SHR-A1811 for Subjects With Her2-positive Gastric Cancer and Gastroesophageal Junction Adenocarcinoma After Progression on or After First-line Anti-HER2 Therapy-containing Regimen

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of SHR-A1811 compared with treatment chosen by the investigator in participants with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) gastric or GEJ adenocarcinoma (based on [American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines who have progressed on or after a first-line anti-HER2 therapy-containing regimen.

Official Title
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A Phase 3, Multicenter, Randomized, Open-label Study of SHR-A1811 (HER2-ADC) Compared With the Chemotherapy Treatment Chosen by the Investigators for Subjects With HER2-positive Metastatic and/or Unresectable Gastric Cancer or Gastroesophageal Junction Adenocarcinoma Who Have Progressed on or After First-line Anti-HER2 Therapy-containing Regimen

Conditions
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HER2-positive Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Drug: SHR-A1811
* Drug: Ramucirumab / Paclitaxel/ Docetaxel/ Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years old, male and female; Histologically or cytologically confirmed gastric or gastroesophageal junction adenocarcinoma, and unresectable locally advanced or metastatic disease Prior anti-HER-2 containing treatment Progression on or after first-line standard treatment (Prior neoadjuvant or adjuvant therapy can be counted as a line of therapy if the subject progressed on or within 6 months of completing neoadjuvant or adjuvant therapy); Centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) as classified by ASCO-CAP on a tumor biopsy At least one measurable lesion according to the solid tumor response Evaluation Criteria (RECIST 1.1); ECOG: 0-1; Expected survival ≥12 weeks; Good blood reserve and liver, kidney and coagulation function; Willing to provide informed consent for study participation. Exclusion Criteria: Receive the last dose of anti-cancer therapy(including chemotherapy, radiotherapy, biological therapy, targeted therapy or immunotherapy) within 4 weeks, prior to the first dose; Known allergies to monoclonal antibodies and inactive ingredients of this product, and allergies to paclitaxel, docetaxel, and irinotecan concurrently; The toxicity of prior anti-tumor therapy did not recover to the level specified by CTCAE v5.0 grade evaluation ≤ Grade 1 or inclusion/exclusion criteria; Clinically active central nervous system metastases; Uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage; Clinically significant gastrointestinal disorder by the opinion of Investigator; Has a history of immunodeficiency, including a positive HIV test; During the screening visits and before the first dose, unexplained fever > 38.5℃, severe infection (CTC-AE > Grade 2), and active pulmonary inflammation were indicated by screening imaging; Subjects with interstitial pneumonia or with ≥ grade 3 interstitial pneumonia during prior treatment with immune checkpoint inhibitors; Active hepatitis B(HBV DNA ≥ 500 IU/mL), hepatitis C (positive for hepatitis C antibody, and HCV-RNA above the lower limit of detection of the analytical method); Clinically significant cardiovascular disease ,such as severe/unstable angina, symptomatic congestive heart failure (NYHA ≥ Class II.), clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention, myocardial infarction within 6 months before the first dose, cerebrovascular accident (including transient ischemic attack); QTcF of 12-lead ECG was ≥470 ms; Left ventricular ejection fraction <50%; Clinically uncontrolled hypertension; Had other malignancies with 5 years; Pregnant or lactating women; Other factors that might have led to drop out the study by the investigator opinion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR-A1811<br> | Drug: SHR-A1811<br>* SHR-A1811 6.4 mg/kg IV infusion every 3 weeks on Day 1 of each 21-day cycle<br>|
| Active Comparator: The investigators' choice<br> | Drug: Ramucirumab / Paclitaxel/ Docetaxel/ Irinotecan<br>* Ramucirumab 8mg/kg，D 1,15 + Paclitaxel 80mg/m2，D1,8,15，Q4W; Paclitaxel 80mg/m2，D1,8,15，Q4W; Docetaxel 75mg/m2，D1，Q3W; Irinotecan 150mg/m2，D1，Q2W.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | defined as the time from date of randomization until death from any cause. | Time from date of randomization until death (due to any cause), up to approximately 42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | defined as the time from date of randomization until first objective radiographic tumor progression or death from any cause, based on Investigator assessment. | Time from date of randomization until first objective radiographic disease progression or death (due to any cause) whichever occurs first, up to approximately 42 months | 
| Objective response rate (ORR) | defined as the proportion of participants who achieve a best response of complete response (CR) or partial response (PR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by Investigator. | From start of treatment to date of documented disease progression, up to approximately 42 months | 
| Duration of response (DoR) | defined time from the initial response (CR or PR) until documented tumor progression or death from any cause and based on Investigator assessment. | Time from initial response (CR or PR) to date of documented disease progression or death (due to any cause) whichever occurs first, up to approximately 42 months | 
| Disease control rate (DCR) | defined as the proportion of participants who achieved CR, PR, or stable disease (SD) for a minimum of 6 weeks during study treatment, based on Investigator assessment. | From start of treatment to date of documented disease progression, up to approximately 42 months | 
| AE and SAE | Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0. | From time subjects signs informed consent form up to 40 days after last study dose | 
| Immunogenicity indicators of SHR-A1811: including anti-SHR-A1811 antibodies (ADA and neutralizing antibodies) |  | approximately 42 months | 
| Serum concentrations of SHR-A1811 toxin-binding antibodies and free toxin SHR169265 |  | approximately 42 months |