Defactinib and VS-6766 for the Treatment of Patients With Metastatic Uveal Melanoma

Inclusion Criteria: * Histologically confirmed metastatic uveal melanoma * Predicted life expectancy of at least 12 weeks * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on spiral computed tomography (CT) or magnetic resonance imaging (MRI) scan, all radiology studies must be performed within 28 days prior to registration. Corrected QT interval (QTc) \< 470 ms (as calculated by the Fridericia correction formula, averaged over 3 electrocardiograms \[ECGs\]) * Hemoglobin (Hb) \>= 9.0 g/dL (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Platelet count \>= 100 x 10\^9/L (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Serum bilirubin =\< 1.5 x upper limit of normal (ULN) (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Albumin \>= 3.0 mg/dL (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Creatine phosphokinase (CPK) =\< 2.5 x ULN (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =\< 2.5 x ULN unless raised due to tumor in which case up to 5 x ULN is permissible (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Calculated creatinine clearance \>= 45 mL/min by the Cockcroft-Gault formula (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * International normalized ratio (INR) =\< 1.5 in absence of anticoagulation or therapeutic levels in presence of anticoagulation (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Partial thromboplastin time (PTT) =\< 1.5 x ULN in absence of anticoagulation or therapeutic levels in presence of anticoagulation (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial) * Patients with adequate cardiac function (left ventricular ejection fraction \>= 50%) by echocardiography or multigated acquisition scan (MUGA) scan * No active retinopathy or retinal vein occlusion confirmed by full ophthalmological exam in the eye unaffected by uveal melanoma * Adequate recovery from toxicities related to prior treatments to at least grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exceptions include alopecia and peripheral neuropathy grade =\< 2. Subjects with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the sponsor * Men and women aged 18 years or over * Females with reproductive potential and their male partners agree to use highly effective method of contraceptive (per Clinical Trial Facilitation Group \[CFTG\] recommendations during the trial and for 3 months following the last dose of study drug) * Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Exclusion Criteria: 1. Radiotherapy (except for palliative reasons), endocrine therapy, biological therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) before treatment. 2. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDU should not exclude the patient. 3. Known untreated or active central nervous system (CNS) metastases (progressing or requiring corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: * Evaluable or measurable disease outside the CNS is present. * Radiographic demonstration of improvement upon the completion of CNS- directed therapy and no evidence of interim progression between the completion of CNS- directed therapy and the baseline disease assessment for at least 28 days. 4. Gilbert syndrome diagnosed with elevated indirect (unconjugated) bilirubin ( \>1.2 mg/dl) at least two occasions with normal direct bilirubin in the absence of hemolysis or structural liver damage. 5. Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrollment and agree to use two medically approved forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) from time of consent, during the trial and for six months afterwards are considered eligible. 6. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of medically approved contraception \[condom plus spermicide\] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the fetus or neonate. 7. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered. 8. Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to low-molecular-weight heparin (LMWH). 9. Acute or chronic pancreatitis. 10. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. 11. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 12. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease. 13. History of abdominal fistula, gastro-intestinal perforation, or diverticulitis. 14. Patients with history of symptomatic cholelithiasis or cholecystitis within six months before enrollment. 15. Concurrent ocular disorders in the eye unaffected by uveal melanoma: 1. Patients with history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes 2. Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure \> 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO. 3. Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. 16. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association \[NYHA\]), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease. 17. Patients exposed to strong CYP3A4 and strong CYP2C9 inhibitors within 7 days prior to the first dose. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. 18. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase II study of VS-6766 in combination with VS- 6063\. Participation in an observational trial would be acceptable. 19. Patients with a history of hypersensitivity to any of the inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational product. 20. Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drugs. 21. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.