A Phase 1 Study of TRS005 in Patients With R/R CD20-positive B-NHL.

Study Overview
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Brief Summary
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This trial is a multicenter, open, single arm, dose increasing and extended clinical trial. The dose was increased according to the 3 + 3 rule. Patients with recurrent or refractory CD20 positive B-cell non-Hodgkin's lymphoma were selected to evaluate the safety, tolerance (DLT, MTD) and pharmacokinetic (PK) characteristics of TRS005 by intravenous drip.

Detailed Description
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The subjects were screened and examined according to the protocol before enrollment。The dose of the enrolled subjects was increased according to the following 7 dose groups: 0.1mg/kg, 0.5mg/kg, 1.0mg/kg, 1.5mg/kg, 1.8mg/kg, 2.0mg/kg and 2.3 mg/kg. (according to the data of the previous study, when the dose climbs to 1.5 mg / kg, there is a serious decline of neutrophils, which shall be subject to the principle of 3 + 3. If the dose group reaches 6 patients and the DLT is less than or equal to 1 case, it continues to increase sequentially (1.8 mg/kg, 2.0 mg/kg, and 2.3 mg/kg). Whether to continue the dose increase or not shall be discussed and decided by the researcher and the sponsor). The incremental process is divided into groups according to the principle of 3 + 3 dose increment. The subjects randomly receive intravenous drip of TRS005 in chronological order. Each subject first carries out a single dose study, and then carries out multiple continuous doses. The first dose is given once in D1. After 21 days of observation, it is decided whether to continue multiple continuous doses according to the situation. They are given once in C2D1, C3D1, C4D1, C5D1 and C6D1 respectively, for a total of 6 cycles and 6 times. Based on the data of pharmacokinetics, safety, tolerability and efficacy of the previous 4 dose groups, the dose group of 1.0 mg/kg, 1.5 mg/kg or 1.8 mg/kg (when the maximum dose exceeds 1.8 mg/kg) will enter the extended trial phase and continue to complete 6 cycles of treatment according to the original research principles. It is expected that the number of research cases in each group will accumulate to 10, a total of about 30 cases; If 2 cases of DLT occur in 6 cases in the 1.5 mg/kg dose group, the dose increase will not continue. At this point, an additional 1.3 mg/kg dose group is required to enter the study, while the extended dose group is expected to select 1.0 mg/kg 1.3 mg/kg, with a cumulative enrollment of 12 subjects, for a total of 24 cases.

Official Title
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A Multicenter, Single-arm, Dose-escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Effectiveness of TRS005 in Patients With Relapsed or Refractory CD20-positive B-NHL

Conditions
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CD20-positive B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Recombinant CD20 monoclonal antibody-MMAE conjugte for injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed CD20-positive B-cell non-Hodgkin lymphoma; Relapse or refractory after receiving at least 2 standard treatment regimens;（Definition of refractory: Patients who did not reach PR in two cycles or CR in four cycles） At least one measurable tumor lesion with the longest transverse diameter ≥ 1.5cm; Previously received anti-tumor treatment (such as radiotherapy, chemotherapy, hormone therapy, biotherapy, immunotherapy) at least 28 days before the first administration of this study; The toxicity of previous anti-tumor treatment has been restored to ≤ grade 1 as defined by NCI-CTCAE v5.0 (except for alopecia)； The laboratory inspection results must meet the following requirements:（It is not allowed to give any blood components, short acting cell growth factor, albumin and other drugs within 7 days before laboratory examination; Long acting cell growth factor is not allowed to be given within the first 14 days）： Hematology: white blood cell count (WBC) ≥ 3 × 109 / L, absolute neutrophil count (ANC) ≥ 1.5 × 109 / L, platelet (PLT) ≥ 100 × 109 / L, hemoglobin (HGB) > 90g / L; Liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal value, and total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal value; Renal function：Serum creatinine (Cr) ≤ 2 times the upper limit of normal value; Coagulation function：International normalized ratio (INR) ≤ 1.5 upper limit of normal value and activated partial thromboplastin time (APTT) ≤ 1.5 upper limit of normal value (The patients were not treated with anticoagulation before enrollment); Measured value / predicted value of vital capacity (VC) ≥ 60%, or predicted value of carbon monoxide diffusion function (DLCO) ≥ 50%; ≥ 18 years , gender is not limited; ECOG performance status 0-1; Life expectancy of greater than 3 months; Female and male patients of childbearing age and their spouses are willing to carry out adequate contraception throughout the study period, and female patients of childbearing age must have negative serum pregnancy test within 7 days before the first administration; Patients voluntarily agree to participate in the study and to sign the informed consent form. Exclusion Criteria: Patients who meet any of the following criteria will be excluded: Received rituximab within 3 months before the first medication; Rituximab ADA positive in peripheral blood at the time of screening; The residual concentration of rituximab in peripheral blood > 24ug / ml at screening; A clear history of drug allergy, and a history of ingredient allergy to heterogeneous proteins, biological agents or test drugs; Active hepatitis B or C (HBsAg positive and / or HBcAb positive and HBV DNA ≥ 104 copy number or ≥ 4000IU/ml; HCV antibody positive) or human immunodeficiency virus (HIV) antibody positive; Tumor-infiltrating diseases of the central nervous system; Accompanied by peripheral or central nervous system diseases; Investigator-assessed diabetes uncontrolled by drug therapy; Patients with other malignancies within the past 5 years; With active autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia, etc.); Accompanied by the following serious cardiovascular diseases: Myocardial infarction in nearly 6 months of screening period; Unstable angina pectoris in the screening period of nearly 3 months; Cardiac insufficiency (cardiac function grade ≥ NYHA class II); Severe arrhythmia (e.g., persistent ventricular tachycardia, ventricular fibrillation); Prolonged QTc interval (male > 450 ms, female > 470 ms); Second or third degree heart block; Drug-poorly controlled hypertension (systolic blood pressure > 160mmHg or diastolic blood pressure > 100mmHg); Accompanied by other serious diseases and serious active infections (such as pneumonia, active tuberculosis, interstitial lung disease, etc.); Received hematopoietic growth factor treatment within 1 week prior to first administration, including colony stimulating factor, interleukin or blood transfusion; The dosage of steroid hormone (prednisone phase equivalent) used greater than 20mg/ day within 1 month prior to first administration for more than 14 consecutive days or immunosuppressive treatment; Various vaccines were inoculated within 1 month prior to first administration; Major surgery (except diagnostic biopsy) within 1 month prior to first administration; Patients who received autologous stem cell transplantation within 3 months prior to first administration; Patients who have received allogeneic stem cell transplantation in the past; Patients with infusion reaction above grade III after previous monoclonal antibody treatment; Participate in clinical trials of other drugs or medical devices within 1 month prior to first administration; Patients previously treated with CAR-T; Investigators assessed as unsuitable to participate in this study for other reasons。

