquisition
(MUGA) scan or transthoracic echocardiogram.

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

- Must have the following hematologic, renal and liver function: Absolute neutrophil
count ≥ 1,000/mm³ (unsupported); platelet count ≥ 75,000/mm³ (unsupported); hemoglobin
≥ 8 g/dL (transfusion support allowed); Creatinine ≤ 1.5 times upper limit of normal
(ULN) OR glomerular filtration rate ≥ 70 ml/min; Bilirubin ≤ 1.5 times ULN; ALT ≤ 2.5
times ULN.

- Be able to provide written informed consent.

- Any neurologic deficits must be stable for ≥ 1 week.

- Be able to swallow tablets.

- Subjects with the potential for pregnancy or impregnating their partner must agree to
follow acceptable birth control methods to avoid conception. Women of childbearing
potential must have a negative pregnancy test.

- Suspend the use of P450 inducing or P450 suppressing agents for a minimum of 10 days
prior to starting lapatinib.

Exclusion Criteria:

- Serious concurrent infection or medical illness, which would jeopardize the ability of
the patient to receive the treatment outlined in this protocol with reasonable safety.

- Pregnant or breast-feeding.

- Receiving concurrent therapy for their tumor (i.e. chemotherapeutics or
investigational agents, radiation or immunotherapy) within 4 weeks of the first dose
of the study drug.

- Concurrent or prior malignancy, other than curatively treated carcinoma-in-situ or
basal cell carcinoma of the skin. Subjects who have been free of disease (any prior
malignancy) for five years are eligible for this study.

- Received cytochrome P450-inducing anticonvulsants (EIADs; e.g., phenytoin,
carbamazepine, phenobarbital, primidone, oxcarbazepine) or similar agents (e.g.,
rifampin) or P450 inhibiting agents (Ketoconazole, Itraconazole, Clarithromycin,
Atazanavir, Indinavir, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin,
Voriconazole) within 10 days prior to starting lapatinib.

- Significant gastrointestinal disorder(s)(e.g., Crohn's disease, ulcerative colitis,
extensive gastric resection).

- Neurologic deficits that are rapidly progressing.

- Known cardiac disease (either arrhythmia or congestive heart failure) requiring
treatment.