A Study of AK104 in the First-line Treatment of Locally Advanced Unresectable or Metastatic G/GEJ Adenocarcinoma

Study Overview
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Brief Summary
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A randomized, Double-blind, Multicenter, phase III Clinical Study of Comparing the Efficacy and Safety of AK104 Plus Oxaliplatin and Capecitabine (XELOX) Versus Placebo Plus XELOX as First-line Treatment for locally advanced Unresectable or Metastatic Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma.

Official Title
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A Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of AK104 Plus Oxaliplatin and Capecitabine (XELOX) Versus Placebo Plus XELOX as First-line Treatment for Locally Advanced Unresectable or G/GEJ Adenocarcinoma

Conditions
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Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Drug: AK104
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be enrolled in the study: Ability to understand and voluntarily sign a written informed consent form (ICF), which must be signed before the specified study procedures required for the study are performed. Males or females aged ≥ 18 to ≤ 75 years at the time of signing informed consent. Histopathologically confirmed gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma. Unresectable locally advanced or metastatic gastric adenocarcinoma or GEJ adenocarcinoma. Subjects have not received prior systemic therapy for locally advanced or metastatic gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction. For subjects who have received prior neoadjuvant/adjuvant chemotherapy or chemoradiotherapy for curative intent, the time between disease progression and last treatment should be at least 6 months. Subjects have at least one measurable tumor lesion per RECIST v1.1; lesions that received radiotherapy are not selected as target lesions, unless the lesion is the only measurable lesion and has unequivocal progression as judged by imaging, it can be considered as a target lesion. Exclusion Criteria: Subjects who meet any of the following criteria are not eligible to participate in this study: Subjects with known HER2-positive gastric or GEJ adenocarcinoma. Histopathology or cytology confirmed other pathological types, such as squamous cell carcinoma, sarcoma, or undifferentiated carcinoma. Subjects who received palliative local therapy for non-target lesions within 2 weeks prior to the first dose; systemic nonspecific immunomodulatory therapy (e.g., interleukin, interferon, thymosin, etc.) within 2 weeks prior to the first dose; and Chinese herbal medicine or traditional Chinese medicinal products with anti-tumor indications within 2 weeks prior to the first dose. Subjects who received any prior treatments targeting the mechanism of tumor immunity. Medical history of gastrointestinal perforation or gastrointestinal fistula within 6 months prior to the first dose. If the perforation or fistula has been treated with resection or repair and the disease has recovered or resolved as judged by the Investigator, enrollment may be allowed. Active or previously documented inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). Active malignancies within the past 3 years, with the exception of tumors in this study and cured local tumors, such as basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma in situ of cervix, carcinoma in situ of breast, localized prostate cancer, etc. Known active or untreated brain metastases, meningeal metastases, spinal cord compression, or leptomeningeal disease. Presence of clinically symptomatic pleural effusion, pericardial effusion, or ascites requiring frequent drainage (≥ 1/month). Active autoimmune disease requiring systemic treatment within 2 years prior to the start of study treatment, or autoimmune diseases that may relapse or require scheduled treatment as judged by the Investigator.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK104 + Oxaliplatin + Capecitabine<br>AK104 in combination with Oxaliplatin and Capecitabine | Drug: AK104<br>* AK104 (administered on Day 1 of each cycle, Q3W)+Oxaliplatin (130 mg/m2 intravenous infusion for 2-6 hours on Day 1, Q3W,up to 6 cycles)+ Capecitabine(1000 mg/m2, p.o., Bid, Q3W,up to 6 cycles) . Afterward, AK104 will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W)<br>* Other names: Capecitabine;|
| Placebo Comparator: Placebo + Oxaliplatin + Capecitabine<br>Placebo in combination with Oxaliplatin and Capecitabine | Drug: Placebo<br>* Placebo (administered on Day 1 of each cycle, Q3W)+Oxaliplatin (130 mg/m2 intravenous infusion for 2-6 hours on Day 1, Q3W,up to 6 cycles)+ Capecitabine(1000 mg/m2, p.o., Bid, Q3W,up to 6 cycles) . Afterward,Placebo will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W)<br>* Other names: Capecitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (os) | OS in the ITT population. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | ORR is the proportion of subjects with CR or PR based on RECIST v1.1 | Up to 2 years | 
| DCR | DCR is defined as the proportion of subjects with CR, PR, or SD, based on RECIST v1.1 | Up to 2 years | 
| DoR | DoR is defined as the duration from the first documentation of objective response to the first documented disease progression or death due to any cause, whichever occurs first. | Up to 2 years | 
| TTR | TTR is defined as the time to response base on RECIST v1.1 | Up to 2 years | 
| PFS | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first assessed by investigator Per RECIST 1.1 | Up to 2 years | 
| AE | Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and clinically significant abnormal laboratory results. | From the subject signs the ICF to 30 days (AE) and 90 days (SAE) after the last dose of study treatment or initiation of other anti-tumor therapy, whichever occurs first | 
| Observed concentrations of AK104 | The endpoints for assessment of PK of AK104 include serum concentrations of AK104 at different timepoints after AK104 administration | From first dose of AK104 through the last dose of AK104, about average of 9 months. | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK104 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs). | From first dose of AK104 through 30 days after last dose of AK104 |