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

ALL Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04601584
• Other study ID #: BIM-HEM-I
• Secondary ID: #652 eff date 12
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 15, 2020
• Est. completion date: June 2025

Study information

• Verified date: March 2024
• Source: AO GENERIUM
• Contact: Eugene V. Zuev, MD
• Phone: +7 9166419698
• Email: evzuev[@]generium.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: June 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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 (?KD-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.

Related Conditions & MeSH terms

• ALL
• B-precursor Acute Lymphoblastic Leukemia
• GNR-084
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Biological:
• Cohort 1, GNR-084
0.01 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
• Cohort 2, GNR-084
0.1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
• Cohort 3, GNR-084
1 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
• Cohort 4, GNR-084
4 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
• Cohort 5, GNR-084
10 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles
• Cohort 6, GNR-084
20 ng/kg 6-hours intravenous infusion once a week; 4 doses per cycle, up to 5 cycles

Locations

Country	Name	City	State
Russian Federation	Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia)	Moscow
Russian Federation	Almazov National Medical Research Centre	Saint Petersburg
Russian Federation	Pavlov First Saint Petersburg State Medical University	Saint Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
AO GENERIUM

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	The frequency of specific toxicity events		Week 104
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Immunogenicity		Week 33
Secondary	Objective response rate (ORR)		After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Secondary	Complete clinical and hematological remission rate (CR)		After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Secondary	Frequency of complete remission with incomplete restoration of blood cellularity (CRi)		After 2 and 5 GNR-084 cycles (each cycle is 28 days)
Secondary	Duration of an objective response (DoR)		Week 104
Secondary	Relapse-free survival (RFS)		Week 104
Secondary	Event-free survival (EFS)		Week 104
Secondary	Overall survival (OS)		Week 104
Secondary	Minimal residual disease (MRD) (-) rate in CR-patient		After 5 GNR-084 cycles (each cycle is 28 days)

External Links

•   Clinical trial registry, Ministry of Health of Russian Federation