A-dmDT390-bisFv(UCHT1) Fusion Protein With Ionizing Radiation and Pembrolizumab for the Treatment of Stage IV Melanoma

Inclusion Criteria:

* All patients must have histologically proven stage IV metastatic melanoma consisting of at least two lesions \>= 1.5 cm that would not occupy the same radiation field. Patients must be treatment naïve except for treatment with BRAF inhibitors. Patients with melanoma must have an anti-DT titer of \<20 μg/ml. Patients with brain metastasis and ocular and mucosal lesions can be enrolled at the discretion of the PI providing that other non-brain and non-ocular metastatic lesions are available as targets for radiation therapy
* Patients must have a performance status of \< 2 on Eastern Cooperative Oncology Group scale (see Appendix). Patients must have fully recovered from toxicity of prior therapy with BRAF inhibitors. Adequate bone marrow function will be defined as ANC \>750 uL, WBC \>1000 uL, platelets \>60,000 uL and Hb \> 9g/dL
* Patients must have:

  * bilirubin \< 1.5 mg/dL,
  * transaminases \< 2.5 X ULN,
  * albumin \> 3 gm/dL,
  * creatinine \< 2.0 mg/dL,
  * adequate pulmonary function by physical exam and pulse oximetry and adequate cardiac reserve (EF \> 50% normal).
* Patients must have a normal echocardiogram without any evidence of cardiac chamber hypertrophy, dilatation or hypokinesis. The Sponsor must be provided with copies of these tests before Sponsor will approve enrollment. In addition, the sponsor must receive a list of current medications taken by the patient before Sponsor will approve enrollment.
* Patients must give written informed consent prior to registration (see Informed Consent).
* Females and males must be willing to use an approved form of birth control while on this study and for 2 weeks after completion.
* Patients of ages 18-80 are eligible provided they have stage IV melanoma and are negative for BRAF or have failed BRAF inhibitor treatment or if they have failed or are intolerant to other established therapy known to provide clinical benefit for their condition or if they have been adequately consented and agreed to forgo FDA approved clinically meaningful therapy.

Exclusion Criteria:

* Failure to meet any of the criteria set forth in Inclusion Criteria.
* Inability to give informed consent because of psychiatric problems, or complicated medical problems.
* Serious concurrent medical problems, uncontrolled infections, or disseminated intravascular coagulopathy (DIC).
* Preexisting cardiovascular disease, the only exception being well controlled essential hypertension with a sitting B.P. of \<155 systolic and \<90 diastolic without any evidence of structural heart disease or one episode of myocardial infarction \> 8 months ago. A past history of the any of the following are exclusions:

  * Congestive heart failure,
  * Atrial fibrillation,
  * Pulmonary hypertension,
  * Anticoagulant drug therapy,
  * Thromboembolic events,
  * Cardiomyopathy or a myocardial infarction within the past 8 months. Referring physicians will be asked to verify that their referred patients do not have these exclusionary histories listed in 3.2 and a copy of this verification must be sent to the Sponsor before the Sponsor will approve of enrollment. Because beta-blockers have been associated with adverse events during anaphylactic reactions and because such reactions can occur with IV infusions of proteins such as the study drug, the sponsor requires that patients receiving beta-blockers for hypertension be converted to another anti-hypertensive reagent 2-3 weeks prior to receiving the study drug. Angiotensin inhibitors, angiotensin receptor blockers and calcium channel blockers are all acceptable.
* Pregnant or nursing women will be excluded from study.
* History of congestive heart failure.
* History of cirrhosis of the liver.
* Prior treatment with alemtuzumab (Campath) or similar agents or procedures that depress blood T cell counts to below 50% of the lower limit of normal.