A Phase I Clinical Study of JS004 in Subjects With Recurrent/Refractory Malignant Lymphoma of China

Study Overview
=================
Brief Summary
-----------------
A First-in-human, dose-escalation, dose-expansion phase I clinical study of JS004 in subjects with recurrent/refractory malignant lymphoma in China, to evaluate the safety, tolerbility, PK, immunogenicity,antitumor activity and biomarkers of JS004, to define MTD and RP2D of JS004. A cycle is 21 days(3 weeks) which includes JS004 being administered IV Q3W and JS004 combine with JS001 being administered IV Q3W. All patients will be treated until disease progression per Lugano response critieria 2014 for Lymphoma or intolerable toxicity per CTCAE 5.0, withdrawal of consent, or end of the study, whichever occurs first. Disease progression must be confirmed at least 4 weeks but no longer than 8 weeks after initial documentation of progression.

Official Title
-----------------
A Phase I Clinical Study of Recombinant Humanized Anti-BTLA Monoclonal Antibody (JS004) in Patients With Recurrent/Refractory Malignant Lymphoma

Conditions
-----------------
Recurrent/Refractory Malignant Lymphoma

Intervention / Treatment
-----------------
* Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion
* Biological: Drug：JS001, Intravenous infusion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1.Able to understand and sign informed consent voluntarily 2.18-70 years old 3.Pathologically confirmed malignant lymphoma 4.ECOG PS: 0-1 5.Expected survival ≥12 weeks 6.At least one measurable lesion per Lugano response critieria 2014 for Lymphoma 7.Adequate organ and marrow function, as defined below: ANC≥1.5×109/L; PLT≥100×109/L and ≥75×109/L for subjects with bone marrow involvement; Hb≥90 g/L; TBIL≤1.5 ULN, ≤2 ULN in those with hep109atic metastasis, except subjects with documented Gilbert's syndrome who must have a baseline conjugated bilirubin ≤3.0 mg/dL; AST and ALT≤2.5 ULN, ≤5 ULN in those with hepatic metastasis; Cr≤1.5 UL, or creatinine clearance≥50mL/min for subject; INR ≤2 ULN and aPTT≤1.5×ULN for those with no prior anticoagulant therapy. 8.According to Fridericia's principle, QTC results need to match : Male≤450 ms，Female≤470 ms 9.Females of childbearing potential need to use effective contraception Exclusion Criteria: Patients with known allergy to macromolecular protein preparations or JS004 components Prior exposure to anti-BTLA or anti-HVEM antibodies Enrolled in other clinical studies within 4 weeks prior to the first dose of study treatment Major surgery within 4 weeks prior to the first dose of study treatmentor still recovering from prior surgery Patients who discontinued previous immunotherapy due to immune-related adverse reactions Immunosuppressive agents have been used within 4 weeks prior to the first dose of study treatment Prior allogeneic bone marrow transplantation or solid organ transplantation Live attenuated vaccine be administered 30 days before the first dose of study treatment Two or more malignancies developed within 5 years prior to first dose of study treatment The patients have symptomatic, untreated, or requiring ongoing treatment central nervous system (CNS) metastases Unresolved toxicities from prior anticancer therapy, defined as having not resolved to baseline or to NCI-CTCAE v5.0 Grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria with the exception of alopecia.Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by TAB004 may be included (e.g., hearing loss) after consultation with the medical monitor. Autoimmune disease within the previous 2 years A history of rapid allergic reaction, eczema, or asthma beyond the control of topical corticosteroids A history of primary immunodeficiency Concomitant disease that is not under control, including but not limited to: persistent or active infection, unexplained fever > 38.5°C, or heart disease, active peptic ulcer disease or gastritis A history of active inflammatory bowel disease HIV(+) Patients with evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Pregnant or lactating woman Patients with vitiligo, alopecia, and hormonal replacement therapy have controlled endocrine defects Any other medical factors that may affect subjects' rights, safety, compliance, ability to sign informed consent, and interpretation of study results. Have a history of psychotropic drug abuse and unable to withdraw or have mental disorders.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: 1mg/kg JS004, Q3W until to 2 years<br>Dose escalation, enrolled 3-6 subjects | Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion<br>* Part A: including dose escalation (1mg/kg JS004; 3mg/lg JS004; 10mg/kg JS004), dose expansion (3mg/kg JS004 and 200mg JS004) and indication expansion. Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>* Other names: TAB004;|
| Experimental: 3mg/kg JS004, Q3W until to 2 years<br>Dose escalation, enrolled 3-6 subjects; Dose expansion, enrolled 9 subjects | Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion<br>* Part A: including dose escalation (1mg/kg JS004; 3mg/lg JS004; 10mg/kg JS004), dose expansion (3mg/kg JS004 and 200mg JS004) and indication expansion. Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>* Other names: TAB004;|
| Experimental: 10mg/kg JS004, Q3W until to 2 years<br>Dose escalation, enrolled 3-6 subjects | Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion<br>* Part A: including dose escalation (1mg/kg JS004; 3mg/lg JS004; 10mg/kg JS004), dose expansion (3mg/kg JS004 and 200mg JS004) and indication expansion. Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>* Other names: TAB004;|
| Experimental: 200mg, Q3W until to 2 years<br>Dose expansion, enrolled 9 subjects and indication expansion if RP2D is 200mg | Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion<br>* Part A: including dose escalation (1mg/kg JS004; 3mg/lg JS004; 10mg/kg JS004), dose expansion (3mg/kg JS004 and 200mg JS004) and indication expansion. Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>* Other names: TAB004;|
| Experimental: 240mg JS004+100mg JS001, Q3W until to 2 years<br>Dose escalation, enrolled 3-6 subjects; Dose expansion, enrolled 6-9 subjects and indication expansion if RP2D is confirmed this arm | Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion<br>* Part A: including dose escalation (1mg/kg JS004; 3mg/lg JS004; 10mg/kg JS004), dose expansion (3mg/kg JS004 and 200mg JS004) and indication expansion. Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>* Other names: TAB004;Biological: Drug：JS001, Intravenous infusion<br>* Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>|
| Experimental: 240mg JS004+200mg JS001, Q3W until to 2 years<br>Dose escalation, enrolled 3-6 subjects; Dose expansion, enrolled 6-9 subjects and indication expansion if RP2D is confirmed this arm | Biological: JS004 , Recombinant humanized IgG4k monoclonal antibody specific to BTLA for injection Intravenous infusion<br>* Part A: including dose escalation (1mg/kg JS004; 3mg/lg JS004; 10mg/kg JS004), dose expansion (3mg/kg JS004 and 200mg JS004) and indication expansion. Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>* Other names: TAB004;Biological: Drug：JS001, Intravenous infusion<br>* Part B: including dose escalation (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001), dose expansion (240mg JS004+100mg JS001; 240mg JS004+ 200mg JS001) and indication expansion.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants and severiaty with treatment-related Adverse events as assessed by CTCAE V5.0 | Safety and Tolerability | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) per Lugano response critieria 2014 for Lymphoma |  | 2 Years | 
| Duration of Response (DOR) per Lugano response critieria 2014 for Lymphoma |  | 2 Years | 
| Disease Control Rate (DCR) per Lugano response critieria 2014 for Lymphoma |  | 2 Years | 
| Progrssion-free survival (PFS) per Lugano response critieria 2014 for Lymphoma |  | 2 Years |