Safety Study of Afatinib for Brain Cancer

This is an open-label, single institution, Phase I 3+3 dose escalation study to describe the
safety and tolerability of afatinib in patients with brain cancer having failed prior therapy
and to determine the recommended phase II dose.

Eligible patients will receive afatinib in treatment cycles of 28 days that will consist of
afatinib administered orally by mouth once every four days. Patients will be assigned to the
dose level open at the time of their enrollment. Patients will continue dosing of afatinib
until disease progression, unacceptable toxicity, withdrawal of consent, or treating
physician determines it is in their best interest to stop. Guidelines for modifying study
drug doses is provided for the management of adverse treatment effects.

All patients will have regular evaluations for assessment of safety parameters as detailed in
the study flow chart. Lumbar puncture and blood draw for assessing afatinib levels will occur
as detailed in the study flow chart.

Neurological imaging and assessment for response will be performed approximately every eight
weeks. Tumor response will be assessed according to Response Assessment in Neuro-Oncology
(RANO) Working Group criteria.

An end of treatment evaluation will occur when a patient permanently discontinues study drug,
as detailed in the study flow chart. Patients will then be followed every four months for
survival.

Inclusion Criteria:

- Diagnosis

1. Dose Escalation Cohorts: Histologically confirmed diagnosis of brain cancer:

1. glioblastoma (GBM),

2. anaplastic astrocytoma (AA),

3. anaplastic oligodendroglioma (AO),

4. anaplastic mixed oligoastrocytoma (AMO),

5. low grade gliomas,

6. brain metastases,

7. meningiomas,

8. leptomeningeal metastases

9. chordomas

10. pituitary tumors

11. medulloblastomas

2. Expansion Cohort: Histologically confirmed diagnosis of high-grade glioma with
altered EGFR (e.g., amplification, mutation), including:

1. glioblastoma (GBM),

2. anaplastic astrocytoma (AA),

3. anaplastic oligodendroglioma (AO),

4. anaplastic mixed oligoastrocytoma (AMO)

- Has failed prior standard therapy including maximal safe surgical resection (when
appropriate for the specific cancer type), radiation therapy (when appropriate for the
specific cancer type), and systemic therapy (when appropriate for the specific cancer
type).

- For diagnosis of GBM: has undergone maximal safe surgical resection, a course of
postoperative radiation therapy with concurrent temozolomide, and maintenance
temozolomide.

- For diagnosis of meningioma: has no other option of standard therapy such as surgical
resection (partial or total resection) or radiation.

- Age 18 years and older.

- Karnofsky Performance Status ≥ 60%.

- Adequate organ function, defined as all of the following:

1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.

2. Platelet count ≥ 100 x 109/L.

3. Hemoglobin ≥ 9.0 g/dL.

4. Total Bilirubin ≤ 1.5 institution's upper limit of normal (ULN).

5. Aspartate amino transferase (AST) ≤ 2.5 x institution's ULN.

6. Alanine amino transferase (ALT) ≤ 2.5 x institution's ULN.

7. Alkaline phosphatase (ALP) ≤ 2.5 x ULN unless considered tumor related.

- Recovered from any previous therapy-related toxicity to Grade 1 or to their clinical
baseline at study entry.

- Women of child-bearing potential has negative serum or urine pregnancy test before the
initiation of study drug dosing.

Exclusion Criteria:

- Insufficient time from prior therapy to study entry:

1. less than 28 days from whole-brain radiotherapy (WBRT) or stereotactic
radiosurgery (SRS);

2. less than 28 days from any investigational agent;

3. less than 28 days from prior cytotoxic therapy (except 23 days from prior
temozolomide, 14 days from vincristine (for GBM: 14 days from irinotecan or
topotecan), 42 days from nitrosoureas, 21 days from procarbazine, irinotecan or
topotecan administration);

4. less than 14 days from hormonal treatment

5. less than 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen,
thalidomide, cis-retinoic acid, etc.

6. When radiation necrosis is suspected, standard of care confirmatory imaging, such
as MRI perfusion, magnetic resonance (MR) spectroscopy and or PET will be
performed, and patients with findings consistent with radiation necrosis will be
excluded.

- Current or anticipated use of enzyme-inducing anti-epileptic drugs (EIAED).

- Major surgery within 4 weeks before starting study treatment or scheduled for surgery
during the projected course of the study.

- Known hypersensitivity to afatinib or its excipients.

- History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA)
classification of 3 or 4, unstable angina or poorly controlled arrhythmia, or
myocardial infarction within 6 months prior to enrollment.

- Pregnant, nursing, or not using acceptable method of birth control.

- Any history of or concomitant condition that would compromise the patient's ability to
comply with the study or interfere with the evaluation of the efficacy and safety of
the test drug.

- Previous or concomitant malignancies at other sites, except effectively treated
non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ
or effectively treated malignancy that has been in remission for more than 3 years and
is considered to be cured.

- Known pre-existing interstitial lung disease.

- Known active hepatitis B infection (defined as presence of Hep B sAg and/ or Hep B
DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV
carrier.

- Prior participation in a blinded afatinib clinical study, even if not assigned to
afatinib treatment.