Trametinib With or Without GSK2141795 in Treating Patients With Metastatic Uveal Melanoma

PRIMARY OBJECTIVES:

I. To compare progression-free survival between those treated with trametinib alone and those
treated with the combination of trametinib and GSK2141795.

SECONDARY OBJECTIVES:

I. To compare overall survival between those treated with trametinib alone and those treated
with the combination of trametinib and GSK2141795.

II. To compare the overall response rate between those treated with trametinib alone and
those treated with the combination of trametinib and GSK2141795.

III. To compare the safety and toxicity between those treated with trametinib alone and those
treated with the combination of trametinib and GSK2141795.

TERTIARY OBJECTIVES:

I. To assess clinical outcomes (response rate, progression-free and overall survival) with
trametinib and GSK2141795 after progression on trametinib.

II. To assess toxicity with trametinib and GSK2141795 after progression on trametinib.

III. To correlate clinical outcome with Gnaq/11 mutational status. IV. To assess the
pharmacodynamic effects of trametinib alone and with GSK2141795, and utilize
whole-transcriptome and reverse phase protein array to identify markers of sensitivity and
primary resistance to trametinib alone and with GSK2141795.

V. To assess for changes in circulating tumor deoxyribonucleic acid (DNA) with therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat
every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who
experience objective disease progression may crossover to Arm B. (no patients will be
enrolled to Arm B or Crossover therapy as of 11/6/2015)

ARM B: Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28.
Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 12
weeks thereafter.

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 metastatic disease will be performed at Memorial Sloan Kettering (MSK)
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

- Patients may not have received prior systemic or hepatic directed
infusional/embolization therapies for advanced uveal melanoma; local therapies such as
radiofrequency ablation or cryotherapy for metastatic disease are permitted but must
have been performed at least 21 days prior to initiation of study therapy; lesions
treated with local modalities such as radiofrequency ablation or cryotherapy may not
be used as target lesions unless they demonstrate growth over a minimum of 3 months on
subsequent imaging studies

- 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

- All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization
and crossover

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

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

- Total bilirubin =< 1.5 x institutional 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])
=< 1.5 x institutional upper limit of normal for patients with no concurrent liver
metastases, OR =< 2.5 x institutional upper limit of normal for patients with
concurrent liver metastases

- Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula)
>= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

- Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by
echocardiogram (ECHO) or multigated acquisition scan (MUGA)

- 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 blood pregnancy test within 14 days prior to start of protocol treatment;
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 4 months after
completion of trametinib administration

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

- 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

- ELIGIBILITY CRITERIA FOR CROSSOVER REGISTRATION

- Previously treated with trametinib on Arm A and experienced objective disease
progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- Not removed from trametinib treatment due to the development of unacceptable toxicity
that is not manageable with dose reduction

- No other drug treatment for malignant melanoma administered after completing study
treatment with trametinib

- Meet all eligibility criteria with the exception of:

- Prior therapy with trametinib will be permitted

- All laboratory parameters must be met as outlined except for ALT and total
bilirubin, which must meet criteria for continued therapy

- Patients who are eligible for cross-over will not need to undergo another
ophthalmologic examination

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 MSK Principal Investigator or the Cancer Therapy
Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet
the requirements specified above

- History of interstitial lung disease or pneumonitis

- Any major surgery or extensive radiotherapy within 21 days prior to randomization and
crossover

- 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
trametinib alone or with GSK2141795 and during the study

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression; treated brain metastases must have been stable for at least 1 month

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to trametinib, GSK2141795, or excipients or to dimethyl sulfoxide
(DMSO)

- Current use of a prohibited medication

- History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment
epithelial detachment (RPED) in the eye unaffected by uveal melanoma

- Patients with abnormal fasting glucose values (values > upper limit of normal [ULN] or
< LLN) at screening will be excluded; in addition, patients with type 1 diabetes will
also be excluded; however, patients with type 2 diabetes will be allowed if diagnosed
>= 6 months prior to enrollment, and if presenting with a normal fasting glucose value
and a regular hemoglobin A1C (HbA1C) =< 8% at screening

- History or evidence of cardiovascular risk including any of the following:

- Left ventricular ejection fraction (LVEF) < LLN

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

- History or evidence of current clinically significant uncontrolled arrhythmias
(exception: patients with controlled atrial fibrillation for > 30 days prior to
randomization are eligible)

- History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within 6 months prior to randomization

- History or evidence of current >= class II congestive heart failure as defined by
the New York Heart Association (NYHA) functional classification system

- Treatment-refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
therapy

- Patients with intra-cardiac defibrillators

- Known cardiac metastases

- Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (patients with
chronic or cleared HBV and HCV infection are eligible); patients with human
immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications

- 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

- The study drug must not be administered to pregnant women or nursing mothers; women of
childbearing potential should be advised to avoid pregnancy and use effective methods
of contraception; men with a female partner of childbearing potential must have either
had a prior vasectomy or agree to use effective contraception; if a female patient or
a female partner of a patient becomes pregnant while the patient receives trametinib,
the potential hazard to the fetus should be explained to the patient and partner (as
applicable)