Crizotinib in High-Risk Uveal Melanoma Following Definitive Therapy

Uveal melanoma is the most common primary intraocular malignancy in adults, and arises from
melanocytes within the choroid plexus of the eye. Melanomas of the ocular and adnexal
structures comprise approximately 5% of all melanomas and are biologically and prognostically
distinct from cutaneous melanoma. In the United States, an estimated 2000 patients are
diagnosed with this disease each year.

The development of metastasis in this disease is common and occurs in approximately 50% of
patients with posterior uveal melanoma within 15 years after the initial diagnosis and
treatment. Uveal melanoma is thought to be particularly resistant to systemic treatment, and
no systemic therapy has yet been demonstrated to improve survival. Drugs commonly used to
treat advanced cutaneous melanoma rarely achieve durable responses in patients with uveal
melanoma.

Inclusion Criteria:

- Primary diagnosis of uveal melanoma at least 12 mm in largest basal diameter as
clinically determined by the treating investigator. Cytologic determination of
diagnosis is not required. Size is based on clinical assessment (e.g. by ultrasound or
direct ophthalmoscopy) prior to enucleation or radiation therapy.

- Definitive therapy of the primary uveal melanoma must have been performed within 90
days of initiating protocol therapy.

- High-risk (class 2) uveal melanoma as determined by gene expression profiling

- No evidence of metastatic disease.

- Age ≥18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (Karnofsky ≥ 70%.

- Life expectancy of greater than 3 months.

- Able to swallow and retain orally-administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count (ANC) >1,000 cells/mm³

- Platelet count >75,000/mm³

- Hemoglobin >9.0g/dL

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <3x upper
limited of normal (ULN)

- Total bilirubin <2x ULN

- Alkaline phosphatase <3x ULN

- Serum creatinine <2x ULN or a creatinine clearance > 60mL/min

- Note: Patients with hyperbilirubinemia clinically consistent with an inherited
disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the
discretion of the treating physician and/or the principal investigator.

- Women of child-bearing 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 until 4 months after completion of crizotinib
administration. Women of child-bearing potential must have a negative serum pregnancy
test within 14 days prior to study entry. Should a woman become pregnant or suspect
she is pregnant while she or her partner is 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 therapy, and 4 months after completion of crizotinib administration.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- History of another malignancy except for those who have been disease-free for 3 years,
or patients with a history of completely resected non-melanoma skin cancer and/or
patients with indolent secondary malignancies not requiring active therapy, are
eligible. Consult the study Principal Investigator if unsure whether second
malignancies meet the requirements specified above.

- Any major surgery or extensive radiotherapy (except that which is required for
definitive treatment of primary uveal melanoma), chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to initiation of study
therapy.

- History of prior crizotinib use.

- Use of other investigational drugs within 28 days (or five half-lives, whichever is
shorter; with a minimum of 14 days from the last dose) preceding the first dose of
study therapy and during the study.

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to crizotinib.

- Concurrent administration of crizotinib and a strong inhibitor or inducer of CYP3A is
not permitted. Many over-the-counter and dietary supplements also inhibit or induce
CYP3A and thus are prohibited.

- A QT interval corrected for heart rate using the Bazett's formula QTcB ≥ 480 msec.

- Concurrent administration of crizotinib and agents that can cause QTc prolongation is
not permitted.

- Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection,
which will be allowed). HIV-positive patients on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with
crizotinib. In addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy.

- Uncontrolled intercurrent illness including, but not limited to, 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.