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

Melanoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04544748
• Other study ID #: APD-SMG-I
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: July 22, 2020
• Est. completion date: January 2025

Study information

• Verified date: March 2024
• Source: AO GENERIUM
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 48
• Est. completion date: January 2025
• Est. primary completion date: November 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Renal Cell
• Melanoma

Intervention

Biological:
• GNR-051
Anti-PD1 monoclonal antibody

Locations

Country	Name	City	State
Russian Federation	SAHI "Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan"	Kazan
Russian Federation	FSAEI HE "I.M. Sechenov First Moscow State Medical University" of the Ministry of Health of 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	FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Healthcare 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	FSII "Treatment and Rehabilitation Center" of the Ministry of Health of the Russian Federation	Moscow
Russian Federation	JSC "MEDSI" Group of Companies"	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	JSC "Modern Medical Technologies"	Saint Petersburg
Russian Federation	LLC "Tentanda Via"	Saint Petersburg
Russian Federation	SBHI "Leningrad Regional Clinical Oncology Dispensary"	Saint Petersburg
Russian Federation	SBHI "St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological)	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	Maximum Tolerated Dose (MTD)	Tolerability of GNR-051	28 Days
Primary	Number of participants with dose-limiting toxicity (DLT)	Tolerability of GNR-051	28 Days
Primary	Laboratory tests	Safety profile of GNR-051; All adverse events (CTCAE 5.0)	36 Months
Primary	Vital signs	Safety profile of GNR-051; All adverse events (CTCAE 5.0)	36 Months
Primary	Physical examination	Safety profile of GNR-051; All adverse events (CTCAE 5.0)	36 Months
Primary	12-lead electrocardiogram	Safety profile of GNR-051; All adverse events (CTCAE 5.0)	36 Months
Primary	ECOG assessment	Safety profile of GNR-051; All adverse events (CTCAE 5.0)	36 Months
Primary	Antidrug antibody	Safety profile of GNR-051; All adverse events (CTCAE 5.0)	36 Months
Secondary	GNR-051 Serum Concentration	Pharmacokinetic parameters GNR-051	6 Months
Secondary	Cmax - Maximum serum concentration after the 1st administration	Pharmacokinetic parameters	6 Months
Secondary	Cmin - Minimum serum concentration after the 1st administration	Pharmacokinetic parameters	6 Months
Secondary	Tmax - Time to peak serum concentration after the 1st administration	Pharmacokinetic parameters	6 Months
Secondary	t½ - Half-life after the 1st administration,	Pharmacokinetic parameters	6 Months
Secondary	CL - Clearance after the 1st administration	Pharmacokinetic parameters	6 Months
Secondary	AUC0-t - Area Under the Curve after the 1st administration	Pharmacokinetic parameters	6 Months
Secondary	Tmax, SS - Time to peak serum concentration at steady state	Pharmacokinetic parameters	6 Months
Secondary	CSS - serum concentration at steady state	Pharmacokinetic parameters	6 Months
Secondary	Cmax, SS - Maximum serum concentration at steady state	Pharmacokinetic parameters	6 Months
Secondary	CLSS - Clearance at steady state	Pharmacokinetic parameters	6 Months
Secondary	Cmin, SS - serum concentration at steady state	Pharmacokinetic parameters	6 Months
Secondary	Vd, SS - Volume of distribution at steady state	Pharmacokinetic parameters	6 Months
Secondary	CAUCt 0-t - Area under the concentration time-curves from zero to the end of the dosing interval at steady state	Pharmacokinetic parameters	6 Months
Secondary	t½,ss - Half-life at steady state	Pharmacokinetic parameters	6 Months
Secondary	AUC0-8 - Area under the concentration time-curves from time zero to infinity after last administration	PharmacoCkinetic parameters	36 Months
Secondary	Accumulation index (Rac; steady-state AUC0-t/single-dose AUC0-t)	Pharmacokinetic parameters	6 Months
Secondary	Time to reach steady state - elimination half-life	Pharmacokinetic parameters	6 Months
Secondary	PD-1 receptor occupancy rate (%) in peripheral blood mononuclear cells (PBMCs)	Pharmacodynamic parameters GNR-051	6 Months
Secondary	Objective Response Rate (ORR)	Objective Response Rate (ORR) - best response of complete remission (CR) or partial remission (PR) according to RECIST 1.1 and IRECIST	36 Months
Secondary	Best objective response rate (complete response (CR) + partial response (PR))	Best objective response rate (complete response (CR) + partial response (PR)) according to RECIST 1.1 and IRECIST	36 Months
Secondary	Progression-Free Survival (PFS)	Progression-Free Survival (PFS) - time from 1st dose administration to progression according to RECIST 1.1 or until death from any cause	36 Months
Secondary	Disease Control Rate (DCR)	Disease Control Rate (DCR) - percentage of patients who have achieved complete response, partial response and stable disease	36 Months
Secondary	Best Overall Response (BOR)	Best Overall Response (BOR) - the best response recorded from the 1st dose administration until the disease progression	36 Months
Secondary	Duration of response (DoR)	Duration of response - the length of time that a tumor continues to respond to treatment without the cancer growing or spreading	36 Months
Secondary	Overall Survival (OS)	Overall Survival (OS) - time from enrollment to the date of death	36 Months