Combination of TST001, Nivolumab and Chemotherapy as First-line Therapy in Advanced or Metastatic GC/GEJ Adenocarcinoma

Study Overview
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Brief Summary
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Gastric/GEJ adenocarcinomas are aggressive tumors with a high probability of death. Current treatment guidelines include two-drug cytotoxic chemotherapy with a fluoropyrimidine (mFOLFOX6: capecitabine or fluorouracil) and a platinum-based agent (CapOx: oxaliplatin or cisplatin). In addition, the FDA has recently approved nivolumab, a PD-1 checkpoint inhibitor, in combination with chemotherapy as first line treatment for advanced or metastatic gastric/GEJ cancer. TST001 is a recombinant humanized monoclonal antibody against Claudin (a tumor marker found in gastric/GEJ cancer. In this study, the combination therapy of chemotherapy or chemotherapy and nivolumab with and without TST001 (a novel recombinant humanized antibody) could provide additional benefits to the management of these tumors.

Detailed Description
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This Phase 3, randomized, double-blind, placebo-controlled study is designed to evaluate the safety and efficacy of TST001 in combination with nivolumab and chemotherapy or chemotherapy alone in subjects with tumors that express markers (HER2 negative, Claudin18.2 positive, known PD-L1 CPS status) in locally advanced or metastatic gastric/GEJ adenocarcinoma. Patients will be randomized in a 1:1 ration to receive TST001 or placebo in combination with nivolumab and chemotherapy or with chemotherapy alone.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating Combination of TST001, Nivolumab and Chemotherapy as First-Line Treatment in Subjects With Claudin18.2 Positive Locally Advanced or Metastatic Gastric or Gastroesophageal Junction (Gastric/GEJ) Adenocarcinoma

Conditions
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Gastric Cancer, Gastroesophageal-junction Cancer, Advanced Cancer

