Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents
ATC code: L01XC34
Moxetumomab pasudotox is a CD22-targeted immunotoxin designed to direct the cytotoxic action of the truncated Pseudomonas exotoxin to cells which express the CD22 receptor. CD22 is a B-lymphocyte restricted transmembrane protein with a similar or higher receptor density in HCL cells relative to normal B cells. Nonclinical data indicate that the anticancer activity of moxetumomab pasudotox is due to the binding of the immunotoxin to CD22-expressing tumour cells, followed by internalisation of the Lumoxiti-CD22 complex and processing to release the active PE38 exotoxin. The exotoxin is translocated to the cytosol where it inactivates elongation factor 2 (EF-2), causing inhibition of protein synthesis leading to apoptotic cell death.
In patients with HCL, treatment with Lumoxiti resulted in a reduction of circulating CD19+ B cells. In Study 1053, circulating CD19+ B cells were reduced by 89% from baseline following the first three infusions of Lumoxiti. This reduction was sustained for at least one month post-treatment.
The efficacy and safety of Lumoxiti were evaluated in Study 1053, a multicentre, single-arm, Phase 3 study in patients with relapsed/refractory HCL. Study 1053 was conducted in patients with histologically confirmed HCL or HCL variant who had received prior treatment with at least 2 systemic therapies, including 1 PNA, with a need for therapy based on at least one of the following criteria: neutrophils <1.0 × 109/L, platelets <100 × 109/L, haemoglobin <10 g/dL or symptomatic splenomegaly.
The study excluded patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks of treatment initiation, patients with history of allogeneic bone marrow transplant, patients with known brain metastases, retinal or choroidal detachment, or uncontrolled illness including uncontrolled infection. Further exclusion criteria were a history of thromboembolism, known congenital hypercoagulable conditions, thrombotic microangiopathy/HUS or clinical evidence of severe disseminated intravascular coagulation.
A total of 80 patients were enrolled; 77 with classic HCL and 3 with HCL variant. The median age was 60 (range 34 to 84) years, 79% were male, and 94% were Caucasian at primary analysis. At baseline, 98% of patients had an ECOG performance status of 0 or 1. The median number of prior treatments was 3 (range 2 to 11); all patients received prior PNA therapy, including 29% in combination with rituximab. The most common other prior treatment regimens were rituximab monotherapy (51%), interferon-alpha (25%), and a BRAF inhibitor (18%). At baseline, 33% (26/80) of patients had low haemoglobin (<10 g/dl), 68% (54/80) of patients had neutropenia (<1.0 × 109 /L), and 84% (67/80) of patients had baseline platelet counts <100 × 109 /L. Almost half (48%) of the patients had enlarged spleens at baseline. During screening, 23.8% of patients had an ongoing infection which was adequately controlled or resolved prior to treatment initiation.
Patients received Lumoxiti 0.04 mg/kg as an intravenous infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles or until documentation of complete response (CR), disease progression, initiation of alternate therapy, or unacceptable toxicity. Approximately 63% of patients completed 6 cycles and 15% of patients completed treatment earlier than 6 cycles with documentation of minimal residual disease (MRD)-negative CR. An independent review committee (IRC) performed efficacy evaluations using blood, bone marrow, and imaging criteria adapted from previous HCL studies and consensus guidelines.
The major efficacy outcome of Study 1053 was durable CR, as confirmed by maintenance of haematologic remission (haemoglobin ≥11.0 g/dL, neutrophils ≥1.5 × 109/L, and platelets ≥100 × 109/L without transfusions or growth factor for at least 4 weeks) more than 180 days after IRC-assessed CR.
At the time of final analysis (cut-off date of 29 April 2019), the median follow-up was 24.6 months (range 1 to 72). The efficacy results from Study 1053 are summarised in Table 5.
Table 5. Efficacy results in patients with HCL in study 1053:
| Final Analysis IRC (N=80) | |
|---|---|
| Durable CR, CR with HR, Duration of HR | |
| Durable CR () [95 CI] | 36 [26, 48] |
| CR with HR ≥360 days, () [95 CI] | 33 [22, 44] |
| Duration of HR from onset of CR, median in months [95% CI] | 63 [36, 63] |
| CR and Time to CR | |
| CRa() [95 CI] | 41 [30, 53] |
| Time to CR, median in months [95% CI] | 6 [5.7, 6.2] |
| Duration of CR, median in months [95% CI] | 63 [36, 63] |
| HR, Duration of HR and Time to HR | |
| HR rate () [95 CI] | 80 [70, 88] |
| Time to HR, median in months [95% CI] | 1 [1.0, 1.2] |
| Duration of HR from onset of HR, median in months [95% CI] | 46 [26, 72] |
| OR, Time to OR, Duration of OR | |
| OR rate () [95 CI] | 75 [64, 84] |
| Time to OR, median in months [95% CI] | 6 [5.7, 5.9] |
| Duration of OR, median in months [95% CI] | 67 [25, 67] |
| Partial response (PR)b (%) | 34 |
| Stable disease (SD)c (%) | 15 |
IRC = Independent Review Committee-Assessed; HR = Haematologic Remission; CI = Confidence Interval; CR = Complete Response; OR = Overall Response.
a CR defined as clearing of the bone marrow of hairy cells by routine Haematoxylin & Eosin stain, radiologic resolution of pre-existing lymphadenopathy and/or organomegaly, and haematologic remission
b PR defined as ≥50% decrease or normalisation (<500/mm³) in peripheral blood lymphocyte count, reduction of pre-existing lymphadenopathy and/or organomegaly, and haematologic remission.
c SD defined as ≥50% decrease of peripheral blood lymphocyte count, reduction of pre-existing lymphadenopathy and/or organomegaly, and haematologic remission or 50% improvement over baseline for haematologic parameters if not meeting haematologic remission criteria.
