Phase II trial of hu14.18-IL2 for patients with metastatic melanoma

Abstract

Phase I testing of the hu14.18-IL2 immunocytokine in melanoma patients (pts) showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m2/day. In this phase II study, fourteen pts with measurable metastatic melanoma were scheduled to receive hu14.18-IL2 at 6 mg/m2/day as 4-hour intravenous infusions on days 1, 2 and 3 of each 28 day cycle. Pts with stable disease (SD) or regression following cycle 2 could receive 2 additional treatment cycles. The primary objective was to evaluate anti-tumor activity and response duration. Secondary objectives evaluated adverse events and immunologic activation. All pts received 2 cycles of treatment. One pt had a partial response (PR) [1 PR of 14 pts = response rate of 7.1%; confidence interval 0.2%−33.9%] and 4 pts had SD and received cycles 3 & 4. The PR and SD responses lasted 3–4 months. All toxicities were reversible and those resulting in dose reduction included grade 3 hypotension (2 pts) and grade 2 renal insufficiency with oliguria (1 pt). Pts had a peripheral blood lymphocytosis on day 8 and increased C-reactive protein. While one PR in 14 pts met protocol criteria to proceed to stage 2 and enter 16 additional pts, we suspended stage 2 due to limited availability of hul 4.18-IL2 at that time and the brief duration of PR and SD. We conclude that subsequent testing of hu14.18-IL2 should involve melanoma patients with minimal residual disease based on compelling preclinical data and the confirmed immune activation with some antitumor activity in this study.

19F-MRI for monitoring human NK cellsin vivo

“…The immunocytokine has shown antitumor effects in vivo in mouse models [37][38][39][40] in a phase I/II clinical trial in pediatric patients with relapsed/refractory neuroblastoma 41,42 and in patients with metastatic melanoma. 43 Therefore, we expected that GD2…”

Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer

“…This immunocytokine is made of wild-type human IL-2 linked to each IgG heavy chain of the hu14.18 mAb, which recognizes disialoganglioside on tumors of neuroectodermal origin, such as neuroblastoma and melanoma [35]. In a phase II clinical trial, fourteen patients received at least two treatment cycles of hu14.18-IL-2, resulting in one partial response (7.1%) [36]. Subsequently, intratumoral administration of hu14.18-IL-2, instead of iv, was tested in the murine NXS2 neuroblastoma model, leading to increased intratumoral infiltration of NK cells and CD8 + T-cells and improved antitumor effects [37].…”

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

“…Nevertheless, no complete or partial responses were seen, suggesting that greater antitumor activity might be seen in patients with less bulky tumors [96]. Furthermore, Phase II trials in patients with MEL demonstrated immune activation with reversible toxicities [98,99] and some patients with refractory NBL that only exhibited disease evaluable by metaiodobenzylguanidine or bone marrow histology demonstrated clear evidence for antitumor activity in the setting of nonbulky disease [100].…”

“…131 I-3F8 was sensitive and specific at detecting sites with metastatic disease as shown by CT/MRI, and identifying tumors that were confirmed histologically as NBLs [114]. Likewise, 99 Tc-14.18 demonstrated superior sensitivity in the detection of tumor recurrence and metastases when compared with metaiodobenzylguanidine, demonstrating the value of these reagents for the assessment of therapy response, disease progression and early detection of metastases [115].…”

“…To capitalize on the activation potential of both of these cytokines, a treatment regimen with ch14.18 + GM-CSF + IL2 + CRA was developed by The Children's Oncology Group (COG) [65]. The No measurable responses; 3 pts showed evidence of antitumor activity [96] hu14.18-IL2 I Metastatic MEL (33) No measurable responses; 8 pts had SD [97] hu14.18-IL2 I/II Stage 4 MEL (9) No measurable responses; 2 pts had SD [98] hu14.18-IL2 II Metastatic MEL (14) PR in 1 pt, SD in 4 pts [99] Hu14.18-IL2 II Relapsed/refractory NBL (38) CR in 5 pts [100] Radiolabeled mAbs 131I-3F8 I GD2+ tumors metastasized to CNS and leptomeninges (15) 3 pts with objective radiographic and/or cytologic responses. 2 pts in remission for more than 3.5 yrs [160] 131I-3F8 or 131I-8H9 I Recurrent NBL metastatic to the CNS (21) 17 pts are alive 7-74 months (median 33 months) since CNS relapse, with all 17 remaining free of CNS NBL [117] CAR T cells [136] GD2-CAR T cells I Recurrent/refractory advanced-stage NBL (11) CR in 1 pt and 4 pts had evidence of tumor necrosis or regressions [161] Anti-idiotype vaccine…”