A TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF SHR-A1904 IN SUBJECTS WITH ADVANCED SOLID TUMORS

Study Overview
=================
Brief Summary
-----------------
The study (dose escalation/expansion) is being conducted to assess the safety and tolerability of SHR-A1904 in subjects with advanced solid tumors, and to determine maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), to assess preliminary efficacy of SHR-A1904, pharmacokinetic (PK) profile and immunogenicity of SHR-A1904 in subjects with advanced solid tumors.

Official Title
-----------------
AN OPEN-LABEL, SINGLE-ARM, MULTI-CENTER PHASE I/IIA CLINICAL STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF SHR-A1904 IN SUBJECTS WITH ADVANCED SOLID TUMORS

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: SHR-A1904


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Evidence of a personally signed and dated ICF indicating that the subject has been informed of all pertinent aspects of the study. Age >18. ECOG performance status of 0-1. Life expectancy of ≥3 months. Subjects with pathologically diagnosed advanced relapsed or refractory solid tumors, either gastric and gastroesophageal junction (GEJ) cancer, or pancreatic cancer, who are intolerable to SoC, have progressed through all available treatment options, or for whom there is no efficacious treatment available. Subjects must have pathological classification (e.g., adenocarcinoma etc.) documented. Positive expression of Claudin 18.2 (>=50% of cells with 2+ or 3+ expression, either from fresh or archival tissue) is required prior to enrollment and participation in this study. Positivity for Claudin 18.2 is defined as tumor cells showing partial or complete membrane staining. The percentage of tumor cells at four different staining intensities will be estimated: 0 (no staining), 1+ (weak), 2+ (moderate), and 3+ (strong). The sum of all 4 percentages should equal 100%. The H-score is determined according to the H-Score formula: [1 x Percentage of tumor cells stained at 1+] + [2 x Percentage of tumor cells stained at 2+] + [3 x Percentage of tumor cells stained at 3+] = H-Score (range 0 or 1-300). Actual figure of Claudin 18.2 expression tested by IHC should be documented. Subjects must have pathological classification (e.g., adenocarcinoma) documented. Has at least one measurable lesion as defined by RECIST v1.1. Has adequate organ and bone marrow function within 7 days prior to administration of study treatment defined below: with no blood transfusion or hematopoietic growth factor support within 2 weeks prior to screening): • Absolute neutrophil count (ANC) ≥1.5 × 109 /L • Platelet count (PLT) ≥100 × 109 /L • Hemoglobin (Hb) ≥90 g/L • TBIL ≤1.5 × ULN • ALT and AST ≤3 × ULN (≤5 × ULN for liver metastasis) • Creatinine clearance ≥60 mL/min/1.73 m2 based on Cockcroft-Gault equation (Appendix 5) • Activated partial thromboplastin time (APTT) and prothrombin time (PT) ≤1.5 × ULN. • Fridericia-corrected QT interval (QTcF) ≤450 msec. If ECG demonstrates QTc >450 msec at screening, an ECG re-examination is allowed, and subjects will be eligible if it demonstrates QTc ≤ 450 msec. • LVEF ≥50%. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 3 days before the first dose. WOCBP and male subjects whose partners are WOCBP must agree to use effective contraception method during the study period and within 5 half-lives of SHR-A1904 + 6 months after the last dose of SHR-A1904. (see Appendix 2 for details). Exclusion Criteria: Plan to receive any other anti-tumor treatments during the treatment period of this study. Subjects participated in a prior investigational study or received anticancer treatment, and have not recovered from side effects of such therapy. Underwent major surgical operation within 4 weeks before the first dose of this IP. Received treatments with strong CYP3A4, CYP2D6, P-gp, or BCRP inhibitors or inducers within < 5 half-lives of the drug before the first dose of the study. Previously received total gastrectomy (only for subjects of the dose-escalation part. Adverse events caused by previous anti-tumor treatments have not recovered to Grade ≤1 according to NCI-CTCAE 5.0 (except for alopecia; some tolerable chronic Grade 2 toxicities may also be excluded as judged by the investigator after consultation with the sponsor). Known to be allergic to any component of SHR-A1904 product (antibody conjugated toxin, antibody), or allergic to humanized monoclonal antibody products. Subjects with known brain metastases, unless the participant is > 1 month from definitive therapy (surgery or radiotherapy), has no evidence of tumor growth on an imaging study and is clinically stable with respect to the tumor at the start of study intervention. Subjects with a second primary cancer, except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, and other solid tumors curatively treated with no evidence of disease for ≥3 years prior to the first dose of the study. Class III-IV cardiac insufficiency as per the New York Heart Association (NYHA) criteria; arrhythmia requiring long-term drug control; unstable angina or acute myocardial infarction within 6 months before the first dose of the study. Subjects with a history of clinically significant lung diseases (e.g., interstitial pneumonia, radiation pneumonia, and pulmonary fibrosis) or who are suspected to have these diseases by chest imaging at screening period. Serious infections that require use of intravenous antibiotics, antiviral drugs, or antifungal drugs during the study period. Hepatitis B (HBV, chronic or acute; defined as having a known positive hepatitis B surface antigen [HbsAg] test at the time of screening) or hepatitis C (HCV) infection requiring treatment Has a history of immunodeficiency (including positive results of HIV test in screening, and other acquired and congenital immunodeficiencies) or organ transplant. Presence of accompanying diseases (such as poorly controlled hypertension, serious diabetes mellitus, thyroid disorder, psychosis, etc.) that may pose serious risks to the safety of the subject or may affect the subject's ability to complete the study, or any other situation as judged by the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: SHR-A1904 in Subjects with Advanced Solid tumors
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Single Arm : SHR-A1904 | Drug: SHR-A1904<br>* Single Arm ：It is a dose-escalation and dose-expansion study of SHR-A1904 in subjects with advanced solid tumors<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | DLT is defined during the first cycle of the study treatment and assessed as certainly or at least possibly related to SHR-A1904 treatment. | the first cycle of administration, up to 21 days | 
| Maximum tolerated dose (MTD) | defined as the dose with the estimated toxicity probability which is the closest to the target toxicity probability. | the first cycle of administration, up to 21 days | 
| Recommended Phase 2 Dose (RP2D) | RP2D is the dose selected for further study based on the phase I study results. | the first cycle of administration, up to 21 days | 
| Adverse events (AEs) and serious adverse events (SAEs) |  | from the signing of informed consent form to the end of safety follow-up period (90 days after the last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | The proportion of efficacy evaluable subjects with the best overall response (BOR) of CR or PR as per RECIST 1.1 criteria. | evaluated until the end of study, approximately 12 months after the first dose of study drug of the last subject, currently estimated March 2026 | 
| Duration of response (DoR) | defined as the time from first documented tumor response (CR/PR) until PD/death. | evaluated until the end of study, approximately 12 months after the first dose of study drug of the last subject | 
| Clinical benefit rate (CBR) | defined as the percentage of subjects who have achieved complete response (CR), partial response (PR) and/or stable disease (SD) lasting over 24 weeks (CR+PR+SD≥24 weeks). | evaluated until the end of study, approximately 12 months after the first dose of study drug of the last subject | 
| Progression-free survival (PFS) | defined as the time from the first dose until PD/death. | evaluated until the end of study, approximately 12 months after the first dose of study drug of the last subject | 
| Overall survival (OS) | defined as the time from first dose of study drug until death from any cause. | until the end of study, approximately 12 months after the first dose of study drug of the last subject | 
| Time to maximum concentration (Tmax) |  | up to 30 days after the last dose | 
| Maximum concentration (Cmax) |  | up to 30 days after the last dose |