Lapatinib Study for Children and Adults With Neurofibromatosis Type 2 (NF2) and NF2-Related Tumors

In this trial, we propose to assess the objective response rates to Lapatinib in patients
with NF2-related tumors. Lapatinib is a commercially available inhibitor of ErbB2 and EGF.
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.

Demonstrating that Lapatinib produces an objective response to reduce tumor volume or
stabilize disease will provide additional treatment options for NF patients with multiple
tumor growth. For patients with VS we expect to see ≥ 10 dB improvement in PTA and/or
improvement in SDS, compared to the audiogram at initiation of treatment. Currently there
are no available treatment options for NF2 patients with multiple tumors. Depending on tumor
cell type, lapatinib has cytostatic or cytotoxic antitumor effects, and in a recent study
assessing the biological effects of Lapatinib on the associated molecular pathways and tumor
growth in patients with solid tumors, a correlation was seen between tumor response and
pre-treatment levels of (phosphor)-ErbB2 and (phosphor)-ERK1/2.

Inclusion Criteria:

1. Patients must be at least 4 years of age.

2. Patients must meet diagnostic criteria for NF2 and at least one volumetrically
measured NF2-related brain or spinal tumor with radiographic evidence of progression
over the past 12 months, designated as the primary target OR volumetrically
measurable VS with ipsilateral progressive hearing loss over the past 12 months,
designated as the primary target tumor.

3. Significant hearing loss criteria for enrollment.

4. Karnofsky (PS) OR Lansky 50-100% (>16 years of age)

5. Absolute neutrophil count ≥ 1,000/mm3 g/dL

6. Hemoglobin ≥ 8 g/dL

7. Creatinine ≤ 1.5 times upper limit of normal (ULN) OR corrected glomerular filtration
rate ≥ 70 ml/min

8. Bilirubin ≤ 1.5 times ULN

9. ALT ≤ 2.5 times ULN

10. Fully recovered from acute toxic effects of any prior chemotherapy, biological
modifiers or radiotherapy.

11. Steroids are allowed for progressive symptoms but patient must be on a stable dose
for at least 1 week prior to study entry.

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

13. Patients 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. The anti-proliferative activity of
this experimental drug may be harmful to the developing fetus.

14. Normal cardiac left ventricular ejection fraction (LVEF) by transthoracic
echocardiogram.

15. Able to provide written informed consent (or consent by parent/legal guardian for
minors)

Exclusion Criteria:

1. Patients with serious concurrent infection or medical illness.

2. Neurological deficits that are rapidly progressing.

3. Patients who are pregnant or breast-feeding.

4. Anti-tumor therapy within 4 weeks prior to enrollment.

5. Radiation therapy within 2 months prior to enrollment.

6. Prior therapy with agents targeting EGFR or ErbB2.

7. Any surgery within 4 weeks prior to enrollment.

8. Significant gastrointestinal disorder(s)

9. Known cardiac disease

10. Patients with a concurrent or prior malignancy are ineligible unless they are
patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the
skin. Patients who have been free of disease (any prior malignancy) for more than
five years are eligible for this study.

11. Patients cannot have 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)