BLINCYTO Powder for concentrate solution Ref.[6566] Active ingredients: Blinatumomab

Source: European Medicines Agency (EU)  Revision Year: 2019  Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, other Antineoplastic agents
ATC code: L01XC19

Mechanism of action

Blinatumomab is a bispecific T-cell engager antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on T-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal in nature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing proteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.

Pharmacodynamic effects

Consistent immune-pharmacodynamic responses were observed in patients studied. During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterised by T-cell activation and initial redistribution, rapid peripheral B-cell depletion, and transient cytokine elevation.

Peripheral T-cell redistribution (i.e. T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of blinatumomab infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients.

Peripheral B-cell counts decreased rapidly to an undetectable level during treatment at doses ≥5 mcg/m²/day or ≥9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week treatment-free period between treatment cycles. Incomplete depletion of B-cells occurred at doses of 0.5 mcg/m²/day and 1.5 mcg/m²/day and in a few non-responders at higher doses.

Peripheral lymphocytes were not measured in paediatric subjects.

Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-a and IFN-c were measured and, IL-6, IL-10 and IFN-c were most elevated. Transient elevation of cytokines was observed in the first two days following start of blinatumomab infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.

Clinical efficacy and safety

Philadelphia chromosome negative relapsed or refractory B-precursor ALL

A total of 456 patients aged ≥ 18 years of age with relapsed or refractory B-precursor ALL were exposed to BLINCYTO during the phase II and phase III clinical studies described below.

The safety and efficacy of BLINCYTO compared to standard of care (SOC) chemotherapy were evaluated in a randomised, open-label, multicentre, phase III study. Eligible patients were ≥18 years of age and ECOG status ≤2 with relapsed or refractory B-cell precursor ALL (had >5% blasts in the bone marrow and either relapse at any time after allogeneic HSCT, untreated first relapse with first remission duration <12 months, or refractory to last therapy).

Patients were randomised 2:1 to receive BLINCYTO or 1 of 4 prespecified, investigator-selected, SOC backbone chemotherapy regimens. Randomisation was stratified by age (< 35 years versus ≥35 years of age), prior salvage therapy (yes versus no), and prior allogeneic HSCT (yes versus no) as assessed at the time of consent. The demographics and baseline characteristics were well-balanced between the two arms (see table 1).

Table 1. Demographics and baseline characteristics in phase III study:

CharacteristicBLINCYTO (N=271)SOC chemotherapy (N=134)
Age
Median, years (min, max)37 (18, 80)37 (18, 78)
Mean, years (SD) 40.8 (17.1)41.1 (17.3)
≥65 Years,, n (%)33 (12.2)15 (11.2)
Prior salvage therapy164 (60.5)80 (59.7)
0114 (42.1)65 (48.5)
191 (33.6)43 (32.1)
≥266 (24.3)26 (19.4)
Prior alloHSCT94 (34.7)46 (34.3)
ECOG status – n (%)
096 (35.4)52 (38.8)
1134 (49.4)61 (45.5)
241 (15.1)20 (14.9)
Refractory status – n (%)
Primary refractory46 (17.0)27 (20.1)
Refractory to salvage therapy87 (32.1)34 (25.4)
Maximum of central/local bone marrow blasts – n (%)
≥50%201 (74.2)104 (77.6)

AlloHSCT = allogeneic haematopoietic stem cell transplantation
SOC = standard of care

BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in case of adverse events. Of the 267 patients who received BLINCYTO, the mean number of completed treatment cycles was 2.0; of the 109 patients who received SOC chemotherapy, the mean number of treatment cycles was 1.3.

The primary endpoint was overall survival (OS). The median OS was 4.0 months (95% CI: 2.9, 5.3) in the SOC chemotherapy arm compared with 7.7 months (95% CI: 5.6, 9.6) in the BLINCYTO arm. The hazard ratio (95% CI) was 0.71 (0.55, 0.93) between treatment arms favouring BLINCYTO, indicated a 29% reduction in hazard rate in the BLINCYTO arm (p-value = 0.012 (stratified log-rank test)), see figure 1. Consistency in OS results was shown in subgroups by stratification factors.

