Temozolomide or Selumetinib in Treating Patients With Metastatic Melanoma of the Eye

PRIMARY OBJECTIVES:

I. To assess the progression-free survival (PFS) in three separate patient populations with
uveal melanoma: Patients on COHORT 1 (guanine nucleotide binding protein [G protein], q
polypeptide [Gnaq]/G protein, alpha 11 [Gna11] mutant uveal melanoma; temozolomide
[TMZ]/dacarbazine [DTIC] naive) treated with AZD6244 (selumetinib) or TMZ (or DTIC);
patients on both COHORT 1 and COHORT 2 (Gnaq/Gna11 mutant and Gnaq/Gna11 wild-type uveal
melanoma; TMZ/DTIC naive) treated with AZD6244 or TMZ (or DTIC); and patients on COHORT 3
(Gnaq/Gna11 mutant or wild-type uveal melanoma; previously treated with TMZ/DTIC) treated
with AZD6244.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Overall response rate (RR). III. To determine the tolerability
of AZD6244 in patients with advanced uveal melanoma.

IV. To correlate PFS, OS, and overall RR with Gnaq and Gna11 mutational status.

TERTIARY OBJECTIVES:

I. To correlate clinical outcome with baseline phosphorylated (p)-extracellular
signal-regulated kinases (ERK), p-v-akt murine thymoma viral oncogene homolog 1 (AKT), and
phosphatase and tensin homolog (PTEN) expression by immunohistochemistry.

II. To correlate clinical outcome with changes in p-ERK, p-AKT, and PTEN expression by
immunohistochemistry.

III. To correlate clinical outcome with changes in Ki67 and cleaved caspase 3. IV. To
explore the overall quality of life (QoL) of the treatment groups as measured by the
Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.

V. To explore the radiographic effects of treatment with AZD6244 as assessed by 18F
fluorothymidine (FLT)-positron emission tomography (PET) imaging.

OUTLINE: Patients in groups 1 and 2 are randomized to 1 of 2 treatment arms. Patients in
group 3 are assigned to arm II.

ARM I: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Patients who
are unable to be treated with temozolomide may be treated with dacarbazine intravenously
(IV) every 3 weeks (with approval from the Principal Investigator). Patients who experience
disease progression may crossover to arm II.

ARM II: Patients receive selumetinib PO twice daily (BID) on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Patients must have metastatic histologically or cytologically confirmed uveal
melanoma; if histologic or cytologic confirmation of the primary is not available,
confirmation of the primary diagnosis of uveal melanoma by the treating investigator
can be clinically obtained, as per standard practice for uveal melanoma; pathologic
confirmation of diagnosis will be performed at Memorial Sloan-Kettering Cancer Center
(MSKCC) or at a participating site

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography
(CT) scan

- Life expectancy of greater than 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9.0 g/dL (not requiring transfusions within the past 2 weeks)

- Total bilirubin =< 1.5 times upper limit of normal; 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

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 times upper limit of normal for patients with no concurrent liver metastases

- AST(SGOT)/ALT(SGPT) =< 5 X institutional ULN for patients with concurrent liver
metastases

- Creatinine =< 1.5 mg/dL

- Tumor Gnaq and Gna11 status must be determined on all patients using a Clinical
Laboratory Improvement Act (CLIA) approved assay; if initial CLIA testing is
performed locally, patients must consent to provide a tumor block or unstained slides
to MSKCC for central review of Gnaq and Gna11 status; this central review may be
performed retrospectively and will not delay patient treatment on study

- Patients must agree to provide all imaging studies for central radiology review; this
central radiology review may be performed retrospectively and will not be utilized
for decision making for patients on study

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

- Eligibility for enrollment in each cohort is dependent upon tumor Gnaq/Gna11 status
and prior therapy as follows:

- Cohort 1: no prior TMZ or DTIC; mutant Gnaq/Gna11 status

- Cohort 2: no prior TMZ or DTIC; wild-type Gnaq/Gna11 status

- Cohort 3: received prior TMZ or DTIC; mutant or wild-type Gnaq/Gna11 status

- Every effort must be made to avoid administration of drugs that are inhibitors or
inducers of cytochrome P450 1A2 (CYP1A2) and CYP3A4

Exclusion Criteria:

- Patients may have had any number of prior therapies, but cannot have previously been
treated with a mitogen-activated protein kinase kinase (MEK) inhibitor; at least 3
weeks must have elapsed since the last dose of systemic therapy; at least 6 weeks
must have elapsed if the last regimen included carmustine (BCNU), mitomycin C or an
anti-CTLA4 antibody; patients must have experienced disease progression on their
prior therapy in the opinion of the treating investigator

- Patients may not be receiving any other investigational agents

- Patients with active or untreated brain metastases; treated brain metastases must
have been stable for at least 2 months

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TMZ or DTIC or AZD6244

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or bleeding, symptomatic congestive heart failure, unstable angina
pectoris, unstable cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women are excluded from this study; breast-feeding should be discontinued if
the mother is treated with AZD6244

- 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; women of child-bearing potential must have a
negative pregnancy test prior to entry; should a woman become pregnant or suspect she
is pregnant while participating in this study, she should inform her treating
physician immediately; please note that the AZD6244 manufacturer recommends that
adequate contraception for male patients should be used for 16 weeks post-last dose
due to sperm life cycle

- Known human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible; patients with compensated HIV, with adequate
cluster of differentiation (CD)4+ T-cell counts, and not requiring antiretroviral
medication will be allowed

- Patients taking vitamin E supplements while on study

- No concomitant anti-cancer chemotherapy or other systemic drugs; palliative radiation
therapy will be allowed as long as the patient meets all other eligibility criteria

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption

- Patients with corrected QT (QTc) interval > 450 msecs or other factors that increase
the risk of QTc prolongation or arrhythmic events (e.g., heart failure, hypokalemia,
family history of long QT interval syndrome) including heart failure that meets New
York Heart Association (NYHA) class III and IV definitions are excluded

- Every effort must be made to avoid the use of a concomitant medication that can
prolong the QTc interval while receiving AZD6244; if the patient cannot discontinue
medications that prolong the QTc interval while receiving AZD6244, close cardiac
monitoring should be performed