Clinical trial NCT04544748: A Phase 1 Study of GNR-051 in Subjects With Advanced Malignancies
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Carcinoma, Renal Cell
Melanoma
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
Lead sponsor: AO GENERIUM
Sponsor class: INDUSTRY
First posted: 2020-09-10
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: 28 Days
measure: Number of participants with dose-limiting toxicity (DLT)
timeFrame: 28 Days
measure: Laboratory tests
timeFrame: 36 Months
measure: Vital signs
timeFrame: 36 Months
measure: Physical examination
timeFrame: 36 Months
measure: 12-lead electrocardiogram
timeFrame: 36 Months
measure: ECOG assessment
timeFrame: 36 Months
measure: Antidrug antibody
timeFrame: 36 Months
Secondary outcomes:
measure: GNR-051 Serum Concentration
timeFrame: 6 Months
measure: Cmax - Maximum serum concentration after the 1st administration
timeFrame: 6 Months
measure: Cmin - Minimum serum concentration after the 1st administration
timeFrame: 6 Months
measure: Tmax - Time to peak serum concentration after the 1st administration
timeFrame: 6 Months
measure: t½ - Half-life after the 1st administration,
timeFrame: 6 Months
measure: CL - Clearance after the 1st administration
timeFrame: 6 Months
measure: AUC0-t - Area Under the Curve after the 1st administration
timeFrame: 6 Months
measure: Tmax, SS - Time to peak serum concentration at steady state
timeFrame: 6 Months
measure: CSS - serum concentration at steady state
timeFrame: 6 Months
measure: Cmax, SS - Maximum serum concentration at steady state
timeFrame: 6 Months
measure: CLSS - Clearance at steady state
timeFrame: 6 Months
measure: Cmin, SS - serum concentration at steady state
timeFrame: 6 Months
measure: Vd, SS - Volume of distribution at steady state
timeFrame: 6 Months
measure: CAUCτ 0-t - Area under the concentration time-curves from zero to the end of the dosing interval at steady state
timeFrame: 6 Months
measure: t½,ss - Half-life at steady state
timeFrame: 6 Months
measure: AUC0-∞ - Area under the concentration time-curves from time zero to infinity after last administration
timeFrame: 36 Months
measure: Accumulation index (Rac; steady-state AUC0-τ/single-dose AUC0-τ)
timeFrame: 6 Months
measure: Time to reach steady state - elimination half-life
timeFrame: 6 Months
measure: PD-1 receptor occupancy rate (%) in peripheral blood mononuclear cells (PBMCs)
timeFrame: 6 Months
measure: Objective Response Rate (ORR)
timeFrame: 36 Months
measure: Best objective response rate (complete response (CR) + partial response (PR))
timeFrame: 36 Months
measure: Progression-Free Survival (PFS)
timeFrame: 36 Months
measure: Disease Control Rate (DCR)
timeFrame: 36 Months
measure: Best Overall Response (BOR)
timeFrame: 36 Months
measure: Duration of response (DoR)
timeFrame: 36 Months
measure: Overall Survival (OS)
timeFrame: 36 Months
Other outcomes:
Locations:
city: Kazan
country: Russian Federation
facility: SAHI "Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan"
city: Moscow
country: Russian Federation
facility: FSBI "N.N. Blokhin National Medical Research Center of Oncology"of the Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: FSBI "Russian Scientific Center of Roentgenoradiology" of the Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: FSAEI HE "I.M. Sechenov First Moscow State Medical University" of the Ministry of Health of Russian Federation
city: Moscow
country: Russian Federation
facility: JSC "MEDSI" Group of Companies"
city: Moscow
country: Russian Federation
facility: FSII "Treatment and Rehabilitation Center" of the Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: FSBI "N.N. Petrov National Medical Research Center of Oncology" of the Ministry of Healthcare of the Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: SBHI "Leningrad Regional Clinical Oncology Dispensary"
city: Saint Petersburg
country: Russian Federation
facility: JSC "Modern Medical Technologies"
city: Saint Petersburg
country: Russian Federation
facility: FSAEI HE "I.P. Pavlov First Saint Petersburg State Medical University" of the Ministry of Health of the Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: SBHI "St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological)
city: Saint Petersburg
country: Russian Federation
facility: LLC "Tentanda Via"
Study officials:
References: