A Phase 1 Study of GNR-051 in Subjects With Advanced Malignancies

• ClinicalTrials.gov Identifier: NCT04544748
• Recruitment Status: Active, not recruiting
• First Posted: September 10, 2020
• Last Update Posted: February 24, 2023
• Sponsor: AO GENERIUM
• Information provided by (Responsible Party): AO GENERIUM

Study Description

Brief Summary:

It is a Phase 1 Multicenter Open-Label Multi-Cohort Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of GNR-051 in Subjects with Advanced Solid Malignancies.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Melanoma	Biological: GNR-051	Phase 1

Detailed Description:

GNR-051 is a monoclonal antibody, targeting the Programmed Death-1 (PD-1) membrane receptor on T lymphocytes and other cells of the immune system. The anti-PD-1 antibody, preventing the binding of the PD-1 receptor with the ligands PD-L1 and PD-L2, reactivates the pool of tumor-specific cytotoxic T-lymphocytes in the tumor microenvironment and, thus, reactivates the antitumor immunity. GNR-051 is able to block the signaling molecule PD-1, which suppresses the antitumor immune response, for the treatment of cancer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Open-Label Multi-Cohort Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of GNR-051 (GENERIUM JSC, Russia) in Subjects With Solid Advanced Malignancies
• Actual Study Start Date: July 22, 2020
• Actual Primary Completion Date: November 7, 2022
• Estimated Study Completion Date: June 2024

Arms and Interventions

Arm	Intervention/treatment
Cohort 1; GNR-051 (0.1 mg/kg)	Biological: GNR-051; Anti-PD1 monoclonal antibody
Cohort 2; GNR-051 (0.3 mg/kg)	Biological: GNR-051; Anti-PD1 monoclonal antibody
Cohort 3; GNR-051 (1 mg/kg)	Biological: GNR-051; Anti-PD1 monoclonal antibody
Cohort 4; GNR-051 (3 mg/kg)	Biological: GNR-051; Anti-PD1 monoclonal antibody
Cohort 5; GNR-051 (10 mg/kg)	Biological: GNR-051; Anti-PD1 monoclonal antibody

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) [ Time Frame: 28 Days ]
   Tolerability of GNR-051
2. Number of participants with dose-limiting toxicity (DLT) [ Time Frame: 28 Days ]
   Tolerability of GNR-051
3. Laboratory tests [ Time Frame: 36 Months ]
   Safety profile of GNR-051; All adverse events (CTCAE 5.0)
4. Vital signs [ Time Frame: 36 Months ]
   Safety profile of GNR-051; All adverse events (CTCAE 5.0)
5. Physical examination [ Time Frame: 36 Months ]
   Safety profile of GNR-051; All adverse events (CTCAE 5.0)
6. 12-lead electrocardiogram [ Time Frame: 36 Months ]
   Safety profile of GNR-051; All adverse events (CTCAE 5.0)
7. ECOG assessment [ Time Frame: 36 Months ]
   Safety profile of GNR-051; All adverse events (CTCAE 5.0)
8. Antidrug antibody [ Time Frame: 36 Months ]
   Safety profile of GNR-051; All adverse events (CTCAE 5.0)

Secondary Outcome Measures :

