Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study

Abstract

Background: Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.

Methods: In this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.

Results: Of the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108-290). Three-year progression-free and overall survival rates were 31% (95% CI 17-47) and 66% (95% CI 47-79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.

Conclusion: Long-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.

Clinical trial registration: The study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).

Fig. 1. Duration of hospitalization and use of intravenous morphine over time.

The duration of hospitalization for antibody treatment (a), proportion of patients requiring intravenous morphine during five treatment cycles with single-agent dinutuximab beta (b) and the daily dose of intravenous morphine required (c). a The box limits are the 1st and 3rd quartile with the median value indicated by the red line and the whiskers represent the most extreme points (1.5 × IQR); outliers are not displayed. + indicates the mean value. The duration of hospitalization was calculated as the date of discharge-date of admission +1. If readmission occurs within 11 days of day 1 of the cycle, the date of readmission is added. b The data represent the mean and in panel c the mean ± SD. DB dinutuximab beta, IQR interquartile range, i.v. intravenous, SD standard deviation.

Fig. 2. Median three-year survival with single-agent dinutuximab beta.

Kaplan–Meier estimates for progression-free survival (a), overall survival (b), progression-free survival by disease status (c), and overall survival by disease status (d). OS overall survival, PFS progression-free survival, MNR median not reached, y years.

Fig. 3. Pharmacokinetics and pharmacodynamics of dinutuximab beta.

Plasma concentration-time curve for dinutuximab beta administered by long-term, continuous infusion over 10 days (a). Pharmacodynamic effects of dinutuximab beta on complement-dependent cytotoxicity in cycles 1, 3 and 5 (b) and antibody-dependent cellular cytotoxicity in cycle 1 (c). Cumulative incidence of human anti-chimeric antibody response after dinutuximab beta treatment (d). a–c Data represent mean ± SD. All P values are versus values on day 1 of cycle 1 using the Mann–Whitney rank sum test: *P < 0.0001; ^#P = 0.0057; ^‡P < 0.0001; ^§P = 0.0208.