Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FX06 
Mechanism of action
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.

Pharmacodynamic effects
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.

Clinical efficacy
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.
Relapsed and refractory patients
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             Study 2             Study 1            Study 2
N=29                N=19                N=15               N=25
Relapsed patients                      Refractory patients
1 year                 45%                 42%               58%                 60% EFS
2 years                31%                 37%               29%                 56%
1 year                 90%                 74%               93%                100% OS
2 years                69%                 42%               70%                 78%

First-line patients who received autologous stem cell transplantation 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) without IL-2                                  with IL-2
N=104                                        N=107
Efficacy
1 year        2 year         3 year        1 year           2 year     3 year 
77%           67%            62%            73%           70%            66% EFS
[67; 84]      [57; 75]       [51; 71]       [63; 80]      [60; 77]       [56; 75] 89%           78%            71%            89%           78%            72% OS
[81; 94]      [68; 85]       [60; 80]       [81; 93]      [68; 85]       [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) without IL-2                                  with IL-2
N=73                                         N=76
Efficacy
1 year       2 year          3 year         1 year           2 year     3 year 67%          58%            46%             72%             62%           54% EFS
[55; 76]     [45; 69]       [33; 58]        [60; 81]        [49; 72]      [41; 65] 83%          73%            54%             86%             71%           63% OS
[72; 90]     [61; 82]       [40; 66]        [75; 92]        [58; 80]      [50; 74] 
Immunogenicity
In 3 clinical studies the appearance of ADA was 57.1% (112/196) in subjects being classed as ADA positive on the basis of having at least one measurable ADA response over the course of treatment.
Neutralising antibody activity was observed in 63.5% (54/85) of the ADA-positive subjects in 2 studies. There was an overall trend of lower dinutuximab beta concentration with increasing ADA titre, (low, medium and high). In 16.8% of subjects (33/196) with a high ADA titre, the reduction in dinutuximab beta concentration impacted on pharmacodynamic responses. Based on the available data it is not possible to determine a quantitative association between ADA titre and impact on efficacy.

No clear associations between ADA response and relevant Selected Safety Events were observed.

From an efficacy and safety perspective, there is no rationale for adjusting or stopping treatment on the basis of measured ADA responses.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Dinutuximab beta has been investigated using short-term infusions (STI - five days of eight- hour infusions at 20 mg/m2/day) and long-term infusions (LTI - ten days of continuous infusion at 100 mg/m2).

Absorption
Dinutuximab beta is administered as an intravenous infusion. The maximum concentration (mean (± SD)) at the end of the long-term infusion was 11.2 (± 3.3) mg/L. Other routes of administration have not been investigated.

Distribution
The population mean (±SD) estimate for the central volume of distribution was 2.04 (± 1.05) L and for the peripheral volume of distribution 2.65 (±1.01) L.
Biotransformation
The metabolism of dinutuximab beta has not been investigated. As a protein, dinutuximab beta is expected to be metabolised to small peptides and individual amino acids by ubiquitous proteolytic enzymes.

Elimination
The clearance after the LTI was 0.72 (± 0.24) L/d/m2. The accumulation ratio for Cmax was 1.13 (± 0.54) after 5 LTI courses (mean (±SD)). The apparent terminal elimination t1/2 was 8.7 (± 2.6) days (mean (± SD)). The clearance of dinutuximab beta increased in the presence of high anti- drug antibody titres regardless of neutralising activity. (See Immunogenicity in Section 5.1).

Linearity/non-linearity
Variations in dose of the first infusion in Study 2 revealed a dose-proportional increase in exposure (AUC∞) up to the recommended dose of 100 mg/m2 per course for 10 days.

Specific populations
The age of patients ranged from 1 to 27 years (median 6 years). Body weight ranged from 9 to 75 kg (median 18.5 kg) and body-surface area ranged from 0.44 to 1.94 m2 (median 0.75 m2). A two- compartment population-PK model with first-order elimination from the central compartment was developed using the data from 224 patients in four studies (STI 30 patients, LTI 194 patients).
Volume and clearance parameters increased across the ranges with increasing body size. Body weight and ADA titre were covariates for clearance while body weight, age and IL-2 co- administration were covariates for volume of distribution.

Age
The population pharmacokinetic analyses showed comparable exposure to dinutuximab beta in patients of all ages studied when dosed at 100 mg/m2.

Gender
The population pharmacokinetic analysis with 89 female (40%) and 135 male (60%) patients showed no clinically meaningful effect of gender on dinutuximab beta pharmacokinetics.

Race
Since the PK analysis population was predominantly Caucasian (92.9%) race was not formally examined as a potential PK covariate.

Weight
Dosing on the basis of body surface area provides consistent exposure across populations.

Renal impairment
No formal studies have been conducted in patients with renal impairment. Renal function was not a significant covariate in population pharmacokinetic analyses that included patients with normal renal function and mild renal impairment.

Hepatic impairment
No formal studies have been conducted in patients with hepatic impairment. Subjects with ALT >3x ULN had comparable pharmacokinetics as subjects with ALT≤3xULN.