a phase 1 study of gnr-051 in subjects with advanced malignancies

Conditions: Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Melanoma

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.

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.

Eligibility criteria:
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.

Keywords: neoplasms neoplasms by histologic type adenocarcinoma carcinoma, non-small-cell lung melanoma carcinoma, renal cell urologic neoplasms lung neoplasms antineoplastic agents, immunological kidney neoplasms