It is an open-label dose-escalating study in sequential cohorts to assess safety and pharmacokinetics of GNR-084.
Acute lymphoblastic leukemias (ALL) are a heterogeneous group of malignant clonal diseases of the blood system originating from precursor cells of hematopoiesis, predominantly of lymphoid differentiation. More than 7,200 new cases of ALL are diagnosed annually in the European Union (EU), with approximately 40% (approximately 3,000 cases) occurring in adults The main reason for the failure of treatment of acute B-cell lymphoblastic leukemias (B-ALL) is the primary refractoriness to chemical exposure and relapses of the disease, which actually occur in 40-50% of adult patients with ALL. The prognosis in these cases is regarded as extremely unfavorable. Escalation of the chemotherapeutic approach is associated with the development of severe toxic infectious and hemorrhagic complications. The active substance of the preparation GNR-084 is a bispecific antibody to CD19 / CD3 in the BiMS format (bispecific IgG-like molecules).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
14
0.01 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
0.1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia)
Moscow, Russia
Almazov National Medical Research Centre
Saint Petersburg, Russia
Pavlov First Saint Petersburg State Medical University
Saint Petersburg, Russia
GNR-084 safety and tolerability.
The GNR-084 safety and tolerability will be assessed based on an analysis of the frequency of adverse events (AEs) over the period of treatment and observation of patients
Time frame: Week 10
The frequency of specific toxicity events
Time frame: Week 104
GNR-084 Peak Plasma Concentration (Cmax)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
GNR-084 area under the plasma concentration versus time curve (AUC)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
GNR-84 half-life (T1/2)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
GNR-084 elimination rate constant (Kel)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
GNR-084 mean retention time (MRT)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
GNR-084 overall clearance (Cl)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
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4 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
10 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
20 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
GNR-084 kinetic volume of distribution (Vz)
Time frame: First infusion: 5 minutes before administration, immediately after infusion, 30 minutes, 1, 3, 6, 12, 18, 24, 48, 72, 96 hours after infusion.
Peripheral blood B-lymphocyte depletion (CD19, CD20).
Time frame: First infusion: 5 minutes before administration, 30 minutes, 1, 24, 48, 96 and 144 hours after infusion. Other infusions: 5 minutes before administration and 1 hour after infusion
CD45+ peripheral cell count
Time frame: First infusion: 5 minutes before administration, 30 minutes, 1, 24, 48, 96 and 144 hours after infusion. Other infusions: 5 minutes before administration and 1 hour after infusion
Peripheral T-lymphocytes count (CD3, CD4, CD8)
Time frame: First infusion: 5 minutes before administration, 30 minutes, 1, 24, 48, 96 and 144 hours after infusion. Other infusions: 5 minutes before administration and 1 hour after infusion
Peripheral T-memory cells (CD45RA+, CD28+, CCR7+) count
Time frame: First infusion: 5 minutes before administration, 30 minutes, 1, 24, 48, 96 and 144 hours after infusion. Other infusions: 5 minutes before administration and 1 hour after infusion
Peripheral B-cells/T-cells ratio
Time frame: First infusion: 5 minutes before administration, 30 minutes, 1, 24, 48, 96 and 144 hours after infusion. Other infusions: 5 minutes before administration and 1 hour after infusion
Cytokine dynamics
Time frame: First infusion: 5 minutes before administration, 30 minutes, 1, 24, 48, 96 and 144 hours after infusion. Other infusions: 5 minutes before administration and 1 hour after infusion
Immunogenicity
Time frame: Week 33
Objective response rate (ORR)
Time frame: After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Complete clinical and hematological remission rate (CR)
Time frame: After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Frequency of complete remission with incomplete restoration of blood cellularity (CRi)
Time frame: After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Duration of an objective response (DoR)
Time frame: Week 104
Relapse-free survival (RFS)
Time frame: Week 104
Event-free survival (EFS)
Time frame: Week 104
Overall survival (OS)
Time frame: Week 104
Minimal residual disease (MRD) (-) rate in CR-patient
Time frame: After 5 GNR-084 cycles (each cycle is 28 days)