Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients

Abstract

Purpose: To evaluate the safety, toxicity, in vivo immunologic activation, and maximum-tolerated dose (MTD) of EMD 273063 (hu14.18-IL-2) in patients with metastatic melanoma.

Patients and methods: Thirty-three patients were treated with EMD 273063, a humanized anti-GD2 monoclonal antibody (mAb) linked to interleukin-2 (IL-2). EMD 273063 was given as a 4-hour intravenous infusion on days 1, 2, and 3 of week 1. Patients with stabilization or regression of disease could receive a second course of treatment at week 5. Dose levels evaluated were 0.8, 1.6, 3.2, 4.8, 6.0, and 7.5 mg/m2/d.

Results: Nineteen of 33 patients completed course 1 with stable disease and went on to receive course 2. Eight patients had stable disease on completion of course 2. Grade 3 adverse events included hypophosphatemia (11 patients), hyperglycemia (three patients), hypotension (two patients), thrombocytopenia (one patient), hypoxia (three patients), elevated hepatic transaminases (two patients), and hyperbilirubinemia (one patient). Opioids were required for treatment-associated arthralgias and/or myalgias during 17 of 52 treatment courses. No grade 4 adverse events were observed. Dose-limiting toxicities at the MTD included hypoxia, hypotension, and elevations in AST/ALT. Grade 3 toxicities were anticipated based on prior studies of IL-2 or anti-GD2 mAbs, and all resolved. Immune activation was induced, as measured by lymphocytosis, increased peripheral-blood natural killer activity, and cell numbers, and increased serum levels of the soluble alpha chain of the IL-2 receptor complex.

Conclusion: Treatment with the immunocytokine EMD 273063 induced immune activation and was associated with reversible clinical toxicities at the MTD of 7.5 mg/m2/d in melanoma patients.

Figures

Fig 1

Mean peripheral-blood lymphocyte count (cell number per mcL ± SE) for (A) the 31 patients completing course 1 and (B) the 12 patients completing both courses at the same dose level. In A, values after d1 are different from pretreatment (P < .0001). Significant differences in B are shown (course 2 v course 1). (*), P < .05; (**), P < .01.

Fig 2

Mean (+ SE) percentage of peripheral-blood mononuclear cell–expressing marker before treatment (day 1) and on day 8 for (A) patients completing course 1 and (B) patients completing courses 1 and 2 at the same dose level. Significant differences are shown for (A) day 1 versus day 8 and (B) for course 2 versus course 1. (*), P < .05; (**), P < .01.

Fig 3

Mean soluble interleukin-2 receptor levels in serum by dose level pre-infusion and 4 hours after starting infusion (days 1 and 3) and on days 2, 4, 5, and 8 for (A) patients completing course 1 and (B) for patients completing course 2.

Fig 4

Antibody-dependent cell-mediated cytotoxicity using the LA-N-5 target with peripheral-blood mononuclear cells obtained from patients on day 1 (before treatment) and day 8. Mean lytic units (+ SE) for cultures containing medium alone, interleukin-2 (IL-2; 100 U/mL), or EMD 273063 (0.25 μg/mL). Significant differences are shown for day 8 versus day 1. (**), P < .01; (***), P < .001.

Fig 5

Serum samples were obtained at the indicated times from patients (PT) 1 and 2 (0.8 mg/m2/d) for assays (see Immunologic Monitoring section of Patients and Methods). (A) Proliferation of interleukin-2 responsive Tf-1β cells (cpm); (B) binding of EMD 273063 to M21 (mean fluorescence intensity units). IL-2, interleukin-2.

Fig 6

Antibody-dependent cell-mediated cytotoxicity using the LA-N-5 target (% cytotoxicity; effector: target ratio of 50:1) with and without effectors (day 8 of course 2) in medium containing autologous serum obtained pretreatment (pre) or after the initial 4-hour infusion, for six consecutive assays on patients at 4.8 to 6.0 mg/m2/d. The killing by effectors in 4 hours’ serum was six-fold greater than with effectors in preserum when calculated using lytic units (not shown).