Trial Information

Exploration and Estimation of Intratumoral Concentration and Activity of Lapatinib in Vivo 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.