GNR-084 Safety and Pharmacological Characteristics in Refractory or Relapse B-cell Precursor ALL

Dose-escalation Sequention Cohort Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GNR-084 in Patients With Refractory or Relapse Acute Lymphoblastic B-cell Precursor Leukemia.

It is an open-label dose-escalating study in sequential cohorts to assess safety and pharmacokinetics of GNR-084.

Study Overview

• Status: Recruiting
• Conditions: ALL; B-precursor Acute Lymphoblastic Leukemia; GNR-084
• Intervention / Treatment: Biological: Cohort 1, GNR-084; Biological: Cohort 2, GNR-084; Biological: Cohort 3, GNR-084; Biological: Cohort 4, GNR-084; Biological: Cohort 5, GNR-084; Biological: Cohort 6, GNR-084

Detailed Description

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
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Eugene V. Zuev, MD; Phone Number: +7 9166419698; Email: evzuev@generium.ru
• Study Contact Backup: Name: Oksana A. Markova, MD; Phone Number: +7 9854418959; Email: oamarkova@generium.ru

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 125167
    • Recruiting
    • Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia)
  • Saint Petersburg, Russian Federation, 191014
    • Recruiting
    • Almazov National Medical Research Centre
  • Saint Petersburg, Russian Federation, 197022
    • Recruiting
    • Pavlov First Saint Petersburg State Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily signed informed consent form to participate in the study;
2. Men and women between aged 18 to 45 inclusive;
3. Patients with incurable morphologically / immunophenotypically confirmed refractory/ relapse of B-cell precursors CD19-positive acute lymphoblastic leukemia from (Ph "-" or Ph "+").
4. Two or more previous lines of anti-leucosis therapy.
5. 5-50% of bone marrow blast cells at screening;
6. Functional status on the scale of the Eastern Cooperative Oncology Group (ECOG) 0-2 points at the screening;
7. Life expectancy ≥ 60 days;

Exclusion Criteria:

1. Hematopoietic stem cells transplantation within 12 weeks prior to study inclusion;
2. Active and widespread chronic graft versus host (GVHD) reaction (grade II-IV), including taking immunosuppressants for the prevention and treatment of GVHD within 2 weeks prior the GNR-084 infusion;
3. Investigator and / or sponsor has doubts that patient will complete the study due to rapid disease progression;

4. Chemotherapeutic agent using within 14 days prior the first GNR-084 infusion;

   Exceptions:

   • Emergency leukapheresis;
   • Emergency hydroxyurea using due to hyperleukocytosis for ≤ 7 days;
   • Other supportive care, including antibiotics, at Investigator's discretion

5. Biochemical blood test:

   • The level of total bilirubin> 1.5 upper limit of norm;
   • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)> 3 upper limit of norm;
   • Glomerular filtration rate (GFR) level ≤30 (СKD-EPI)
6. Medical history of blinatumomab and other bispecific antibodies using;
7. Persistent toxicity event of 3rd and 4th severity degrees (CTCAE ver 5.0) due to previous treatment;
8. HIV-positive status and / or detection of any hepatitis B and / or hepatitis C blood markers;
9. Severe cardiovascular diseases: uncontrolled arterial hypertension, New York Heart Association (NYHA) functional class III or IV chronic heart failure, unstable angina pectoris, stroke, myocardial infarction, transient ischemic attack, coronary artery bypass grafting and coronary revascularization within last 12 months, or signs of pericardial effusion;

10. Individual sensitivity to:

    • GNR-084 components / excipients;
    • human or humanized investigational drug antibodies;
11. Major surgical interventions, accompanied by hospitalization and anesthesia application within 30 days before the patient is included in the study (biopsy is not a significant surgical intervention);
12. Any other malignant neoplasm presence at the present time or within 5 years prior to inclusion in the study;
13. Known suspected Central Nervous System (CNS) lesion by any genesis now or in medical history, including, but not limited to: neuroleukemia, epilepsy, ischemic or hemorrhagic stroke, severe traumatic brain injury, dementia, Parkinson's disease, organic brain damage, cerebellar disorders, psychosis;
14. Extramedullary lesion of any localization;
15. Other clinical trials participation within 30 days before screening;
16. Mental, physical and other reasons hindering patient to adequately assess their behavior and correctly comply with the conditions of the research protocol;
17. Pregnancy and / or lactation;
18. Male and female patients refusal to use adequate methods of contraception throughout the study;
19. Drug addiction;
20. Alcohol addiction.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GNR-084, dose level 1; Anti-CD19/CD3 antibody	Biological: Cohort 1, GNR-084; 0.01 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles; Other Names: Anti-CD19/CD3 antibody
Experimental: GNR-084, dose level 2; Anti-CD19/CD3 antibody	Biological: Cohort 2, GNR-084; 0.1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles; Other Names: Anti-CD19/CD3 antibody
Experimental: GNR-084, dose level 3; Anti-CD19/CD3 antibody	Biological: Cohort 3, GNR-084; 1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles; Other Names: Anti-CD19/CD3 antibody
Experimental: GNR-084, dose level 4; Anti-CD19/CD3 antibody	Biological: Cohort 4, GNR-084; 4 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles; Other Names: Anti-CD19/CD3 antibody
Experimental: GNR-084, dose level 5; Anti-CD19/CD3 antibody	Biological: Cohort 5, GNR-084; 10 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles; Other Names: Anti-CD19/CD3 antibody
Experimental: GNR-084, dose level 6; Anti-CD19/CD3 antibody	Biological: Cohort 6, GNR-084; 20 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles; Other Names: Anti-CD19/CD3 antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Week 10

Secondary Outcome Measures

Outcome Measure	Time Frame
The frequency of specific toxicity events	Week 104
GNR-084 Peak Plasma Concentration (Cmax)	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)	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)	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)	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)	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)	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 kinetic volume of distribution (Vz)	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).	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	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)	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	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	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	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	Week 33
Objective response rate (ORR)	After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Complete clinical and hematological remission rate (CR)	After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Frequency of complete remission with incomplete restoration of blood cellularity (CRi)	After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Duration of an objective response (DoR)	Week 104
Relapse-free survival (RFS)	Week 104
Event-free survival (EFS)	Week 104
Overall survival (OS)	Week 104
Minimal residual disease (MRD) (-) rate in CR-patient	After 5 GNR-084 cycles (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: AO GENERIUM
• Investigators: Study Chair: Oksana A. Markova, MD, AO GENERIUM

Publications and helpful links

General Publications

• Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.

Helpful Links

• Clinical trial registry, Ministry of Health of Russian Federation

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2020
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: October 13, 2020
• First Submitted That Met QC Criteria: October 19, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Immune System Diseases; Pathologic Processes; Neoplasms; ALL; Leukemia; Antineoplastic Agents; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphatic Diseases; Leukemia, Lymphoid; Neoplasms by Histologic Type; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Blood Diseases; Neoplastic Processes; GNR-084
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins
• Other Study ID Numbers: BIM-HEM-I; #652 eff date 12.11.2019 (Other Identifier: Ministry of Health of Russian Federation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No