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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04601584
Recruitment Status : Recruiting
First Posted : October 26, 2020
Last Update Posted : October 26, 2021
Sponsor:
Information provided by (Responsible Party):
AO GENERIUM

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

Condition or disease Intervention/treatment Phase
B-precursor Acute Lymphoblastic Leukemia ALL GNR-084 Biological: GNR-084, 0.01 ng/kg Biological: GNR-084, 0.1 ng/kg Biological: GNR-084, 1 ng/kg Biological: GNR-084, 4 ng/kg Biological: GNR-084, 20 ng/kg Biological: GNR-084, 60 ng/kg Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Sequential dose-increase cohorts in B-ALL patients
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label Multicenter Non-comparative Clinical Trial of Tolerability, Safety, Pharmacokinetics and Pharmacodynamics of GNR-084 in Patients With Refractory or Relapse Acute Lymphoblastic B-cell Precursor Leukemia in Sequential Cohorts With Dose Escalation
Actual Study Start Date : October 15, 2020
Estimated Primary Completion Date : June 25, 2023
Estimated Study Completion Date : June 27, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Safety

Arms and Interventions
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Arm Intervention/treatment
Experimental: GNR-084, 0.01 ng/kg
Anti-CD19 / CD3 antibody
 Biological: GNR-084, 0.01 ng/kg
0.01 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Other Name: Anti-CD19 / CD3 antibody, 0.01 ng/kg
Experimental: GNR-084, 0.1 ng/kg
Anti-CD19 / CD3 antibody
 Biological: GNR-084, 0.1 ng/kg
0.1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Other Name: Anti-CD19 / CD3 antibody, 0.1 ng/kg
Experimental: GNR-084, 1 ng/kg
Anti-CD19 / CD3 antibody
 Biological: GNR-084, 1 ng/kg
1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Other Name: Anti-CD19 / CD3 antibody, 1 ng/kg
Experimental: GNR-084, 4 ng/kg
Anti-CD19 / CD3 antibody
 Biological: GNR-084, 4 ng/kg
4 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Other Name: Anti-CD19 / CD3 antibody, 4 ng/kg
Experimental: GNR-084, 20 ng/kg
Anti-CD19 / CD3 antibody
 Biological: GNR-084, 20 ng/kg
20 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Other Name: Anti-CD19 / CD3 antibody, 20 ng/kg
Experimental: GNR-084, 60 ng/kg
Anti-CD19 / CD3 antibody
 Biological: GNR-084, 60 ng/kg
60 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
Other Name: Anti-CD19 / CD3 antibody, 60 ng/kg


Outcome Measures
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Primary Outcome Measures :
  1. GNR-084 safety and tolerability. [ Time Frame: Week 10 ]
    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


Secondary Outcome Measures :
  1. The frequency of specific toxicity events [ Time Frame: Week 104 ]
  2. 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. ]
  3. 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. ]
  4. 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. ]
  5. 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. ]
  6. 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. ]
  7. 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. ]
  8. 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. ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. Immunogenicity [ Time Frame: Week 33 ]
  16. Objective response rate (ORR) [ Time Frame: After 2 and 5 GNR-084 cycles (each cycle is 28 days) ]
  17. Complete clinical and hematological remission rate (CR) [ Time Frame: After 2 and 5 GNR-084 cycles (each cycle is 28 days) ]
  18. 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) ]
  19. Duration of an objective response (DoR) [ Time Frame: Week 104 ]
  20. Relapse-free survival (RFS) [ Time Frame: Week 104 ]
  21. Event-free survival (EFS) [ Time Frame: Week 104 ]
  22. Overall survival (OS) [ Time Frame: Week 104 ]
  23. Minimal residual disease (MRD) (-) rate in CR-patient [ Time Frame: After 5 GNR-084 cycles (each cycle is 28 days) ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04601584


Contacts
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Contact: Eugene V. Zuev, MD +7 9166419698 evzuev@generium.ru
Contact: Oksana A. Markova, MD +7 9854418959 oamarkova@generium.ru

Locations
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Russian Federation
Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia) Recruiting
Moscow, Russian Federation, 125167
Almazov National Medical Research Centre Recruiting
Saint Petersburg, Russian Federation, 191014
Pavlov First Saint Petersburg State Medical University Recruiting
Saint Petersburg, Russian Federation, 197022
Sponsors and Collaborators
AO GENERIUM
Investigators
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Study Chair: Oksana A. Markova, MD AO GENERIUM
More Information
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Additional Information:

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Responsible Party: AO GENERIUM
ClinicalTrials.gov Identifier: NCT04601584    
Other Study ID Numbers: BIM-HEM-I
#652 eff date 12.11.2019 ( Other Identifier: Clinical trial approval number, Ministry of Health of Russian Federation )
First Posted: October 26, 2020    Key Record Dates
Last Update Posted: October 26, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AO GENERIUM:
Leukemia
GNR-084
ALL
Blood Diseases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
 Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplastic Processes
Pathologic Processes
Antineoplastic Agents
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
 Immunoproliferative Disorders
Immune System Diseases
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs