Safety, Tolerability and Pharmacokinetics of a Recombinant Humanized mAb Specific to B-and T-Lymphocyte Attenuator (BTLA) for Injection in Subjects With Advanced Malignancies

A Phase I Clinical Study of JS004, a Recombinant Humanized mAb Specific to B-and T-Lymphocyte Attenuator (BTLA), in Subjects With Advanced Solid Malignancies

A 3-part (dose-escalation, dose-expansion and cohort-expansion) phase I clinical study of JS004 in subjects with advanced solid malignancies in China for the first time, to evaluate the safety, tolerability, PK, immunogenicity, antitumor activity and biomarkers of JS004, define the MTD and RP2D. A cycle is 21 days (3 weeks) which includes JS004 being administered IV Q3W. All patients will be treated until disease progression per RECIST v1.1 and iRECIST, 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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Biological: Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijin, Beijing, China, 100021
      • Cancer Hospital Chinese Academy of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able to understand and willing to sign the Informed Consent Form;
2. 18-70 years(included), male or female;
3. Subjects with histologically or cytologically confirmed advanced solid tumor.
4. In Dose Escalation and Dose Expansion, patients must have received, or be ineligible for or intolerant of all available approved or standard therapies known to confer clinical benefit, or for whom no standard therapy exists; in Indication Extension, patients with advanced solid tumors, who must have received at least one line of therapy for advanced or metastatic disease, but are not required to have received all standard therapies known to confer clinical benefit;
5. ECOG performance status of 0 or 1;
6. Life expectancy ≥12 weeks;
7. At least one measurable lesion per RECISTv1.1 and iRECIST;
8. Willingness to provide consent for fresh pre-treatment biopsies, or,an archival specimen could be required within two years prior to the first dose of study drug;
9. Adequate organ and marrow function per protocol specifically defined;
10. Females of childbearing potential ,and males who are sexually active with a female partner of childbearing potential, must use effective contraception from time of screening, and must agree to continue using such precautions for 3 months after the final dose of JS004; HCG testing will be conducted and negative result within 7 days before randomization for females of childbearing potential, and must not be breast-feeding;

Exclusion Criteria:

1. Known allergic reaction to any monoclonal antibody or the ingredients and compositions of JS004 .
2. Prior exposure to anti-BTLA, or anti-HVEM antibodies.
3. Concurrent enrollment in another clinical study within 4 weeks prior to first dose of JS004, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
4. Major surgery (as defined by the investigator) within 4 weeks prior to first dose of JS004 or still recovering from prior surgery.Any concurrent chemotherapy within 4 weeks prior to first dose of JS004 , radiotherapy, immunotherapy, or biologic therapy for cancer treatment. Traditional Chinese/Chinese Patent Medicine preparations within 2 weeks prior to first dose of JS004 for treating tumors approved by NMPA.Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Isolated lesions for palliative intent is acceptable (e.g., by local surgery or radiotherapy) without influence in efficacy assessment.
5. Patients who have discontinued prior immune therapy due to immune mediated adverse reaction(s).
6. Current or prior use of immunosuppressive medication within 4 weeks prior to the first dose of JS004, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids not to exceed 10 mg/day of prednisone or equivalent.
7. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
8. Receipt of live attenuated vaccination within 30 days of receiving JS004.
9. Two or more malignant tumors within 5 years prior to the first dose of JS004. Except the following conditions: radically cured early malignant tumor (carcinoma in situ or stage I tumor), for example, adequately treated cervical carcinoma in situ, basal or squamous cell skin cancer.
10. Symptomatic or untreated central nervous system (CNS) metastases or requiring ongoing treatment for CNS metastases, including corticosteroids and antiepileptic agents. Subjects with previously treated brain metastases may participate unless clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging metastases, and are off steroids.
11. 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 JS004 may be included (e.g., hearing loss) after consultation with the medical monitor.
12. Active or prior documented autoimmune disease, such as but not limited to systemic lupus erythematosus or multiple sclerosis, within the past 2 years.
13. History of anaphylaxis, eczema that cannot be controlled with topical corticosteroids, or asthma.
14. History of primary immunodeficiency.
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, fever of unknown origin > 38.5 °C ( Subjects with tumorous fever will be determined by investigator), symptomatic congestive heart failure according to New York Heart Association (NYHA) Functional Classification ≥ 3, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis
16. Patients with known history of active tuberculosis, and drug-induced interstitial lung disease or pneumonitis ≥ Grade 2.
17. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
18. Subjects who are known to be human immunodeficiency virus (HIV) positive.
19. Subjects with evidence of hepatitis B or C virus infection, unless their hepatitis is considered to have been cured. (Note that subjects with prior hepatitis B virus [HBV] infection, HBc Ab positive and HBs Ag negative at screening visit, must have HBV viral load [VL] less than the local normal range of study site before study enrollment; hepatitis C virus [HCV] infection must have, HCV RAV negative before study enrollment.
20. Pregnant or breastfeeding women.
21. Patients with vitiligo, alopecia and controlled endocrine deficiency by hormone replacement therapy, such as hypothyroidism, can be included. Patients with rheumatoid arthritis and other joint diseases, Schering's syndrome, chylosis and psoriasis that have been controlled with topical administration, and patients with positive serological tests such as antinuclear antibody (ANA) and antithyroid antibody, should be assessed whether target organs are affected and systemic treatment required. It is up to the investigator to determine if the patient could be enrolled or not.
22. Having other factors that may possibly cause halfway-termination of this study as judged by investigators, for example, which may influence the right & benift、safety of subjects, incompliance with the protocol, the capability to be informed consent, and other medical (e.g. the conditions or disease of respiratory, metabolic, congenital, endocrine and central nervous system, etc), family or social factors.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 0.3mg/kg repeat dose every 21 days up to 2 years	Biological: Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Other Names: TAB004
Experimental: 1 mg/kg repeat dose every 21 days up to 2 years;	Biological: Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Other Names: TAB004
Experimental: 3 mg/kg repeat dose every 21 days up to 2 years;	Biological: Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Other Names: TAB004
Experimental: 10 mg/kg repeat dose every 21 days up to 2 years;	Biological: Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Drug: JS004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Intravenous infusion; Other Names: TAB004

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT, MTD, Number of participants and severiaty with treatment-related Adverse events (AEs) as assessed by CTCAE v5.0	DLT, MTD, Number of participants and severity with treatment-related Adverse events (AEs) as assessed by CTCAE v5.0	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	Objective Response Rate(ORR) by RECIST 1.1	2 years
DOR	Duration of Response (DOR) by RECIST 1.1	2 years
DCR	Disease Control Rate (DCR) by RECIST 1.1	2 years
PFS	Progression-free survival(PFS) by RECIST 1.1	2 years
OS	Overall survival(OS) by RECIST 1.1	2 years
RO	BTLA receptor of occupancy (RO) of blood	2 years
Cmax	Maximum Plasma Concentration(Cmax) after injection of JS004	2 years
Tmax	Perk Time(Tmax) after injection of JS004	2 years
Area Under the Cure(AUC) after injection of JS004	AUC	2 years
t1/2 half life	t1/2 after injection of JS004	2 years
Plasma Clearance(CL)	Plasma Clearance(CL) after injection of JS004	2 years
Volume of distribution(V)	Apparent volume of distribution after injection of JS004	2 years
Cmin	Minimum Plasma concentration(Cmin) of steady state after multiple dose injection of JS004	2 years
volume of distribution of steady state (Vss)	Apparent volume of distribution of steady state (Vss) after multiple dose injection of JS004	2 years
ADA	The presence of anti-drug antibody (ADA) after multiple dose injection of JS004	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictive biomarkers	Predictive biomarkers, including but not limited to, BTLA and HVEM	2 years

Collaborators and Investigators

• Sponsor: Shanghai Junshi Bioscience Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2020
• Primary Completion (Actual): July 13, 2023
• Study Completion (Actual): July 13, 2023

Study Registration Dates

• First Submitted: February 18, 2020
• First Submitted That Met QC Criteria: February 19, 2020
• First Posted (Actual): February 20, 2020

Study Record Updates

• Last Update Posted (Actual): June 19, 2025
• Last Update Submitted That Met QC Criteria: June 18, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Antibodies; Antibodies, Monoclonal
• Other Study ID Numbers: JS004-001-I

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No