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.

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.

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.