Carcinoma, Non-Small-Cell Lung, Carcinoma, Renal Cell, Melanoma
Conditions
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
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.
Interventions
BIOLOGICALGNR-051
Anti-PD1 monoclonal antibody
Sponsors
AO GENERIUM
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| Vital signs | 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) |
| Antidrug antibody | 36 Months | Safety profile of GNR-051; All adverse events (CTCAE 5.0) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GNR-051 Serum Concentration | 6 Months | Pharmacokinetic parameters GNR-051 |
| 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 - Time to peak serum concentration after the 1st administration | 6 Months | Pharmacokinetic parameters |
| t½ - Half-life after the 1st administration, | 6 Months | Pharmacokinetic parameters |
| CL - Clearance after the 1st administration | 6 Months | Pharmacokinetic parameters |
| AUC0-t - Area Under the Curve after the 1st administration | 6 Months | Pharmacokinetic parameters |
| Tmax, SS - Time to peak serum concentration at steady state | 6 Months | Pharmacokinetic parameters |
| CSS - serum concentration at steady state | 6 Months | Pharmacokinetic parameters |
| Cmax, SS - Maximum serum concentration at steady state | 6 Months | Pharmacokinetic parameters |
| CLSS - Clearance at steady state | 6 Months | Pharmacokinetic parameters |
| Cmin, SS - serum concentration at steady state | 6 Months | Pharmacokinetic parameters |
| Vd, SS - Volume of distribution 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 |
| t½,ss - Half-life 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 |
| Accumulation index (Rac; steady-state AUC0-τ/single-dose AUC0-τ) | 6 Months | Pharmacokinetic parameters |
| Time to reach steady state - elimination half-life | 6 Months | Pharmacokinetic parameters |
| PD-1 receptor occupancy rate (%) in peripheral blood mononuclear cells (PBMCs) | 6 Months | Pharmacodynamic parameters GNR-051 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Overall Survival (OS) | 36 Months | Overall Survival (OS) - time from enrollment to the date of death |
Countries
Russia
Outcome results
None listed