Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma

Inclusion Criteria 1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Patients must be willing and able to provide written informed consent for this trial. 2. Age ≥ 18 years at the time of consent. 3. Histologically or cytologically confirmed metastatic uveal melanoma. Staging per AJCC manual edition 8. 4. One or more lesions that could be accurately measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 1). 6. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 14 days prior to registration. * Leukocytes ≥ 2,000 µ/l * Absolute Neutrophil Count (ANC) ≥ 1,500 K/mm3 * Platelets ≥ 100,000/µl * Hemoglobin (Hgb) ≥ 9 g/dL * Serum Creatinine ≤ 1.5 x ULN * Calculated creatinine clearance ≥ 40 mL/min * Total Bilirubin ≤ 1.5 mg/dL * Aspartate aminotransferase (AST) ≤ 2.5 × ULN * Alanine aminotransferase (ALT) ≤ 2.5 × ULN * Alkaline Phosphatase ≤ 2.5 × ULN * Partial Thromboplastin Time (PTT) \< 1.5 × ULN 7. Subjects must have archival tissue (metastatic disease preferred) available or undergo a biopsy prior to Cycle 1 Day 1 of treatment. Subjects that do not have archival tissue or cannot undergo a biopsy are not eligible for the study. 8. Prior therapy is allowed but must have been completed 21 days prior to initiation of protocol therapy and all toxicities must be \< Grade 2. 9. Palliative radiation must have been completed 2 weeks prior to the initiation of study therapy. 10. Patient with known brain metastases must have been treated at least 2 weeks prior to enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be receiving a supra-physiologic dose of steroids (\>10 mg prednisone daily or equivalent). 11. Women must not be pregnant or breastfeeding. All women of childbearing potential (WOCBP) must have a blood human chorionic gonadotrophin (hCG) test or urine hCG test within 2 weeks prior to registration to rule out pregnancy. 12. Women of childbearing potential (WOCBP) must agree to use contraception as outlined in the protocol from the time of informed consent, during the study and for 3 months after the last dose of study drug(s). Abstinence from heterosexual intercourse is an acceptable form of contraception. Women of childbearing potential are those who have not been surgically sterilized or have not been free of menses \>1 year 13. Male patients who are sexually active with WOCBP must agree to use contraception as outlined in the protocol from the time of initiation of study treatment, during the study and for 3 months after the last dose of study drug(s). Abstinence from heterosexual intercourse is an acceptable form of contraception. 14. The participant is capable of understanding and complying with the protocol and has signed informed consent document. Exclusion Criteria 1. Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0). 2. Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption. 3. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 4. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay. For patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBcAb\] and absence of HBsAg), the patient is only eligible if they are negative for HBV DNA. 5. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. NOTE: Radiation-induced lung disorders are not included in this exclusion criterion. 6. History of retinal pigmented epithelial detachment, central serous retinopathy, or retinal vein occlusion in the unaffected eye; or intraocular pressure 21 mmHg or uncontrolled glaucoma (irrespective of intraocular pressure) in the unaffected eye. 7. History of uncontrolled seizures. 8. History of ataxia. 9. Allergies and adverse drug reaction: History of allergy to study drug components. 10. Thromboembolic events requiring therapeutic anticoagulation. Concomitant anticoagulation with oral anticoagulants (warfarin, direct thrombin or factor Xa inhibitors), platelet inhibitors (e.g. Clopidogrel, high dose aspirin) is prohibited. Low-dose aspirin (\<100 mg/day), low-dose warfarin (\<1 mg/day) and prophylactic low molecular weight heparin (LMWH) or similar agent are permitted. 11. History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study. 12. History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval \> 450 milliseconds from ECGs performed at least 24 hours apart). 13. History of additional risk factors for torsades de pointes (e.g., family history of long QT syndrome). 14. Cardiovascular disorders including unstable angina pectoris, clinically-significant cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic attack \[TIA\], or other ischemic event) within 6 months prior to registration. 15. Active infection requiring intravenous systemic treatment. 16. Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration. 17. Known uncontrolled, symptomatic brain metastasis or cranial epidural disease. 18. Known additional malignancies which require systemic treatment. 19. Inability to swallow intact tablets. 20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the sponsor-investigator.