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant CD20 monoclonal antibody-MMAE conjugte for injection (TRS005)<br>To evaluate the safety and tolerability of TRS005 in patients with recurrent or refractory CD20-positive B-cell non-Hodgkin's lymphoma with treatment at one or more times, and to recommend the dose for phase II clinical trials (RP2D). | Drug: Recombinant CD20 monoclonal antibody-MMAE conjugte for injection<br>* The dose of the enrolled subjects was increased according to the following 7 dose groups: 0.1mg/kg, 0.5mg/kg, 1.0mg/kg, 1.5mg/kg, 1.8mg/kg, and 2.1mg/kg. (according to the data of the previous study, when the dose climbs to 1.5 mg / kg, there is a serious decline of neutrophils, which shall be subject to the principle of 3 + 3.<br>* Other names: TRS005;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutropenia | Hematology DLT, grade 4 neutropenia, which cannot return to grade 2 or baseline within 7 days after G-CSF treatment, and the disease itself involvement / infiltration is excluded | At the end of cycle 1(each cycle is 21 days) | 
| Thrombocytopenia | Hematology DLT, grade 4 Thrombocytopenia; | At the end of cycle 1(each cycle is 21 days) | 
| Neurotoxic | Non hematological DLT,neurotoxic reaction of grade 2 or above | At the end of cycle 1(each cycle is 21 days) | 
| MTD，Maximum Tolerated Dose | After the dose increment is completed, the incidence of DLT in each dose group is summarized and analyzed. The highest dose group closest to 1 / 3 of the preset incidence of DLT is MTD | At the end of cycle 1(each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADA/Nab，anti-drug antibody(ADA) /neutralizing antibody (Nab) | Evaluate the changes of anti drug antibody and neutralizing antibody produced by the subjects. | At the first day of cycle 2、cycle 3、cycle 5 (each cycle is 21 days) | 
| ORR，overall response rate | Summarize the number and percentage of objective remission (Complete remission (CR) or Partial remission (PR)) | At the end of cycle 2、cycle 4 and cycle 6 (each cycle is 21 days) | 
| Cmax | Peak concentration. Obtained directly from the measured data of blood drug concentration-time. | At the day3/day5/day8/day15 in cycle one；and at the first day of Cycle 2-6 (each cycle is 21 days) | 
| AUC0-t | Area under the curve from zero to the lowest detectable plasma concentration. Calculated by linear trapezoidal rule: AUC(i, i+1)=(Ti+1-Ti)(Ci+Ci+1)/2, AUC 0-t is the sum of all AUC (I, I + 1). | At the day3/day5/day8/day15 in cycle one；and at the first day of Cycle 2-6 (each cycle is 21 days) | 
| AUC0-∞ | Area under the curve extrapolated from zero to infinity time. AUC0-∞=AUC0-t+Ct/λ z(Ct is the last measurable plasma concentration) | At the day3/day5/day8/day15 in cycle one；and at the first day of Cycle 2-6 (each cycle is 21 days) | 
| Tmax | Peak time. Obtained directly from the measured data of blood drug concentration-time. | At the day3/day5/day8/day15 in cycle one；and at the first day of Cycle 2-6 (each cycle is 21 days) |