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

• 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

Primary Outcome Measures

Name	Time	Method
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)
Vital signs	36 Months	Safety profile of GNR-051; All adverse events (CTCAE 5.0)

Secondary Outcome Measures

Name	Time	Method
t½ - Half-life after the 1st administration,	6 Months	Pharmacokinetic parameters
CL - Clearance after the 1st administration	6 Months	Pharmacokinetic parameters
Accumulation index (Rac; steady-state AUC0-τ/single-dose AUC0-τ)	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)

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

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

FSBI "Russian Scientific Center of Roentgenoradiology" 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

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

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

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

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