Primary objective is to define the maximum tolerated dose (MTD) for the combination of AEB071 and BYL719. Secondary objectives are to define the safety and tolerability of AEB071 and BYL719.

Uveal melanoma is the most common primary intraocular malignancy in adults and is thought to be particularly resistant to systemic treatment, and no systemic therapy has yet been demonstrated to improve survival. Drugs commonly used to treat advanced cutaneous melanoma rarely achieve durable responses in patients with uveal melanoma. Because of the lack of effective systemic treatment options, outcomes are poor once metastatic disease occurs, and the median survival from the time of the development of distant metastatic disease is 6 to 12 months. Although it is clear that novel effective therapies are desperately needed for this disease, the development of such therapies has been hampered by the rarity of uveal melanoma.

Inclusion Criteria:

• Metastatic histologically or cytologically confirmed uveal melanoma with pathologic confirmation at a participating center that is judged to be progressive in the opinion of the treating physician.
• Measurable disease. Patients with biopsy-proven metastatic disease that do not meet criteria for measurable disease may be eligible at the discretion of the principal investigator.
• Prior cytotoxic therapy and immunotherapy are allowed. For the dose escalation, prior targeted therapy with a MEK inhibitor, Protein Kinase C inhibitor, Akt, or mechanistic target of rapamycin (mTOR) inhibitor are allowed. For the dose expansion cohort, no prior PKC, Akt, or mTOR inhibitors are allowed. 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.
• Age greater than or equal to 18 years
• Willingness to undergo core biopsies at baseline, mid-Cycle 1, and/or at progression unless contraindicated by medical risk in the opinion of the treating physician.
• Easter Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60 percent).
• Life expectancy of greater than 3 months.
• Able to swallow and retain 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.
• Fasting plasma glucose (FPG) less than 140 mg/dL / 7.8 mmol/L.
• All prior treatment-related toxicities must be grade less than or equal to 1 (except alopecia).
• Patients must have adequate organ and marrow function within 14 days of starting Cycle 1, Day 1 of therapy
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• History of another malignancy except for those who have been disease-free for 24 months. Patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies not requiring active therapy are eligible.
• Any major surgery or extensive radiotherapy within 28 days prior to screening
• Use of other investigational drugs within 28 days (or five half-lives, whichever is longer) preceding the first dose of AEB071 and BYL719.
• 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 AEB071 or BYL719.
• Current use of a prohibited medication.
• Type I Diabetes Mellitus (DM), Type II DM patients requiring insulin for chronic blood glucose control, and any patients with a fasting blood glucose greater than 140 mg/dL at screening.
• History or evidence of cardiovascular risk.
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with impairment of gastrointestinal function or gastrointestinal disease that could interfere with the absorption of AEB071 or BYL719 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Patients who have received prior systemic anti-cancer treatment, such as cyclical chemotherapy or biological therapy within a period of time that is shorter than the cycle length used for that treatment (e.g. 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment.