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

Study Overview
=================
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.

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

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

Intervention / Treatment
-----------------
* Biological: GNR-051


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neoplasms, Neoplasms by Histologic Type, Adenocarcinoma, Carcinoma, Non-Small-Cell Lung, Melanoma, Carcinoma, Renal Cell, Urologic Neoplasms, Lung Neoplasms, Antineoplastic Agents, Immunological, Kidney Neoplasms