Consistent results were observed after censoring at the time of HSCT; median OS, censored at the time of HSCT, was 6.9 months (95% CI: 5.3, 8.8) in the BLINCYTO group and 3.9 months (95% CI: 2.8, 4.9) in the SOC group (HR, 0.66; 95% CI: 0.50, 0.88; p value = 0.004). The mortality rate following alloHSCT among all responders who did not receive anti-leukemic therapy was 10/38 (26.3%; 95% CI: 13.4, 43.1) in the BLINCYTO group and 3/12 (25%; 95% CI: 5.5, 57.2) in the SOC group; such mortality rate at 100 days post alloHSCT was 4/38 (12.4%; 95% CI: 4.8%, 29.9%) in the BLINCYTO group and 0/12 (0%; 95% CI: not estimable) in the SOC group. Efficacy results from other key endpoints in the study are summarised in table 2.

Figure 1. Kaplan-Meier curve of overall survival:

Table 2. Efficacy results in patients ≥18 years of age with Philadelphia chromosome negative relapsed or refractory B-cell precursor ALL:

 BLINCYTO (N=271) SOC chemotherapy (N=134)
Complete remission (CR)
CRa/CRh*b/CRic, n (%) [95% CI] 119 (43.9) (37.9, 50.0) 33 (24.6) (17.6, 32.8)
Treatment difference [95% CI] 19.3 (9.9, 28.7)
p-value p<0,001
CR, n (%) [95% CI] 91 (33.6) (28.0, 39.5) 21 (15.7) (10.0, 23.0)
[95% CI] 17.9 (9.6 – 26.2)
p-value p<0.001
Event-free survivald
6-month estimate, % [95% CI] 30.7 (25.0, 36.5) 12.5 (7.2, 19.2)
18-months estimate, % [95% CI] 9.5 (5.1, 15.6) 7.9 (3.7, 14.2)
HR [95% CI] 0.55 (0.43, 0.71)
Duration of haematological response – Median time to event συμbάμaτος [95% CI]
CR 8.3 (5.7, 10.7) 7.8 (2.2, 19.0)
CR/CRh*/CRi 7.3 (5.8, 9.9) 4.6 (1.8, 19.0)
MRDe response for CR/CRh*/CRi
MRD evaluable patients () [95 CI]f 74/97 (76.3) (66.6, 84.3) 16/33 (48.5) (30.8, 66.5)
Duration of MRD response -
v [95% CI] 4.5 μήνες (3.6, 9.0) 3.8 μήνες (1.9, 19.0)
Postbaseline alloHSCT – n (%)
Overall subjects 65 (24) 32 (23.9)
Hematological responders (CR/CRh*/CRi) 50 (42.0) 18 (54.5)
Time to alloHSCT among all transplanted patients
Median time to event (Interquartile range) 3.7 μήνες (3.0, 5.3) (N=65) 3.1 μήνες (2.6, 4.3) (N=32)
Time to alloHSCT among CR/CRh*/CRi responders
Median time to event [95% CI] (KM estimate) 11.3 μήνες (5.2, NE) (N=119) 3.6 μήνες (.,3, 7.2) (N=33)
100 day mortality after alloHSCT
n/n (%), [95% CI] 4/38, 12.4% (4.8, 29.9) 0/12, 0.0% (0.0, NE)

a CR was defined as ≤5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microlitre and absolute neutrophil counts [ANC] >1,000/microlitre).
b CRh* (complete remission with partial haematologic recovery) was defined as ≤5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microlitre and ANC >500/microlitre).
c CRi (complete remission with incomplete haematologic recovery) was defined as ≤5% blasts in the bone marrow, no evidence of disease, and incomplete recovery of peripheral blood counts (platelets >100,000/microlitre or ANC >1,000/microlitre).
d EFS time was calculated from the time of randomisation until the date of disease assessment indicating a relapse after achieving a CR/CRh*/CRi or death, whichever is earlier. Subjects who fail to achieve a CR/CRh*/CRi within 12 weeks of treatment initiation are considered treatment failures and assigned an EFS duration of 1 day.
e MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry <1 × 10-4.
f Patients who achieved CR/CRh*/CRi and had an evaluable post baseline MRD assessment.

