IT-hu14.18-IL2 With Radiation, Nivolumab and Ipilimumab for Melanoma

Inclusion Criteria:

* Subjects must have histologically proven, malignant melanoma, that is advanced (stage IV) or is unresectable and therefore considered surgically incurable
* Subject's disease must be measurable by immune-related RECIST criteria using clinical assessments or imaging
* Subjects must have at least one (1), but preferably two (2), sites of readily accessible, superficial disease (i.e., cutaneous, subcutaneous, and/or readily-palpable lymphadenopathy) that are amenable to repeated hu14.18-IL2 injections and two (2) to four (4) biopsies (designated Lesions A (index lesion) and B). These lesions must be at least 1 cm, but no greater than 5 cm, in longest diameter.

  * If there are two lesions, one will be injected with hu14.18-IL2 and undergo biopsies. The second will not undergo injections with hu14.18-IL2, but will undergo two biopsies and be observed clinically. It is preferable, but not required, that these lesions have not received prior RT.
* Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Subjects must have received or declined at least one FDA approved immunotherapy treatment demonstrating an impact on survival (i.e: anti-CTLA-4 antibody, anti-PD-1 antibody, IL2, etc).
* Subjects with Central Nervous System (CNS) metastases are eligible if the CNS lesions are stable for at least 2 months and if tapered off treatment doses of systemic corticosteroids for at least 2 weeks prior to enrollment on the trial. Management with maintenance physiologic doses of corticosteroids is acceptable.
* Subjects to be entered into Phase IB, IC and ID must be evaluated by a radiation oncologist and determined to have a need for palliative RT based on current or imminent symptoms at a tumor site that is also injectable. If palliative RT is needed to one or more disease sites, a separate site of disease that does not require RT must remain to enable assessment of systemic disease response.
* Subjects must have adequate bone marrow, liver, and renal function as defined by:

  * Total White Blood Cell (WBC) \> 3,000/mm3 (or total neutrophil count \> 1,500/mm3), platelets \>100,000/mm3, and hemoglobin \> 10 g/dL.
  * AST/ALT ≤ 3 x the upper limit of normal. Total bilirubin ≤ 1.5 x the upper limit of normal (\< 3.0 mg/dL for subjects with Gilbert's Syndrome).
  * Serum creatinine ≤ 1.5 x the upper limit of normal
* Subjects with a history of ischemic cardiac disease must complete a stress radionuclide scan with results that show no evidence of myocardial ischemia or heart failure, as well as normal pulmonary function
* Subjects must be willing and able to provide informed written consent for the study.
* Subjects must have no immediate requirements for palliative chemotherapy, or surgery. Subjects in Arm 1A must have no immediate requirement for palliative RT.
* Subjects must be willing and able to discontinue antihypertensive medications if advised to do so for the days of hu14.18-IL2 administration.
* Subjects must have a washout period of at least 28 days between any prior systemic anti-cancer therapy (including immunotherapies) and the first dose of study drug(s).

Exclusion Criteria:

* Subjects with a diagnosed auto-immune disease (exceptions: subjects with controlled diabetes mellitus type I, thyroid disease, vitiligo and alopecia areata not requiring treatment with immunosuppressants are eligible)

  * Subjects with a history of diabetes mellitus requiring systemic therapy within the past 3 months (i.e. either oral hypoglycemic agents or insulin) must have a documented Hemoglobin A1c \<8.0% at the time of enrollment.
* Subjects with known genetic conditions causing pre-disposition to RT toxicity (i.e: Li-Fraumeni, ATM deficiency, active scleroderma, etc).
* Subjects who cannot provide independent, legal, informed consent.
* Women of childbearing potential will be excluded if they are pregnant, nursing, or not willing to use effective contraception, as discussed with the treating physician, during the treatment period. A negative pregnancy test (serum or urine) is required for women of child bearing potential within 14 days before study registration.

  * A person of childbearing potential is anyone (regardless of sexual orientation, gender identity, having undergone tubal ligation, or remaining celibate by choice) who was born with a uterus and at least one ovary and meets the following criteria

    * Has not undergone a hysterectomy or bilateral oophorectomy; or
    * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had a menses at any time in the preceding 12 consecutive months).
* Subjects with symptoms of ischemic cardiac disease, congestive heart failure, or myocardial infarction within the immediate preceding 6 months and/or uncontrolled cardiac rhythm disturbance
* Subjects with significant psychiatric disabilities or seizure disorders
* Subjects with symptomatic pleural effusions or ascites.
* Subjects with organ allografts
* Subjects who require, or are likely to require, systemic treatment doses of corticosteroids, or other immunosuppressive drugs, or have used them within 2 weeks of registration (clarification: subjects receiving physiologic maintenance or replacement doses of systemic steroids are eligible).
* Subjects with significant intercurrent illnesses per physician discretion.
* Subjects with active or acute infections or active peptic ulcers, unless these conditions are adequately corrected or controlled, in the opinion of the treating physician.
* Subjects with a second malignancy other than adequately treated non-melanoma skin cancer. Subjects will be considered eligible if they have been continuously disease free for \> 5 years from a second malignancy prior to the time of enrollment.
* Subjects with known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or hepatitis C infection, or with clinical evidence of hepatitis.
* Subjects with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade ≥2).
* Subjects with known hypersensitivity to hu14.18-IL2 or human immunoglobulin, or those who experienced significant immune-related adverse events requiring treatment with steroids or other immunosuppressant therapy during prior treatment with ipilimumab, or anti-PD1/PD-L1 checkpoint blockade therapy.