A Phase II Trial of MAP Kinase Inhibition With AZD6244 Hydrogen Sulfate in Combination With MK-2206 (Akt Inhibitor) in Patients With BRAF V600-Mutant Advanced Melanoma Whose Disease Has Progressed on Prior Therapy With a Selective BRAF Inhibitor (i.e., Vemurafenib, Dabrafenib, LGX818)

Inclusion Criteria:

- Patients must have incurable unresectable stage III or IV histologically confirmed
Melanoma with V600-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 if possible 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

- 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 computed tomography (CT) scan

- Patients must have received prior therapy and progressed following a selective BRAF
inhibitor (i.e., vemurafenib, dabrafenib, LGX818, etc.); patients must have completed
prior therapy a minimum of 4 weeks previously (6 weeks for 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 48 hours following the completion of BRAF
inhibitor; 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

- Patients must not be refractory to the BRAF inhibitor; patients must demonstrate some
degree of tumor regression initially on BRAF inhibitor prior to progression; (tumor
regression does not require RECIST objective response); they cannot have progressive
disease at the time of first evaluation (4 or 8 weeks) on the BRAF inhibitor

- Baseline Ophthalmologic exam must be done at screening to include slit lamp exam and
fundoscopy; an OCT scan should be considered in case of retinal abnormality at exam

- Life expectancy of greater than or equal to 3 months

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

- Absolute neutrophil count ≥ 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 pyruvate
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

- Fasting blood glucose < 160 mg/dL OR

- HgbA1C < 8% disease (uncontrolled diabetes)

- 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

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

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with AZD6244 hydrogen sulfate and MK-2206

- Baseline echocardiogram or MUGA must be performed at screening and patients must have
LVEF > 55%; additionally baseline EKG must be performed and corrected QTc must be <
480 milliseconds

- Baseline electrocardiogram(EKG) must be performed and corrected QTc must be < 480
milliseconds

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

- No 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

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, 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), baseline ejection fraction < 55% or the lower limit of
institutional normal, heart failure NYHA Class II or above, prior or current
cardiomyopathy, atrial fibrillation with heart rate > 100 bpm, and uncontrolled
angina (Canadian Cardiovascular society grade II-IV despite medical therapy); acute
coronary syndrome within 6 months from starting therapy

- Patients must have completed prior therapy a minimum of 4 weeks previously (6 weeks
for 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

- No 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 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

- Patients may not be receiving any other investigational agents at the same time as
study treatment

- Patients receiving medications or substances that are strong inhibitors or inducers
of cytochrome P450 3A4 (CYP3A4) are ineligible

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

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