Health related quality of life

In this open-label study, Health related quality of life (HRQoL) reported by patients were measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30). In a post-hoc sensitivity analysis, compared to SOC, BLINCYTO consistently delayed the time to clinically meaningful deterioration of HRQoL (≥10-point worsening from baseline) for global health status [median BLINCYTO versus SOC: 8.1 months versus 1.0 month; HR = 0.60 (95% CI = 0.42, 0.85)], functional scales, symptom scales and individual items. Because the health-related quality of life results are based on a post-hoc sensitivity analysis, the results should be interpreted with caution.

BLINCYTO was also evaluated in an open-label, multicentre, single-arm phase II study of 189 patients. Eligible patients were ≥ 18 years of age with Philadelphia chromosome negative relapsed or refractory B-precursor ALL (relapsed with first remission duration of ≤12 months in first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic HSCT, and had ≥ 10% blasts in bone marrow).

Premedication, BLINCYTO dose per treatment cycle and route of administration were identical to those in the phase III study. Patients were premedicated with a mandatory cerebrospinal fluid prophylaxis consisting of an intrathecal regimen according to institutional or national guidelines within 1 week prior to start of BLINCYTO treatment. BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in the case of adverse events. The treated population included 189 patients who received at least 1 infusion of BLINCYTO; the mean number of cycles per patient was 1.6. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years (range: 18 to 79 years, including 25 patients ≥65 years of age), 64 of 189 (33.9%) had undergone HSCT prior to receiving BLINCYTO and 32 of 189 (16.9%) had received more than 2 prior salvage therapies.

The primary endpoint was the complete remission/complete remission with partial haematological recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eighty-one of 189 (42.9%) patients achieved CR/CRh* within the first 2 treatment cycles with the majority of responses (64 of 81) occurring within 1 cycle of treatment. In the elderly population (≥65 years of age) 11 of 25 patients (44.0%) achieved CR/CRh* within the first 2 treatment cycles (see section 4.8 for safety in elderly). Four patients achieved CR during consolidation cycles, resulting in a cumulative CR rate of 35.4% (67/189; 95% CI: 28.6% - 42.7%). Thirty-two of 189 (17%) patients underwent allogeneic HSCT in CR/CRh* induced with BLINCYTO (see table 3).

Table 3. Efficacy results in patients ≥18 years of age with Philadelphia chromosome negative relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL):

 n (%) n=18995% CI
Complete remission (CR)1/Complete remission with partial haematological recovery (CRh*)281 (42.9%)[35.7% – 50.2%]
CR63 (33.3%)[26.7% – 40.5%]
CRh* 18 (9.5%)[5.7% – 14.6%]
Blast free hypoplastic or aplastic bone marrow317 (9%)[5.3% – 14.0%]
Partial remission45 (2.6%)[0.9% - 6.1%]
Relapse5-free survival (RFS) for CR/CRh*5.9 months[4.8 to 8.3 months]
Overall survival6.1 months[4.2 to 7.5 months]

In a prespecified exploratory analysis, 60 of 73 MRD evaluable patients with CR/CRh* (82.2%) also had a MRD response (defined as MRD by PCR <1 × 10-4).

Patients with prior allogeneic HSCT had similar response rates to those without prior HSCT, older patients had similar response rates to younger patients, and no substantial difference was observed in remission rates based on the number of lines of prior salvage treatment.

