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.

PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of intratumoral (IT)-Hu14.18-IL2 fusion protein (hu14.18-IL2) in subjects with advanced melanoma (Phase IA) II. Evaluate the safety and tolerability of IT-hu14.18-IL2 when given alone (Phase IA) III. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of IT-hu14.18-IL2 after receiving palliative radiation therapy (RT) in subjects with advanced melanoma (Phase IB) IV. Evaluate the safety and tolerability of the combination of palliative RT with IT-hu14.18-IL2 (Phase IB) V. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of IT-hu14.18-IL2 after receiving palliative RT and in combination with nivolumab in subjects with advanced melanoma (Phase IC) VI. Evaluate the safety and tolerability of the combination of palliative RT, nivolumab and IT-hu14.18-IL2 (Phase IC) VII. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of IT-hu14.18-IL2 after receiving palliative RT and in combination with nivolumab and ipilimumab in subjects with advanced melanoma (Phase ID) VIII. Evaluate the safety and tolerability of the combination of palliative RT, nivolumab, ipilimumab and IT-hu14.18-IL2 (Phase ID) IX. Evaluate local and systemic objective tumor responses to treatment with IT-hu14.18-IL2 in combination with palliative RT, nivolumab, and ipilimumab (Phase ID) SECONDARY OBJECTIVES: I. Evaluate progression-free survival (PFS), overall survival (OS), clinical benefit (CB, defined as complete response (CR) + partial response (PR) + stable disease (SD)) and duration of response to hu14.18-IL2 in combination with RT, nivolumab and ipilimumab. II. Evaluate pathologic (tissue) evidence of immune response at the injection site and untreated sites. III. Evaluate PFS, CB and duration of response to hu14.18-IL2 in combination with palliative RT, nivolumab and ipilimumab based on resistance to prior treatment with anti-CTLA-4 and/or anti PD1/PD-L1 antibody. IV. Evaluate serial serum samples to determine the pharmacokinetics of hu14.18-IL2 administered intratumorally. V. Evaluate each subject's tumor cells for expression of GD2 and PD-L1, and determine if either antitumor activity or selected treatment-associated biologic effects are more likely for tumors that are GD2+ then GD2- and PD-L1+ than PD-L1-. VI. Evaluate whether PD-L1 expression is induced or augmented from baseline following initiation of treatment (by comparing serial biopsies). VII. Evaluate the immunologic activation induced in vivo by IT-hu14.18-IL2, addressed by in vitro cellular, serologic and flow cytometry immune assays. VIII. Evaluate for histological evidence of antitumor activity based on the presence of necrotic tumor cells, inflammatory infiltrate, cellular phenotype of infiltrate, and presence of hu14.18-IL2 within the tumor at selected post-treatment timepoints. IX. Evaluate circulating tumor cells, exosomes, endogenous antibodies, and/or deoxyribonucleic acid (DNA) as exploratory biomarkers associated with clinical response to IT-hu14.18-IL2 in combination with RT, nivolumab and ipilimumab. X. Evaluate serial peripheral blood mononuclear cell (PBMC) samples to monitor the induction of T cell responses to melanoma-associated antigens. XI. Evaluate objective tumor responses, both locally and systemically (by immune-related response criteria), in Phases IA, IB and IC of this trial (involving IT-hu14.18-IL2 alone and in combinations with palliative RT, and with palliative RT and nivolumab, respectively). OUTLINE: This is a dose escalation study of hu14.18-IL2 fusion protein. PHASE IA: Participants receive hu14.18-IL2 fusion protein intratumorally (IT) once daily (QD) on days 1-3. Treatment repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. A total of 9-18 participants will be enrolled in 3 escalating dose levels to determine the Maximum Tolerated Dose (MTD)/Maximum Administered Dose (MAD) of hu14.18-IL2 in Phase IA. PHASE IB: Participants undergo palliative RT on days -8 to -4 of cycle 1 only. Participants also receive hu14.18-IL2 fusion protein IT as in phase IA. Treatment with hu14.18-IL2 repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. The MTD/MAD of IT-hu14.18-IL2 following palliative RT will be determined starting 1 dose level below the Phase IA determined MTD/MAD of IT-hu14.18-IL2 up to the Phase IA determined MTD/MAD. PHASE IC: Participants undergo palliative RT on days -8 to -4 of cycle 1 only. Nivolumab (3 mg/kg) is given every 2 weeks for up to 1 year with the initial dose given between day -7 and day -1 of cycle 1. Participants also receive hu14.18-IL2 fusion protein IT as in phase IA. Treatment with hu14.18-IL2 repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. The MTD/MAD of IT-hu14.18-IL2 following palliative RT in combination with nivolumab will be determined starting 1 dose level below the Phase IB determined MTD/MAD of IT-hu14.18-IL2 up to the Phase IB determined MTD/MAD. PHASE ID: Participants undergo palliative RT on days -8 to -4 of cycle 1 only. Nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) is given every 3 weeks for 4 cycles with the initial dose given between day -7 and day -1 of cycle 1. Following 4 cycles, no additional ipilimumab will be administered. Following cycle 4, maintenance nivolumab (3 mg/kg) can be given for up to one year. Participants also receive hu14.18-IL2 fusion protein IT as in phase IA. Treatment with hu14.18-IL2 repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. The MTD/MAD of IT-hu14.18-IL2 following palliative RT in combination with nivolumab and ipilimumab will be determined starting 1 dose level below the Phase IC determined MTD/MAD of IT-hu14.18-IL2 up to the Phase IC determined MTD/MAD. A total of 28 participants will be enrolled at the Phase ID MTD/MAD of IT-hu14.18-IL2.