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

Phase 1

Active, not recruiting

• Conditions: Melanoma; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung
• Interventions: Biological: GNR-051

• Registration Number: NCT04544748
• Lead Sponsor: AO GENERIUM

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.

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 Timeline

• Study Start: 2020-07-22
• Study First Submitted: 2020-08-31
• Study First Submitted QC: 2020-09-07
• Study First Posted: 2020-09-10
• Primary Completion: 2022-11-07
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-05
• Last Update Posted: 2024-03-06
• Study Completion: 2025-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 48

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1	GNR-051	GNR-051 (0.1 mg/kg)
Cohort 3	GNR-051	GNR-051 (1 mg/kg)
Cohort 4	GNR-051	GNR-051 (3 mg/kg)
Cohort 5	GNR-051	GNR-051 (10 mg/kg)
Cohort 2	GNR-051	GNR-051 (0.3 mg/kg)

Primary Outcome Measures

Name	Time	Method
Vital signs	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Antidrug antibody	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Maximum Tolerated Dose (MTD)	28 Days	Tolerability of GNR-051
Number of participants with dose-limiting toxicity (DLT)	28 Days	Tolerability of GNR-051
Laboratory tests	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)
Physical examination	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)
12-lead electrocardiogram	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)
ECOG assessment	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)

Secondary Outcome Measures

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

Trial Locations

Locations (12)

LLC "Tentanda Via"; 🇷🇺 Saint Petersburg, Russian Federation

FSBI "Russian Scientific Center of Roentgenoradiology" of the Ministry of Health of the Russian Federation; 🇷🇺 Moscow, Russian Federation

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

SBHI "St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological); 🇷🇺 Saint Petersburg, Russian Federation

SAHI "Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan"; 🇷🇺 Kazan, Russian Federation

SBHI "Leningrad Regional Clinical Oncology Dispensary"; 🇷🇺 Saint Petersburg, Russian Federation

FSII "Treatment and Rehabilitation Center" of the Ministry of Health of the Russian Federation; 🇷🇺 Moscow, Russian Federation

FSBI "N.N. Blokhin National Medical Research Center of Oncology"of the Ministry of Health of the Russian Federation; 🇷🇺 Moscow, Russian Federation

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

JSC "MEDSI" Group of Companies"; 🇷🇺 Moscow, Russian Federation

FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Healthcare of the Russian Federation; 🇷🇺 Moscow, Russian Federation

JSC "Modern Medical Technologies"; 🇷🇺 Saint Petersburg, Russian Federation