Phase Ⅰ Study to Evaluate the Safety and Tolerability of Using F520

Study Overview
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Brief Summary
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Recombinant Programmed death-1(PD-1) humanized monoclonal antibody injection (company code: F520) is joint developed by Shandong New Time Pharmaceutical Co., LTD., it is the reorganization of deoxyribonucleic acid (DNA) technology in the Chinese hamster ovary (CHO) cells express system expressed in a immunoglobulin G1 (IgG1) kappa type single resistance to predominate. F520 had the different new amino acid sequence and molecular structure compared with two marketed PD-1 monoclonal antibody injection and got the approval of China Food and Drug Administration (CFDA) for clinical trial.Pharmaceutical research indicated F520 cell strain had security source, production process is stable, quality can control, preparation stability, has good compatibility with packaging materials, it has the condition of industrialization, can prepare investigational medicinal product with safety, effective, and controlled quality for clinical research.Pharmacodynamics study show the targets and mechanisms of F520is clear, tumor suppression effect is obvious.Toxicology studies show this product in high doses with low toxic, and the toxic is reversible, the most common toxicity is specific to the drug action mechanism.

Official Title
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Phase Ⅰ Study to Evaluate the Safety and Tolerability of Using F520 by Advanced Tumor Subjects

Conditions
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Advanced Solid Tumor，Recurrent Solid Tumor，Lymphoma，Recurrent Lymphocyte Depleted Classical Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 18-65 years of age; Histologically or cell confirmed advanced, unresectable or metastatic disease tumor and failure to standard therapies or lack of standard therapy(disease progress or failed to tolerate the toxicity, such as chemotherapy, targeted therapy, and other immunotherapies other than PD-1/PD-L1); Agree to provide archived tumor tissue specimens or fresh tissue specimens; ECOG performance status of 0 or 1; Life expectancy ≥ 12 weeks.; At least one measurable and evaluable tumor lesion (in accordance with international working group criteria/RANO/cheson 2007)； Adequate laboratory parameters during the screening period as evidenced by the following（No blood components and cell growth factors are allowed within 28 days prior to screening）: routine blood tests: Absolute neutrophil count ≥1.0×109/L ;Platelets ≥100×109/L;Hemoglobin ≥ 9.0 g/dL; Liver function：Total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN), ALT and AST ≤2.5ULN; for subjects with liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5×ULN, Total bilirubin (TBIL) ≤3×upper limit of normal (ULN); Renal function CCr≤1.5×ULN，Creatinine clearance≥50 mL/min; Thyroid function indicators: thyroid-stimulating hormone (TSH) and free thyroxine (FT3/FT4) are within the normal range; Understand study procedures and contents, and voluntarily sign the written informed consent form. Exclusion Criteria: Subjects with any active autoimmune disease or history of autoimmune disease, including but not limited to the following: Immune-related neurological diseases, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, systemic lupus erythematosus, connective tissue disease, scleroderma, inflammatory bowel disease including Crowe Enthusiasm and ulcerative colitis, autoimmune hepatitis, toxic epidermal necrolysis or Stevens-Johnson syndrome； Presence of symptomatic central nervous system (CNS) metastases； Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10 mg/day prednisone or equivalent are prohibited within 14 days before entering the group and during the study period; Prior radiotherapy, systemic chemotherapy hormone therapy, surgery or target therapy within 4 weeks or 5 half-lives(whichever is longer) before the study drug administration, or any unresolved AEs > CTC-AE Grade 1; Autologous hematopoietic stem cell transplantation (ASCT) has been completed at least 3 months before receiveing first dose; Known history of hypersensitivity to macromolecular protein preparation or any components of the F520 formulation； Patients receiving any anti-infection vaccine within 4 weeks before enrollment; History or concurrent with other malignant