1. GNR-051 Serum Concentration [ Time Frame: 6 Months ]
   Pharmacokinetic parameters GNR-051
2. Cmax - Maximum serum concentration after the 1st administration [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
3. Cmin - Minimum serum concentration after the 1st administration [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
4. Tmax - Time to peak serum concentration after the 1st administration [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
5. t½ - Half-life after the 1st administration, [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
6. CL - Clearance after the 1st administration [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
7. AUC0-t - Area Under the Curve after the 1st administration [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
8. Tmax, SS - Time to peak serum concentration at steady state [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
9. CSS - serum concentration at steady state [ Time Frame: 6 Months ]
   Pharmacokinetic parameters
10. Cmax, SS - Maximum serum concentration at steady state [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
11. CLSS - Clearance at steady state [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
12. Cmin, SS - serum concentration at steady state [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
13. Vd, SS - Volume of distribution at steady state [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
14. CAUCτ 0-t - Area under the concentration time-curves from zero to the end of the dosing interval at steady state [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
15. t½,ss - Half-life at steady state [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
16. AUC0-∞ - Area under the concentration time-curves from time zero to infinity after last administration [ Time Frame: 36 Months ]
    PharmacoCkinetic parameters
17. Accumulation index (Rac; steady-state AUC0-τ/single-dose AUC0-τ) [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
18. Time to reach steady state - elimination half-life [ Time Frame: 6 Months ]
    Pharmacokinetic parameters
19. PD-1 receptor occupancy rate (%) in peripheral blood mononuclear cells (PBMCs) [ Time Frame: 6 Months ]
    Pharmacodynamic parameters GNR-051
20. Objective Response Rate (ORR) [ Time Frame: 36 Months ]
    Objective Response Rate (ORR) - best response of complete remission (CR) or partial remission (PR) according to RECIST 1.1 and IRECIST
21. Best objective response rate (complete response (CR) + partial response (PR)) [ Time Frame: 36 Months ]
    Best objective response rate (complete response (CR) + partial response (PR)) according to RECIST 1.1 and IRECIST
22. Progression-Free Survival (PFS) [ Time Frame: 36 Months ]
    Progression-Free Survival (PFS) - time from 1st dose administration to progression according to RECIST 1.1 or until death from any cause
23. Disease Control Rate (DCR) [ Time Frame: 36 Months ]
    Disease Control Rate (DCR) - percentage of patients who have achieved complete response, partial response and stable disease
24. Best Overall Response (BOR) [ Time Frame: 36 Months ]
    Best Overall Response (BOR) - the best response recorded from the 1st dose administration until the disease progression
25. Duration of response (DoR) [ Time Frame: 36 Months ]
    Duration of response - the length of time that a tumor continues to respond to treatment without the cancer growing or spreading
26. Overall Survival (OS) [ Time Frame: 36 Months ]
    Overall Survival (OS) - time from enrollment to the date of death

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed Informed Consent Form and the subject's ability to follow the Protocol requirements;
• Age: 18 years and older at the signing of the informed consent;
• Histologically confirmed metastatic solid malignant tumors (non-small cell lung cancer, renal cell carcinoma, melanoma), refractory or recurrent after one or more courses of previous therapy and not subject to surgical treatment and radiation therapy. Melanoma - regardless of the presence and success of previous treatment;
• ECOG performance status ≤ 2;
• At least one RESICT 1.1-defined measurable target lesion;
• Completion of the previous drug treatment of the underlying disease (if applicable) at least 28 days before the first administration of GNR-051;
• Resolution or stabilization of toxicity manifestations of previous radiation or chemotherapy.

Exclusion Criteria:

• Prior treatment with anti-CTLA4 and/or anti-PD-1/PD-L1/PD-L2 agents;
• Hypersensitivity to any of the components of GNR-051;
• Progression (growth of previous, appearance of new) metastases in the brain and meninges, identified by CT or MRI, in a period of less than 56 days before the first administration of GNR-051; worsening of neurological symptoms in a patient with metastases in the brain or meninges within a period of less than 28 days before the first administration of GNR-051; or continued treatment of metastases in the brain or meninges with glucocorticosteroids (GCS) for a period of less than 14 days before the first administration of GNR-051 (except for a maintenance daily dose of GCS equivalent to 10 mg of prednisolone);
• Inability to conduct a biopsy according to the protocol;
• Left ventricular ejection fraction (LVEF) <50% (EchoCG);
• The need to use anticancer drugs, other than the investigated one, for at least 3 months after the first administration of the drug;
• Patients who need radiotherapy or surgical therapy;
• Previous radiotherapy ended <28 days before the first dose administration;
• Previous stereotactic radiation therapy ended <14 days before the first dose administration;
• Therapeutic use of radiopharmaceuticals ≤56 days prior to first dose administration;
• Patients who have received another experimental drug (not registered in Russia) within 28 days or 5 half-lives of the experimental drug before the first administration GNR-051;
• Patients who have received vaccines against infectious diseases (eg influenza virus) within 28 days before the first administration of the drug;
• Patients who have received narcotic analgesics <14 days before the first administration of GNR-051;
• Surgery with general anesthesia <28 days before the first administration of GNR-051.
• Surgery with regional / epidural anesthesia <72 hours and / or not all post-anesthetic AEs resolved before the first administration of GNR-051;