In patients with non-CNS/non-testes extramedullary disease (defined as at least 1 lesion ≥1.5 cm) at screening (N=8/189) clinical response rates (25% [95% CI: 3.2-65.1] were lower compared with patients with no evidence of extramedullary disease (N=181, 43.6% [95% CI: 36.3 – 51.2]) (see figure 2).

Patients with the highest tumour burden as measured by the percentage of bone marrow blast cells at baseline (≥90%) still had a clinically meaningful response with a CR/CRh* rate of 21.6% (CI 12.9 – 32.7) (see figure 2). Patients with low tumour burden (<50%) responded best to BLINCYTO treatment with CR/CRh* rate of 72.9% (CI 59.7 – 83.6).

Figure 2. Forest plot of CR/CRh* rate during the first two cycles for study MT103-211 (primary analysis set):

There is limited data in patients with late first relapse of B-precursor ALL defined as a relapse occurring more than 12 months after first remission or more than 12 months after HSCT in the first remission. In clinical phase II studies, 88.9% (8/9) of patients with late first relapse as defined in the individual studies achieved CR/CRh* within the first 2 treatment cycles with 62.5% (6/9) achieving MRD response and 37.5% (3/9) undergoing allogeneic HSCT after treatment with BLINCYTO. The median overall survival (OS) was 17.7 months (CI 3.1 – not estimable).

In the randomised, open-label, multicentre, phase III study, 70% (7/10) of post-transplant patients in late first relapse treated with BLINCYTO compared to 20% (1/5) treated with SOC chemotherapy achieved CR/CRh* within the first 2 treatment cycles. Fifty percent (5/10) compared to 0% (0/5) achieved MRD response and 20% (2/10) compared to 40% (2/5) underwent allogeneic HSCT after treatment. The median OS was 15.6 months (CI 5.5 – not estimable) for the BLINCYTO group and 5.3 months (CI 1.1 – not estimable) for the SOC chemotherapy group.

MRD positive B-precursor ALL

The safety and efficacy of BLINCYTO in adult patients with MRD positive B-precursor ALL were evaluated in an open-label, multicentre, single-arm study. Eligible patients were ≥18 years of age with no prior HSCT, had received at least 3 blocks of standard ALL induction therapy, were in complete haematologic remission (defined as <5% blasts in bone marrow, absolute neutrophil count ≥1,000/microlitres, platelets ≥ 50,000/microlitres, and haemoglobin level ≥9 g/dL) and had molecular failure or molecular relapse (defined as MRD ≥10-3), see table 4. MRD status at screening was determined from bone marrow aspirations using flow cytometry or polymerase chain reaction (PCR) at a minimum sensitivity of 10-4 based on local site evaluations. A central laboratory subsequently confirmed MRD levels by PCR. Final interpretation of MRD results followed EuroMRD Consortium guidelines.

Table 4. Demographics and baseline characteristics in MRD study:

CharacteristicBLINCYTO (N=116)
Age
Median, years (min, max) 45 (18, 76)
Mean, years (SD)44.6 (16.4)
≥65 years,, n (%)15 (12.9)
Males,, n (%)68 (58.6)
Race, n (%)
Asian1 (0.9)
Other (mixed)1 (0.9)
White102 (87.9)
Unknown12 (10.3)
Relapse history n (%)
Patients in 1st CR75 (64.7)
Patients in 2nd CR39 (33.6)
Patients in 3rd CR2 (1.7)
Επίπεδο της MRD κaτά την ένaρξη της μελέτης* n (%)
≥10-1 and <19 (7.8)
≥10-2 and <10-145 (38.8)
≥10-3 and <10-252 (44.8)
<10-33 (2,6)
Below lower limit of quantification5 (4.3)
Unknown2 (1.7)

* Centrally assessed in an assay with minimum sensitivity of 10-4

BLINCYTO was administered as a continuous intravenous infusion. Patients received BLINCYTO at a constant dose of 15 mcg/m²/day (equivalent to the recommended dosage of 28 mcg/day) for all treatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case of adverse events. The treated population included 116 patients who received at least one infusion of BLINCYTO; the mean number of completed treatment cycles was 1.8 (range: 1 to 4).