disease, except completely cured basal cell skin cancers and carcinoma in situs of cervix; Uncontrolled clinically significant heart disease, including but not limited to the following: (1) >2 NYHA 2 congestive heart failure; (2) unstable angina, (3) myocardial infarction within the past 1 year; (4) clinically significant supraventricular arrhythmia or ventricular arrhythmia requirement for treatment or intervention; Active infection（needing therapy） or an unexplained fever > 38.5°C during screening or before the first scheduled day of dosing (subjects with tumor fever may be enrolled at the discretion of the investigator); Patients with active pulmonary tuberculosis; patients who previously had active pulmonary tuberculosis; History of immunodeficiency (HIV) or active hepatitis(Hepatitis B: HBsAg, Anti-HBs, HBeAg, Anti-HBe, Anti-HBc,HBV-DNA; Hepatitis C: Anti-HCV,HCV-RNA) Participation in a clinical study or less than 1 month from the last dose of investigational drug to sign ICF; History of PD-1/PD-L1 or CTLA-4 therapy; Patients with drug abuse history or alcohol addiction history; Patients with current or previous interstitial lung diseases; Female and male who have reproductive potential must be willing and able to employ a highly effective method of birth control/contraception to prevent pregnancy while on treatment and for at least 6 months after receiving the last dose of study treatment. Other factors that may lead to the termination of the participation in the study at the discretion of the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F520 0.2mg/kg single-dose<br>F520 0.2mg/kg single-dose | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 1.0mg/kg single-dose<br>F520 1.0mg/kg single-dose | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 3.0mg/kg single-dose<br>F520 3.0mg/kg single-dose | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 200mg/times single-dose<br>F520 200mg/times single-dose | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 10mg/kg single-dose<br>F520 10mg/kg single-dose | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 1mg/kg multiple dosing, every 2 weeks<br>F520 1mg/kg every 2 weeks | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 3mg/kg multiple dosing, every 2 weeks<br>F520 3mg/kg every 2 weeks | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 200mg/times multiple dosing, every 2 weeks<br>F520 200mg/times every 2 weeks | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 10mg/kg multiple dosing, every 2 weeks<br>F520 10mg/kg every 2 weeks | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 3mg/kg multiple dosing, every 3 weeks<br>F520 3mg/kg every 3 weeks | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|
| Experimental: F520 200mg/times multiple dosing, every 3 weeks<br>F520 200mg/times every 3 weeks | Drug: Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection<br>* Biological: F520 single-dose:0.2mg/kg, 1.0mg/kg, 3.0mg/kg, 200mg/times, 10mg/kg; multiple dosing: 1mg/kg, 3mg/kg, 200mg/times, 10mg/kg, treat every 2 weeks; multiple dosing: 3mg/kg, 200mg/times, treat every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0. |  | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PD-1 receptor occupancy of blood |  | 3 years | 
| Objective Response Rate (ORR) by irRC/ RECIST 1.1/RANO/cheson2007 |  | 3 years | 
| Disease Control Rate (DCR) by irRC/ RECIST 1.1/RANO/cheson2007 |  | 3 years | 
| Maximum Plasma Concentration (Cmax) after single dose injection of Anti-PD-1 Monoclonal Antibody (mAb) |  | 1.5years | 
| Peak Time (Tmax) after single dose injection of Anti-PD-1 mAb |  | 1.5years | 
| Area Under the Curve (AUC) after single dose injection of Anti-PD-1 mAb |  | 1.5years | 
| t1/2 after single dose injection of Recombinant Humanized Anti-PD-1 mAb |  | 1.5years | 
| Plasma clearance (CL) after single dose injection of Anti-PD-1 mAb |  | 1.5years | 
| Apparent volume of distribution (V) after single dose injection of Anti-PD-1 mAb |  | 1.5years | 
| Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of Anti-PD-1 mAb |  | 1.5years | 
| Average Plasma Concentration (Cavg) of steady state after multiple dose injection of Anti-PD-1 mAb |  | 1.5years | 
| degree of fluctuation (DF) of steady state after multiple dose injection of Anti-PD-1 mAb |  | 1.5years | 
| Apparent volume of distribution of steady state (Vss) after multiple dose injection of Anti-PD-1 mAb |  | 1.5years |