• Laboratory parameters:

  • Absolute leukocyte count <2000 / μL;
  • Absolute neutrophil count <1500 / μL;
  • Absolute platelet count <100 × 103 / μL;
  • Hemoglobin level <9.0 g / dL;
  • Creatinine> 2 mg / dL;
  • AST> 2.5 × the upper limit of normal (ULN) in the absence of liver metastases, or> 5 × ULN with the liver metastases;
  • ALT > 2.5 × ULN in the absence of liver metastases, or> 5 × ULN with the liver metastases;
  • Total bilirubin> 2 × ULN;
• Systemic autoimmune diseases (including but not limited to SLE, Crohn's disease, ulcerative colitis, systemic scleroderma, inflammatory myopathy, mixed connective tissue disease, overlap syndrome, etc.);
• Concomitant cancer (except for basal or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, prostate, or breast);
• Patients who need therapy with corticosteroids or other immunosuppressants;
• Systemic therapy with corticosteroids or immunosuppressants for ≤7 days before the first administration GNR-051;
• Any other concomitant condition (e.g., medical condition, mental disorders, alcohol/drug abuse) that constitutes an unacceptable risk to the patient's health during the investigational therapy or prevents a patient from following the Protocol procedures;
• Active HBV/HCV/HIV infection;
• Pregnant or lactating female;
• Patients with reproductive potential who do not agree to practice acceptable methods of birth control throughout the entire trial period, starting from signing the informed consent and up to 6 months after the last dose of GNR-051;
• Simultaneous participation in other clinical trials.

Contacts and Locations

Locations

Russian Federation

SAHI "Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan"

Kazan, Russian Federation, 420029

SBHI "Leningrad Regional Clinical Oncology Dispensary"

Leningrad Region, Russian Federation, 188663

FSBI "N.N. Blokhin National Medical Research Center of Oncology"of the Ministry of Health of the Russian Federation

Moscow, Russian Federation, 115478

FSBI "Russian Scientific Center of Roentgenoradiology" of the Ministry of Health of the Russian Federation

Moscow, Russian Federation, 117997

FSAEI HE "I.M. Sechenov First Moscow State Medical University" of the Ministry of Health of Russian Federation

Moscow, Russian Federation, 119991

JSC "MEDSI" Group of Companies"

Moscow, Russian Federation, 123056

FSII "Treatment and Rehabilitation Center" of the Ministry of Health of the Russian Federation

Moscow, Russian Federation, 125367

FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Healthcare of the Russian Federation

Moscow, Russian Federation, 197758

JSC "Modern Medical Technologies"

Saint Petersburg, Russian Federation, 190013

FSAEI HE "I.P. Pavlov First Saint Petersburg State Medical University" of the Ministry of Health of the Russian Federation

Saint Petersburg, Russian Federation, 197022

SBHI "St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological)

Saint Petersburg, Russian Federation, 197758

LLC "Tentanda Via"

Saint Petersburg, Russian Federation, 198035

Sponsors and Collaborators

AO GENERIUM

More Information

• Responsible Party: AO GENERIUM
• ClinicalTrials.gov Identifier: NCT04544748
• Other Study ID Numbers: APD-SMG-I
• First Posted: September 10, 2020
• Last Update Posted: February 24, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AO GENERIUM:

Neoplasms; Neoplasms by Histologic Type; Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Melanoma; Carcinoma, Renal Cell; Urologic Neoplasms; Lung Neoplasms; Antineoplastic Agents, Immunological; Kidney Neoplasms

Additional relevant MeSH terms:

Carcinoma; Melanoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Kidney Diseases; Urologic Diseases