The primary endpoint was the proportion of patients who achieved a complete MRD response within one cycle of BLINCYTO treatment. Eighty-eight out of 113 (77.9%) evaluable patients achieved a complete MRD response after one cycle of treatment; see table 5. Two subjects achieved a complete MRD response with 1 additional cycle of BLINCYTO. MRD response rates by age and MRD level at baseline subgroups were consistent with the results in the overall population. RFS in patients with Philadelphia chromosome negative B-precursor ALL at 18 months censored at HSCT or post-BLINCYTO chemotherapy was 54% (33%, 70%). RFS at 18 months not censored at HSCT or post-BLINCYTO chemotherapy was 53% (44%, 62%).

Table 5. Efficacy results in patients ≥18 years of age with MRD positive B-precursor ALL:

Complete MRD responsea, n/n (%), [95% CI]88/113b (77.9) [69.1, 85.1]
≥65 years old12/15 (80.0) [51.9-95.7]
Patients in 1st CR60/73 (82.2) [71.5-90.2]
Patients in 2nd CR27/38 (71.1) [54.1-84.6]
Patients in 3rd CR½ (50.0) [1.3-98.7]
Duration of complete MRD response [95% CI]17.3 months [12.6, 23.3]

a Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 10-4
b One hundred thirteen patients (97.4%; 113/116) were included in the primary endpoint full analysis set

Paediatric population

The safety and efficacy of BLINCYTO were evaluated in an open-label, multicentre, single-arm study in 93 paediatric patients with relapsed or refractory B-precursor ALL (second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments, and also with >25% blasts in bone marrow). This was a two-part study, a dose-finding part to determine the appropriate dosing regimen, followed by a single-arm efficacy part using this regimen.

BLINCYTO was administered as a continuous intravenous infusion. In the dose-finding part of the study, doses of up to 30 mcg/m²/day were evaluated. The recommended dose for the PK expansion and efficacy parts of the study was determined to be 5 mcg/m²/day on days 1-7 and 15 mcg/m²/day on days 8-28 for cycle 1, and 15 mcg/m²/day on days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO.

The treated population (in the dose-finding, PK expansion, and efficacy parts) included 70 patients who received at least 1 infusion of BLINCYTO at the recommended dose; the mean number of treatment cycles was 1.5. Among treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7%) had refractory disease. Most patients had a high tumour burden (≥ 50% leukaemic blasts in bone marrow) at baseline with a median of 75.5% bone marrow blasts.

Twenty out of 70 (28.6%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 20 (85%) occurring within cycle 1 of treatment. Four patients achieved M1 bone marrow but did not meet the peripheral blood count recovery criteria for CR or CRh*. Eleven of the 20 patients (55%) who achieved CR/CRh* received an allogeneic HSCT. The CR/CRh* for patients less than 2 years of age was 40% (4/10), for patients 2 to 6 years was 30.0% (6/20); and for patients aged 7 to 17 years was 25% (10/40). 3 patients <1 year of age refractory to prior treatment and without prior alloHSCT received one cycle of Blincyto at a dose of 5-15 μg/m²/day. None of the 3 subjects <1 year old achieved a CR/CRh*, 1 patient had progressive disease (OS 2.3 months) and 2 were non-responders (OS 1.1 months and 8.7 months, respectively). The type of adverse events observed in infants were similar to those observed in the overall paediatric population. See table 6 for the efficacy results.