Intervention / Treatment
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* Drug: TST001, CapOx or mFOLFOX6 and NIVO or (Substudy) TST001, Oxaliplatin and capecitabine or 5-fluorouracil (5-FU)
* Drug: Placebo CapOx or mFOLFOX6 and NIVO or (Substudy) Placebo, Oxaliplatin and capecitabine or 5-fluorouracil (5-FU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of previously untreated, unresectable locally advanced or metastatic gastric/GEJ adenocarcinoma. Must be willing and able to provide archival or fresh tissue sample, a formalin-fixed, paraffin-embedded (FFPE) block, or 10 or more unstained, freshly cut, serial sections (on slides) from an FFPE tumor specimen from a tumor lesion (either primary or metastatic) not previously irradiated or fresh biopsy tissue fixed in formalin solution. FFPE tissue blocks are preferred to slides. Biomarkers positive CDLN18.2 expression and PD-L1 CPS Status Must have at least one measurable lesion or evaluable disease Subjects should be eligible to receive chemotherapy per local guidelines Exclusion Criteria: Any prior systemic anticancer treatment (chemotherapy, immunotherapy, biologic therapy, or targeted therapy) for gastric/GEJ adenocarcinoma. Has received prior radiotherapy within 2 weeks before randomization Anti-CLDN18.2 agents at any time. Any traditional Chinese medicine or proprietary Chinese medicine with anti-tumor effect within 7 days before randomization. Any vaccines (live, attenuated, or research vaccines) within 30 days of dosing. Gastrointestinal abnormalities including: Documented unresolved gastric outlet obstruction or persistent vomiting defined as ≥3 episodes within 24 hours within 2 weeks before randomization. Uncontrolled peptic ulcer disease Clinically significant gastrointestinal bleeding as evidenced by hematemesis, hematochezia, or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy Squamous cell or undifferentiated gastric cancer HER2 positive tumor defined as immunohistochemistry 3+ or ISH/FISH positive Known additional malignancy that is progressing or has required active treatment within the past 5 years. Known symptomatic or progressive CNS metastases and/or carcinomatous meningitis. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior randomization. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of immunomodulatory agents, corticosteroids or immunosuppressive drugs). Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. Has Grade ≥ 2 peripheral sensory neuropathy Has an active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy within 2 weeks of Cycle 1 Day 1 (first dose of study treatment). Has a known history of HIV infection. Subjects with a CD4+ T cell count > 350 cells/µL and no history of an AIDS-defining opportunistic infections are eligible for entry. HIV testing is required only for the subject's safety at the discretion of the investigator. Has active viral hepatitis. Subjects with serologic evidence of HBV infection (defined by a positive hepatitis B surface antigen test) who have a viral load below the limit quantification (HBV DNA titer < 1000 cps/mL or 200 IU/mL) and are not currently on viral suppressive therapy may be eligible. Subjects with a history of HCV infection should have completed curative antiviral treatment and have a viral load below the limit of quantification. Major surgery within 4 weeks prior to study entry; Minor surgery within 2 weeks prior to study entry. Has not recovered from the procedure and/or any complications from the surgery prior to randomization. Severe cardiovascular disease, including cerebral vascular accident, transient ischemic attack, myocardial infarction, or unstable angina, NYHA class III or IV heart failure or ≥ Grade 2 uncontrolled arrhythmia within 6 months of screening. Corrected QTcF ≥470 ms (male) and ≥480 ms (female) at baseline (Fridericia); taking concomitant medications that would prolong the QT interval; or with family history of long QT syndrome Prior stem cell, bone marrow or solid organ transplant. Has a history or current evidence of any condition (including psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Randomized, Double-Blind, Placebo-Controlled
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TST001<br>TST001 | Drug: TST001, CapOx or mFOLFOX6 and NIVO or (Substudy) TST001, Oxaliplatin and capecitabine or 5-fluorouracil (5-FU)<br>* All medications administered intravenously<br>* Other names: TST001 and Oxaliplatin and capecitabine or 5-fluorouracil (5-FU), folinic acid and oxaliplatin and Nivolumab;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo CapOx or mFOLFOX6 and NIVO or (Substudy) Placebo, Oxaliplatin and capecitabine or 5-fluorouracil (5-FU)<br>* All medications administered intravenously<br>* Other names: Placebo and Oxaliplatin and capecitabine or 5-fluorouracil (5-FU), folinic acid and oxaliplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) based on RECIST (1.1) | Compare PFS of patients treated with TST001 or Placebo in addition to CapOx or mFOLFOX6 and nivolumab or CapOx or mFOLFOX6 | From date of randomization until the date of documented progression, assessed up to 100 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) based on RESIST (log-rank test) | Compare OS of patients treated with TST001 or Placebo in addition to CapOx or mFOLFOX6 and nivolumab or CapOx or mFOLFOX6 | rom date of randomization until the date of documented progression, assessed up to 100 days after last dose | 
| Overall Response Rate (ORR) based on RESIST progressive disease (log-rank test) | Compare complete response (CR) or partial response (PR) between treatment arms of patients treated with TST001 or Placebo in addition to CapOx or mFOLFOX6 and nivolumab or CapOx or mFOLFOX6. | From date of randomization until the date of documented CR or PR assessed up to 100 days after last dose | 
| Quality of Life (QOL) assessed on EuroQol EQ5D-5L | Change in QOL assessments from baseline of patients treated with TST001 or Placebo in addition to mFOLFOX6 and nivolumab or CapOx or mFOLFOX6. Assessments include Cancer QOL questionnaires (QLC-STO22, EQ5D-5L, and QLQ-C30) | From date of randomization until the date of documented progression, assessed up to 100 days after last dose | 
| Disease Control Rate (DCR) based on RESIST assessed as the percentage of subjects with measurable disease | Compare complete response (CR), partial response (PR), or stable disease (SD) between treatment arms of patients treated with TST001 or Placebo in addition to CapOx or mFOLFOX6 and nivolumab or CapOx or mFOLFOX6. | From date of randomization until the date of documented progression, assessed up to 100 days after last dose | 
| Duration of Response (DOR) based on RESIST (log-rank test) | Compare duration of response between treatment arms of patients treated with TST001 or Placebo in addition to CapOx or mFOLFOX6 and nivolumab or CapOx or mFOLFOX6. | From date of randomization until the date of documented progression, assessed up to 100 days after last dose | 
| Time to Response (TTR) of progression based on RESIST | Compare the time of response between treatment arms of patients treated with TST001 or Placebo in addition to CapOx or mFOLFOX6 and nivolumab or CapOx or mFOLFOX6 based on CR or PR. | From date of randomization until the date of documented progression, assessed up to 100 days after last dose |