Randomized Phase II Trial of MAP Kinase Inhibition With AZD6244 Hydrogen Sulfate in Combination With MK-2206 (Akt Inhibitor) in Patients With BRAF V600E Mutant Advanced Melanoma Who Have Previously Failed Prior Therapy With a Selective BRAF Inhibitor (PLX4032/RG7204 or GSK2118436)

Inclusion Criteria:

- Patients must have incurable unresectable stage III or IV histologically confirmed
Melanoma with V600E/K/D/R mutant BRAF disease and must have progressed after therapy
on selective BRAF inhibitor. All patients must have biopsiable tumor and a biopsy
must be performed with the collection of FFPE and FF prior to initiation of treatment
on this protocol. Archival tumor tissue must also be obtained if at all available.
This required biopsy will not be necessary if a previous biopsy of progressing tumor
after selective BRAF therapy had already been obtained and is adequate.

- 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 computed tomography (CT) scan.

- Must have received prior therapy and progressed following a selective BRAF inhibitor
(i.e., PLX4032, GSK2118436, etc.). Patients must have completed prior therapy a
minimum of 4 weeks previously (6 weeks for bis-chloroethylnitrosourea (BCNU) and/or
mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for localized radiation
therapy. All treatment related toxicity must have resolved to grade 2 or less as
well. Patients may initiate the protocol treatment at 14 days following the BRAF
inhibitor has been stopped. Patients must have had no more than 2 prior chemotherapy
regimens. Patients cannot receive chemotherapy after the BRAF inhibitor treatment and
prior to enrollment on this protocol. Up to two prior immunotherapy regimens for
advanced disease are allowed and one may be given between BRAF inhibitor therapy and
this trial.

- Must not be primary refractory to the BRAF inhibitor. Patients must demonstrate some
degree of tumor regression initially and have progressive disease. (Tumor regression
does not require response evaluation criteria in solid tumors (RECIST) objective
response. They cannot have progressive disease at the time of first evaluation (6 or
8 weeks) on the BRAF inhibitor.

- Life expectancy ≥ 3 months

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

- Must have normal organ and marrow function: Absolute neutrophil count (ANC) ≥ 1,500
mm³; Hemoglobin ≥ 9.0 g/dL (Patients may be transfused to achieve level); Platelet
count > 100,000/μL; serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic
pyruvic transaminase (SGPT) < 2.5 X upper limit of normal (ULN); Total Bilirubin <
1.5 mg/dl; Serum creatinine ≤ 2.0 mg/dl or creatinine clearance > 50 ml/min,
determined by 24 hour urine collection

- Women of child-bearing potential (WOCBP) 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. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, the patient should inform the treating physician immediately.

- Baseline echocardiogram or multigated acquisition (MUGA) scan must be performed at
screening and patients must have left ventricular ejection fraction (LVEF) ≥50%.
Additionally baseline electrocardiogram (EKG) must be performed and corrected QTc
must be <480 milliseconds.

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

- Patients must have a negative serum pregnancy test prior to being eligible to take
part in the study.

- Patients must be able to swallow tablets and capsules to participate in the study.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients may not be receiving any other investigational agents.

- Patients with active central nervous system (CNS) metastases are excluded. Patients
with a history of CNS metastasis that have been treated must be stable for 8 weeks
after completion of treatment, with image documentation required.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD6244 hydrogen sulfate, MK-2206 or other agents used in the study.

- Patients receiving medications or substances that are strong inhibitors or inducers
of CYP3A4 are ineligible.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, psychiatric illness/social situations that would limit compliance with
study requirements, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, uncontrolled hypertension (BP ≥ 150/95 despite optimal therapy),
heart failure New York Heart Association (NYHA) Class II or above, prior or current
cardiomyopathy, baseline LVEF ≤ 50%, atrial fibrillation with heart rate > 100 bpm,
and unstable ischemic heart disease (myocardial infarction (MI) within 6 months prior
to starting treatment or angina requiring use of nitrates more than once weekly).

- Pregnant women are excluded from this study because AZD6244 hydrogen sulfate is at
MEK inhibitor and MK-2206 is an Akt inhibitor with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with AZD6244 hydrogen
sulfate and MK-2206 breastfeeding should be discontinued if the mother is treated
with AZD6244 hydrogen sulfate and MK-2206. These potential risks may also apply to
other agents used in this study.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with AZD6244 hydrogen sulfate 44 and
MK-2206. In addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy. Appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated.

- Patients must not have received chemotherapy in the time between the failure of BRAF
inhibitor and the enrollment onto the present trial.

- Patients who cannot swallow capsules or tablets are ineligible.

- Absolute Neutrophil Count (ANC) < 1,500 per mm³