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

This phase I/II trial is designed to determine the maximum tolerated dose or the maximum administered dose of intratumoral administration of hu14.18-IL2 and to evaluate side effects of intratumoral hu14.18-IL2 when given alone, after radiation therapy, after radiation therapy and in combination with nivolumab, and after radiation therapy and in combination with nivolumab and ipilimumab in patients with melanoma that is advanced (stage IV) or with melanoma that cannot be removed by surgery and is considered surgically incurable. Hu14.18-IL2 is a molecule called a fusion protein that can bind to some tumor cells and cause immune cells to become activated to kill tumor cells. Radiation therapy is a type of cancer treatment that uses beams of high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with immune checkpoint inhibitors, such as nivolumab and ipilimumab, can help the body's immune system attack cancer by releasing the "brakes" on the immune system to allow cancer fighting immune cells to remain activated. This study will evaluate whether giving intratumoral hu14.18-IL2 with radiation therapy, nivolumab and ipilimumab has antitumor activity for participants with advanced melanoma. After completion of study treatment, participants are followed up at 30 days, every 12 weeks for up to 2 years, and then every 6 months thereafter.

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 \ 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.