Phase I/II trial of intratumoral administration of hu14.18-IL2, with local radiation, nivolumab, and ipilimumab in subjects with advanced melanoma.

Abstract

TPS9591 Background: We are studying an intratumoral (IT) in situ vaccine strategy using the GD2-reactive hu14.18-IL2 immunocytokine (hu-IC) to convert the injected tumor into a site of enhanced tumor antigen presentation, as has been shown in mice. Hu-IC is a humanized monoclonal antibody (mAb) covalently linked to two molecules of IL-2 at the Fc region. The hu14.18 mAb recognizes GD2, a disialoganglioside found in tumors of neuroectodermal origin. We previously studied intravenous (IV) hu-IC and reported immune activation and reversible toxicities (1). Surgery to resect recurrent stage III or stage IV melanoma combined with 3 courses of IV hu-IC resulted in prolonged tumor-free survival in some patients (2). Murine GD2+ tumor models showed enhanced antitumor activity and recruitment of T cells using hu-IC IT versus IV (3). In these models, the combination of radiation therapy (RT) followed by IT hu-IC dramatically potentiates the antitumor response and enhanced response to immune checkpoint blockade (4). Biological samples (blood and tumor) will be interrogated to identify biological mechanisms and develop biomarkers for future testing. Methods: This outpatient phase I/II trial uses a 3 + 3 design to determine maximum tolerated or maximum administered dose of IT hu-IC (planned dose level: 2 mg/m2/day; de-escalation dose level: 1 mg/m2/day) when given alone (Phase 1A: 3-12 patients), after RT (Phase 1B: 6-12 patients), after RT and in combination with nivolumab (Phase 1C: 6-12 patients), and after RT and in combination with nivolumab and ipilimumab (Phase 1D: 31-34 patients). The trial will evaluate safety, antitumor activity, and immunologic endpoints and includes an expanded Phase II cohort (Phase 1D). The IT injections (once daily x 3 days) are delivered every 21 days for 4 cycles and can then continue every 28 days for up to 13 cycles if there is response/stable disease and residual injectable tumor. Key inclusion criteria: 1) histologically proven, malignant melanoma that is advanced (Stage IV) or surgically incurable; 2) at least 1 (preferably 2) sites of disease amenable to safe repeated IT injections; and 3) must have received or declined at least one FDA approved therapy, either in the adjuvant setting or for metastatic disease, with an impact on survival. Two subjects have been accrued into Phase IA as of 2-4-2021.