Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma

Abstract

Purpose: The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis.

Patients and methods: Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course).

Results: Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and β (terminal phase) half-lives were 1.74 and 21.1 days, respectively.

Conclusion: The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.

Trial registration: ClinicalTrials.gov NCT00743496.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Course one (A) maximum plasma concentration (Cmax) and (B) area under the concentration-time curve (AUC) plotted by dose.

Fig 2.

Predicted (blue line) and average predicted (gold line) hu14.18K322A serum levels for 11 patients treated at 60 mg/m2 (maximum-tolerated dose) based on two-compartment model. Blue dots represent observed hu14.18K322A serum levels for representative patient who had median body-surface area among patients treated at 60 mg/m2. Peak serum level on day 4 (immediately after four daily infusions) was greater than that after first infusion on day 1. Elimination of agent after peak on day 1 showed similar pattern to that seen after peak on day 4.

Fig 3.

Tumor response in patients treated with hu14.18K322A. Tumor response was assessed by two methods: metaiodobenzylguanidine (MIBG) score and RECIST. No patient met criteria for objective response by RECIST. Majority of patients (n = 31) had sites of disease apparent by MIBG. Using MIBG score, tumor response (complete response [CR]/partial response [PR]) was observed in six patients. Five of these patients had disease that was only apparent by MIBG. One patient had an MIBG-avid lesion that resolved (CR by MIBG score: persistent abnormalities measureable by RECIST have remained stable for 3 months off therapy). BM, bone marrow; HVA, homovanillic acid; PD, progressive disease; SD, stable disease; VMA, vanillylmandelic acid. (*) Two patients not evaluable for response (both withdrew consent; one before receiving any study drug, and one after second dose of drug during course one). (†) MIBG-avid lesion resolved; lesions measureable by RECIST stable. (‡) One patient was removed from therapy after course one because of toxicity; four patients were removed from therapy at end of course two because of PD. (§) Removed from therapy after course one because of toxicity.