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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Biological: GNR-051

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 Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Svetlana B. Korotkova, MD, PhD; Phone Number: +7 9166816567; Email: sbkorotkova@generium.ru
• Study Contact Backup: Name: Oksana A. Markova, MD, MSc; Phone Number: +7 9854418959; Email: oamarkova@generium.ru

Study Locations

• Russian Federation
  • Kazan, Russian Federation, 420029
    • SAHI "Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan"
  • Moscow, Russian Federation, 119991
    • FSAEI HE "I.M. Sechenov First Moscow State Medical University" of the Ministry of Health of Russian Federation
  • Moscow, Russian Federation, 115478
    • FSBI "N.N. Blokhin National Medical Research Center of Oncology"of the Ministry of Health of the Russian Federation
  • Moscow, Russian Federation, 117997
    • FSBI "Russian Scientific Center of Roentgenoradiology" of the Ministry of Health of the Russian Federation
  • Moscow, Russian Federation, 123056
    • JSC "MEDSI" Group of Companies"
  • Moscow, Russian Federation, 125367
    • FSII "Treatment and Rehabilitation Center" of the Ministry of Health of the Russian Federation
  • Moscow, Russian Federation, 197758
    • FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Healthcare of the Russian Federation
  • Saint Petersburg, Russian Federation, 190013
    • JSC "Modern Medical Technologies"
  • Saint Petersburg, Russian Federation, 197022
    • FSAEI HE "I.P. Pavlov First Saint Petersburg State Medical University" of the Ministry of Health of the Russian Federation
  • Saint Petersburg, Russian Federation, 197758
    • SBHI "St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological)
  • Saint Petersburg, Russian Federation, 198035
    • LLC "Tentanda Via"
  • Saint Petersburg, Russian Federation, 188663
    • SBHI "Leningrad Regional Clinical Oncology Dispensary"

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GNR-051 Serum Concentration	Pharmacokinetic parameters GNR-051	6 Months
Cmax - Maximum serum concentration after the 1st administration	Pharmacokinetic parameters	6 Months
Cmin - Minimum serum concentration after the 1st administration	Pharmacokinetic parameters	6 Months
Tmax - Time to peak serum concentration after the 1st administration	Pharmacokinetic parameters	6 Months
t½ - Half-life after the 1st administration,	Pharmacokinetic parameters	6 Months
CL - Clearance after the 1st administration	Pharmacokinetic parameters	6 Months
AUC0-t - Area Under the Curve after the 1st administration	Pharmacokinetic parameters	6 Months
Tmax, SS - Time to peak serum concentration at steady state	Pharmacokinetic parameters	6 Months
CSS - serum concentration at steady state	Pharmacokinetic parameters	6 Months
Cmax, SS - Maximum serum concentration at steady state	Pharmacokinetic parameters	6 Months
CLSS - Clearance at steady state	Pharmacokinetic parameters	6 Months
Cmin, SS - serum concentration at steady state	Pharmacokinetic parameters	6 Months
Vd, SS - Volume of distribution at steady state	Pharmacokinetic parameters	6 Months
CAUCτ 0-t - Area under the concentration time-curves from zero to the end of the dosing interval at steady state	Pharmacokinetic parameters	6 Months
t½,ss - Half-life at steady state	Pharmacokinetic parameters	6 Months
AUC0-∞ - Area under the concentration time-curves from time zero to infinity after last administration	PharmacoCkinetic parameters	36 Months
Accumulation index (Rac; steady-state AUC0-τ/single-dose AUC0-τ)	Pharmacokinetic parameters	6 Months
Time to reach steady state - elimination half-life	Pharmacokinetic parameters	6 Months
PD-1 receptor occupancy rate (%) in peripheral blood mononuclear cells (PBMCs)	Pharmacodynamic parameters GNR-051	6 Months
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
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
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
Disease Control Rate (DCR)	Disease Control Rate (DCR) - percentage of patients who have achieved complete response, partial response and stable disease	36 Months
Best Overall Response (BOR)	Best Overall Response (BOR) - the best response recorded from the 1st dose administration until the disease progression	36 Months
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
Overall Survival (OS)	Overall Survival (OS) - time from enrollment to the date of death	36 Months

Collaborators and Investigators

• Sponsor: AO GENERIUM

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2020
• Primary Completion (Actual): November 7, 2022
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: August 31, 2020
• First Submitted That Met QC Criteria: September 7, 2020
• First Posted (Actual): September 10, 2020

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Neoplasms; Adenocarcinoma; Melanoma; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Neoplasms by Histologic Type; Urologic Neoplasms; Lung Neoplasms
• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma; Melanoma
• Other Study ID Numbers: APD-SMG-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No