Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: EUSA Pharma (Netherlands) B.V., Beechavenue 54, 1119PW Schiphol-Rijk, Netherlands
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: L01XC
Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells.
Dinutuximab beta has been shown in vitro to bind to neuroblastoma cell lines known to express GD2 and to induce both complement dependent cytoxicity (CDC) and antibody dependent cell-mediated cytoxicity (ADCC). In the presence of human effector cells, including peripheral blood nuclear cells and granulocytes from normal human donors, dinutuximab beta was found to mediate the lysis of human neuroblastoma and melanoma cell lines in a dose-dependent manner. Additionally, in vivo studies demonstrated that dinutuximab beta could suppress liver metastasis in a syngeneic liver metastasis mouse model.
Neurotoxicity associated to dinutuximab beta is likely due to the induction of mechanical allodynia that may be mediated by the reactivity of dinutuximab beta with the GD2 antigen located on the surface of peripheral nerve fibres and myelin.
The efficacy of dinutuximab beta has been evaluated in a randomised controlled trial comparing the administration of dinutuximab beta with or without IL-2 in the first-line treatment of patients with high-risk neuroblastoma and in two single-arm studies in the relapsed/refractory setting.
In a compassionate use programme (study 1), 54 patients received 10 mg/m²/day dinutuximab beta given by continuous 10-day intravenous infusion in a 5-week treatment course, concurrently with subcutaneous IL-2 (6×106 IU/m²/day given on days 1-5 and 8-12 of each course) and followed by oral 13-cis-RA treatment (160 mg/m²/day for 14 days per course). The same treatment regimen was used in a Phase II study (study 2), which enrolled 44 patients.
Overall, these 98 patients had primary refractory neuroblastoma (40) or relapsed neuroblastoma (49) with an additional 9 patients enrolled after first-line therapy. These were 61 boys and 37 girls, aged 1 to 26 years (median 5 years). Most had an initial diagnosis of INSS stage 4 disease without MYCN amplification (16% of the subjects had MYCN amplified tumours and in 14% this information was missing). Most patients with relapsed disease were enrolled after their first relapse and the median time from diagnosis to first relapse was about 14 months. Treatment of disease before immunotherapy included intensive chemotherapy regimen followed by autologous stem cell transplantation (ASCT), radiotherapy, and surgery. At baseline, 72 patients had measurable disease and 26 patients had no detectable disease.
Survival rates (event-free survival, overall survival) are presented by type of disease in Table 1. The overall response rate (complete response plus partial response) in patients with evidence of disease at baseline was 36% (95% confidence interval [25; 48]) and was more favourable in patients with refractory disease (41% [23; 57]) than in patients with relapsed disease (29% [15; 46]).
Table 1. Event-free survival (EFS) and overall survival (OS) rates in relapsed and refractory patients:
| Study 1 N=29 | Study 2 N=19 | Study 1 N=15 | Study 2 N=25 | ||
|---|---|---|---|---|---|
| Relapsed patients | Refractory patients | ||||
| EFS | 1 year | 45% | 42% | 58% | 60% |
| 2 years | 31% | 37% | 29% | 56% | |
| OS | 1 year | 90% | 74% | 93% | 100% |
| 2 years | 69% | 42% | 70% | 78% | |
In study 3, patients with high-risk neuroblastoma were enrolled after they had received induction chemotherapy and achieved at least a partial response, then myeloablative therapy and stem cell transplantation. Patients with progressive disease were excluded. Dinutuximab beta was administered at a dose of 20 mg/m²/day on 5 consecutive days, given by 8-hour intravenous infusion in a 5-week treatment course, and was combined with 13-cis-RA and with or without additional subcutaneous IL-2 at the same posologies as in the previous studies.
A total of 370 patients were randomised and received treatment. These included 64% male and 36% female patients with a median age of 3 years (0.6 to 20); 89% had a tumour INSS stage 4 and MYCN amplification was reported in 44% of the cases. The primary efficacy endpoint was 3-year EFS and secondary endpoint was OS. EFS and OS rates are presented in Tables 2 and 3 according to the evidence of disease at baseline.
For patients without evidence of disease at baseline, addition of IL-2 did not improve EFS and OS.