Table 6. Efficacy results in patients <18 years of age with relapsed or refractory B-cell precursor ALL:

 N=70
CRa/CRh*b, n (%) [95% CI]20 (28.6%) [18.4% – 40.6%]
CR, n (%) [95% CI]11 (15.7%) [8.1% – 26.4%]
CRh*, n (%) [95% CI]9 (12.9%) [6.1% – 23.0%]
Complete MRD response for CR/CRh*c , n1/n2d () [95 CI]11/20 (55.0%) [31.5 – 76.9]
CR, n1/n2d () [95 CI]6/11 (54.5%) [23.4 – 83.3]
CRh*, n1/n2d () [95 CI]5/9 (55.6%) [21.2 – 86.3]
Median relapsee-free survival (RFS)e for CR/CRh* [95% CI]6.8 months] [2.2 to 12.0 months]]
Median overall survival [95% CI]7.5 months] [4.0 έως 11.8 months]]
100-day mortality after alloHSCTf 
n/n (%), [95% CI]1/6 (16,7%) [2.5% – 72.7%]

a CR was defined as M1 marrow (≤5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary disease, and full recovery of peripheral blood counts (platelets >100,000/microlitre and absolute neutrophil counts [ANC] >1,000/microlitre) and no relapse within 28 days.
b CRh*was defined as M1 marrow (≤5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary disease, and partial recovery of peripheral blood counts (platelets >50,000/microlitre and ANC >500/microlitre) and no relapse within 28 days.
c Complete MRD response No detectable signal for leukemic cells either by PCR or flow cytometry.
d n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. One CR/CRh*responder with missing MRD data was considered as a MRD-nonresponder.
e Relapse was defined as haematological relapse (blasts in bone marrow greater than 25% following CR) or an extramedullary relapse.
f Only patients with HSCT in CR/CRh* remission (with no anti-leukemia agents used prior to HSCT) are included.

Pharmacokinetic properties

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m²/day (approximately equivalent to 9-162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed/refractory ALL, the mean (SD) Css was 230 (359) pg/mL and 612 (532) pg/mL, respectively. The pharmacokinetics of blinatumomab in patients with MRD positive B-precursor ALL was similar to patients with relapsed or refractory ALL.

Distribution

The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L with the continuous intravenous infusion of blinatumomab.

Biotransformation

The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination

The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was 2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.

Body surface area, gender and age

A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics on blinatumomab pharmacokinetics. Results suggest that age (7 months to 80 years) and gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.37 to 2.70 m²) influences the pharmacokinetics of blinatumomab. However the influence is negligible in adults and body surface area based dosing is recommended in the paediatric population.

Renal impairment

No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment.

Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal dysfunction and normal renal function. However high inter-patient variability was discerned (CV% up to 95.6%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function, no clinically meaningful impact of renal function on clinical outcomes is expected.

Hepatic impairment

No formal pharmacokinetic studies of blinatumomab have been conducted in patients with hepatic impairment. Baseline ALT and AST levels were used to assess the effect of hepatic impairment on the clearance of blinatumomab. Population pharmacokinetic analysis suggested that there was no association between ALT or AST levels and the clearance of blinatumomab.

Paediatric population

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m²/day in paediatric patients. At the recommended doses, the mean (SD) steady state concentration (Css) values were 162 (179) and 533 (392) pg/mL at 5 and 15 mcg/m 2 /day doses, respectively. The estimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were 3.91 (3.36) L/m², 1.88 (1.90) L/hr/m 2 and 2.19 (1.53) hours, respectively.

Preclinical safety data

Repeat-dose toxicity studies conducted with blinatumomab and the murine surrogate revealed the expected pharmacologic effects (including release of cytokines, decreases in leukocyte counts, depletion of B-cells, decreases in T-cells, decreased cellularity in lymphoid tissues). These changes reversed after cessation of treatment.

Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or teratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice but haematological effects were not assessed in foetuses. No studies have been conducted to evaluate treatment-related effects on fertility. There were no effects on male or female reproductive organs in toxicity studies with the murine surrogate.

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.