Intermittent Selumetinib for Uveal Melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and arises
from melanocytes within the choroid plexus of the eye. The development of metastasis is
common and occurs in approximately 50% of patients with posterior UM within 15 years of
initial diagnosis and treatment. As no effective systemic therapy has yet been identified for
this disease, outcomes for metastatic UM are poor with a median survival of 12 months.

There is no FDA approved therapy for patients with advanced UM. Studies have shown that
inhibition of the Mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor
selumetinib (hyd-sulfate AZD6244) is an effective therapy for uveal melanoma but despite this
treatment, cures are not achieved. Although drugs such as selumetinib have been studied when
patients take the treatment every day, research has shown that in some cases, it may be
better to use the treatment on an intermittent schedule. Such a strategy may reduce the side
effects, allow higher doses of the drug to be used, more completely block the MAPK pathway,
and prevent the development of drug resistance mechanisms within the tumor.

Inclusion Criteria:

- Histopathologically confirmed diagnosis of metastatic or unresectable uveal melanoma.
Note - Documentation of mutation status for uveal melanoma will not be required
prospectively given the high rate of GNAQ/11 mutations (>90%) in this population

- Able to provide informed consent prior to initiation of study

- Age ≥ 18 years old

- Measurable indicator lesion by RECIST v1.1

- 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 for
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.

- Karnofsky Performance Status ≥ 60% or Eastern Cooperative Oncology Group (ECOG) ≤2

- Ability to take oral medications

- All clinically significant toxicities from prior therapy must be ≤ grade 1 (with the
exception of alopecia)

- Organ and marrow function and laboratory values as follows:

- Adequate marrow function

- absolute neutrophil count (ANC) >1500 cells/mm3

- platelet count >100,000/mm3

- hemoglobin >9.0g/dL

- Adequate hepatic function

- Angiotensin Sensitivity Test/alternative (AST/ALT)<2.5x upper limit of normal if
no documented liver disease or <5x upper limit of normal if documented liver
disease

- Total bilirubin <1.5X upper limit of normal unless known diagnosis of Gilbert's
disease

- Alkaline phosphatase <2.5x upper limit of normal if no documented liver disease
or <6x upper limit of normal if documented liver or bone disease

- Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal.

- Negative pregnancy test (serum or urine) for women of child bearing potential

- The effects of selumetinib on the developing human fetus are unknown. For this reason,
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 and 4 weeks after study discontinuation. 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 participation, and 3 months after
completion of selumetinib administration.

Exclusion Criteria:

- Patients who have had chemotherapy or immunotherapy within 4 weeks or radiation
therapy within 2 weeks prior to entering the study or those who have not recovered
from adverse events due to agents administered more than 4 weeks earlier.

- Patients who are receiving any other investigational agents concurrently. Palliative
radiation therapy will be allowed as long as the patient meets all other eligibility
criteria.

- Have had recent major surgery within a minimum 4 weeks prior to starting study
treatment, with the exception of surgical placement for vascular access.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to selumetinib

- Every effort must be made to avoid the use of a concomitant medication that can
prolong the corrected QT (QTc) interval while receiving selumetinib (hyd-sulfate
AZD6244). If the patient cannot discontinue medications that prolong QTc interval
while receiving selumetinib, close cardiac monitoring should be performed.

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

- Prior or current cardiomyopathy including but not limited to the following: known
hypertrophic cardiomyopathy, known arrhythmogenic right ventricular cardiomyopathy,
previous moderate or severe impairment of left ventricular systolic function (LVEF
<45% on echocardiography or equivalent on MuGA) even if full recovery has occurred.

- Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest

- Baseline Left ventricular ejection fraction (LVEF) below the LLN or <55% measured by
echocardiography or institution's lower limit of normal (LLN) for MUGA

- Severe valvular heart disease

- Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical
therapy

- Acute coronary syndrome within 6 months prior to starting treatment

- 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.

- Pregnant women are excluded from this study because selumetinib may be teratogenic or
have abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with selumetinib,
breastfeeding should be discontinued if the mother is treated with selumetinib.

- HIV positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with selumetinib.

- Prior treatment with a MEK, Ras or Raf inhibitor

- History of current evidence/risk of retinal vein occlusion (RVO) or retinal pigment
epithelial detachment (RPED) in the eye unaffected by uveal melanoma; intraocular
pressure (IOP) >21mmgHG or uncontrolled glaucoma

- History of interstitial lung disease or pneumonitis

- Patients with known Hepatitis B or C

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

- Patients taking vitamin E supplements while on study

- Have known or suspected brain metastases or spinal cord compression, unless the
condition has been asymptomatic, has been treated with surgery and / or radiation, and
has been stable for at least 4 weeks prior to the first dose of study medication

- Any unresolved toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy, except for
alopecia

- Have evidence of any other significant clinical disorder or laboratory finding that,
as judged by the investigator, makes it undesirable for the patient to participate in
the study.

- Patients being actively treated for a secondary malignancy