MRD was evaluated by IRC via immunohistochemistry assessment of bone marrow biopsies. At the time of the final analysis, of the 33 patients who achieved IRC-assessed CR, 82% (27/33) were MRD-negative and 26 of the 29 patients (89.7%) who achieved a durable CR were MRD-negative. The median duration of CR was 12.0 months for MRD-positive patients (n=6) and 62.8 months for MRD-negative patients (n=27).
Pre-specified sub-group analyses of primary and secondary endpoints were performed for the ITT population including age (<65 years, ≥65 years), gender, baseline spleen status (splenectomy, <14 cm, ≥14 cm), number of prior treatments with PNA (1, 2, >2) and HCL histology (classic, variant). The analyses showed that the effect on durable CR rate and CR rate across the majority of sub-groups evaluated were consistent with the results for the ITT population. For subjects ≥65 years, the durable CR rate was 19% (95% CI: 8%, 38%) and the CR rate assessed by IRC was 26% (95% CI: 12%, 47%). Data are limited for the splenectomy and HCL variant subgroups. No CRs were reported; 2 of 4 patients in the splenectomy subgroup and 1 of 3 patients in the HCL variant subgroup achieved a PR.
The European Medicines Agency has waived the obligation to submit the results of studies with Lumoxiti in all subsets of the paediatric population in HCL (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease 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.
The pharmacokinetics (PK) of moxetumomab pasudotox was studied in 68 patients with HCL at a dose of 0.04 mg/kg administered intravenously over 30 minutes on Days 1, 3, and 5 of a 28-day cycle. PK exposure increased after subsequent infusions compared with the first infusion, which is likely related to the depletion of malignant B cells after treatment with moxetumomab pasudotox and subsequent reduction of the CD22 sink. All trough concentration levels were negligible, indicating there was no systemic accumulation of moxetumomab pasudotox.
Based on noncompartmental PK analysis and consistent with restriction to extracellular fluid, the mean Cycle 1 Day 5 volume of distribution was 6.06 L, with an inter individual variability (CV) of 46.3%.
The exact pathway through which moxetumomab pasudotox is metabolised has not been characterised. Like other protein therapeutics, moxetumomab pasudotox is expected to undergo proteolytic degradation into small peptides and amino acids via catabolic pathways.
Based on noncompartmental PK analysis, moxetumomab pasudotox Cycle 1 Day 5 estimated mean (CV%) systemic clearance was 4.8 L/hr (82.3%) and the mean elimination half-life (t1/2) was 2.32 hours (range: 0.17 to 57.4). The elimination half-life following the first dose (Cycle 1 Day 1) could only be estimated in 6 out of 68 patients (mean t1/2=0.98 hours).
The primary elimination pathways of moxetumomab pasudotox are assumed to include CD22- mediated internalisation and proteolysis or catabolism. Renal excretion has not been studied for moxetumomab pasudotox. Data from a similar precursor compound indicate that intact protein is excreted into urine. However, renal excretion is not expected to be a major elimination pathway due to the molecular size.
Age (34 to 84 years), sex, race, mild hepatic impairment (total bilirubin > ULN to 1.5 x ULN or AST > ULN; n=7), or mild renal impairment (creatinine clearance 60-89 mL/min; n=19), had no clinically meaningful effect on the PK of moxetumomab pasudotox, based on an analysis of noncompartmental PK data by covariates. With body weight dosing, a trend of increased exposure was observed with increasing weight. No dose adjustments are recommended for these demographics.
Moxetumomab pasudotox has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN or AST = Any) and moderate or severe renal impairment (creatinine clearance <60 mL/min).
There is a trend of reduced Cmax with increased ADA titre at later treatment cycles (Cycle 3 and beyond); however, these results are not conclusive due to the limitation of the bioanalytical method for moxetumomab pasudotox at high ADA titres.
No studies have been conducted to assess the carcinogenic or genotoxic potential of moxetumomab pasudotox.
Moxetumomab pasudotox was studied in cynomolgus monkeys for 13 weeks. At doses ≥10-times the human recommended dose, minimal to moderate degeneration of heart tissue was observed microscopically without corresponding changes in ECG. At doses of approximately 34-times the human recommended dose, microscopic evidence of gliosis and axonal degeneration was observed in the brain and spinal cord, respectively, along with observations of body tremors.
Animal fertility studies have not been conducted with moxetumomab pasudotox. In a 3-month repeat-dose toxicity study using sexually mature cynomolgus monkeys, no adverse findings on male or female reproductive organs were observed at doses approximately 34-times the human recommended dose.
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