Sotrastaurin Acetate and Alpelisib in Treating Patients with Metastatic 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; for the dose escalation portion of the trial only, patients with non-uveal melanoma harboring a GNAQ or GNA11 mutation will also be eligible
• 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 computed tomography (CT) scan; 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 mTOR inhibitor are allowed; for the dose expansion cohort, no prior MEK, protein kinase C (PKC), Akt, or mTOR inhibitors are allowed, and registration is limited to 10 total patients; 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 or regional 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
• Willingness to undergo core biopsies at baseline and mid-cycle 1 unless contraindicated by medical risk in the opinion of the treating physician and discussed with the principal investigator
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (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
• Fasting plasma glucose (FPG) < 140 mg/dL/7.8 mmol/L, where fasting is defined as no food intake for 8 hours prior to measurement
• 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 enrollment
• 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]) =< 2.5 X institutional upper limit of normal for patients with no concurrent liver metastases, OR =< 5 X institutional upper limit of normal for patients with concurrent liver metastases
• Creatinine =< 1.5 x upper limit of normal (ULN)
• 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 during screening; 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 and women 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 AEB071 and BYL719 administration; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during dosing * Highly effective contraception methods include: ** Total abstinence OR ** Male or female sterilization OR ** Combination the following: *** Placement of an intrauterine device (IUD) or intrauterine system (IUS) *** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
• 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; consult the study principal investigator if unsure whether second malignancies meet the requirements specified above
• Any major surgery or extensive radiotherapy within 28 days prior to screening
• Use of a systemic treatment regimen for metastatic disease within 28 days 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; these include: * Patients who are receiving treatment with medications that are known to be strong inducers or inhibitors of CYP3A4/5 and CYP3A4/5 substrates with QT prolongation risk that cannot be discontinued prior to study entry * Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing torsades de pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
• Type I diabetes mellitus (DM), type II DM patients requiring insulin for chronic blood glucose control, and any patients with a fasting blood glucose > 140 mg/dL (7.8 mmol/L) at screening will be excluded
• Patients with a history of pulmonary disease or findings present on baseline high-resolution chest CT scan that, in the opinion of the treating investigator, would put the patient at risk of complications of pneumonitis will be excluded
• History or evidence of cardiovascular risk including any of the following: * A corrected QT interval using the Bazett’s formula QTcB >= 480 msec * History or evidence of current clinically significant uncontrolled arrhythmias or patients that require medications with a narrow therapeutic window, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete atrioventricular (AV)-blockage (exception: patients with chronic atrial fibrillation with heart rate less than 100 for > 30 days prior to randomization are eligible) * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting within 6 months prior to randomization * Current class II or higher 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 > 150 mmHg and/or diastolic > 90 mmHg despite adequate attempts at anti-hypertensive therapy
• 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