Table 2. Event-free survival (EFS) and overall survival (OS) rates [95% confidence interval] in patients without evidence of disease at baseline (complete response to initial treatment):
| Efficacy | without IL-2 N=104 | with IL-2 N=107 | ||||
|---|---|---|---|---|---|---|
| 1 year | 2 year | 3 year | 1 year | 2 year | 3 year | |
| EFS | 77% [67; 84] | 67% [57; 75] | 62% [51; 71] | 73% [63; 80] | 70% [60; 77] | 66% [56; 75] |
| OS | 89% [81; 94] | 78% [68; 85] | 71% [60; 80] | 89% [81; 93] | 78% [68; 85] | 72% [61; 80] |
Table 3. Event-free survival (EFS) and overall survival (OS) rates [95% confidence interval] in patients with evidence of disease at baseline (no complete response to initial treatment):
| Efficacy | without IL-2 N=73 | with IL-2 N=76 | ||||
|---|---|---|---|---|---|---|
| 1 year | 2 year | 3 year | 1 year | 2 year | 3 year | |
| EFS | 67% [55; 76] | 58% [45; 69] | 46% [33; 58] | 72% [60; 81] | 62% [49; 72] | 54% [41; 65] |
| OS | 83% [72; 90] | 73% [61; 82] | 54% [40; 66] | 86% [75; 92] | 71% [58; 80] | 63% [50; 74] |
The development of anti-drug antibodies is a class effect of monoclonal chimeric antibodies. Overall, measurable ADA titres were detected in 65 (62%) of the 105 patients examined.
Given the limitation of the bioanalytical methods, data are currently insufficient to properly evaluate the impact of the formation of anti-drug antibodies on pharmacokinetic and pharmacodynamic parameters, as well as on the efficacy and safety of dinutuximab beta.
The European Medicines Agency has deferred the obligation to submit the results of studies with Qarziba in one or more subsets of the paediatric population in neuroblastoma (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’.
This means that for ethical reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
Calculations of pharmacokinetic parameters for dinutuximab beta are based upon measurements using non-validated bioanalytical methods. This has to be taken into consideration when interpreting PK parameters (Cmax, exposure, half-life) listed below.
The pharmacokinetics of dinutuximab beta, based on 10-day continuous intravenous infusion of 10 mg/m²/day (equal to a total dose of 100 mg/m²/course) were evaluated in studies 1 and 2. Mean plasma Cmax levels (around 12 micrograms/mL) were reached on the last day of infusion. Mean plasma Cmax levels, observed during 8-hour infusions (20 mg/m²/day on five consecutive days), were determined in another study (n=15). The observed Cmax levels were slightly higher (16.5 micrograms/mL) and were reached on the fifth infusion.
Dinutuximab beta is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzmes. Classical biotransformation studies have not been performed.
The half-life observed in studies 1 and 2 was in the range of 190 hours, i.e. 8 days.
A population pharmacokinetic modelling approach was used to investigate the influence of covariates. The population pharmacokinetic model included allometric scaling (reference weight of 18.1 kg) on clearance and volume of distribution with exponents of 0.75 and 1, respectively.
The exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion) is predicted to be similar in subjects with ages less than or equal to 12 years and decreases slightly for older, heavier subjects. Effects of gender and age were not found to influence the pharmacokinetics of dinutuximab beta but data in children less than 2 years of age are very limited and insufficient to support dosing.
An effect of ADA formation on the volume of distribution was found (increase of 37% in volume). Therefore, ADA formation would be predicted to have a slight impact (less than 10% decrease) on exposure within 24 hours after administration, under non-steady state conditions. After reaching steady state, no difference in exposure is predicted, with and without ADA formation.
Markers for renal (eGFR) and hepatic (bilirubin) function did not show a relationship with exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion).
Dinutuximab beta has been administered to male and female juvenile Guinea pigs, as well as male and female young cynomolgus monkeys, as repeat-dose regimens that exceeded the recommended clinical dose. Findings of note included changes (decrease) in thymus weight as well as bone marrow changes (atrophy affecting myeloid and erythroid precursor cell lines). The bone marrow changes were slight to severe and recovered after cessation of dosing. No effects on cardiovascular functions (ECG, blood pressure) were observed in monkeys.
No non-clinical studies to evaluate the potential of dinutuximab beta to cause carcinogenicity, genotoxicity or developmental and reproductive toxicity have been conducted. In the repeat-dose toxicity studies in Guinea pigs and cynomolgus monkeys, no adverse effects of dinutuximab beta were observed on reproductive organs at exposure levels above clinical levels.
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