Phase Ib/II Study to Evaluate the Safety and Efficacy of Nivolumab in Combination With Paclitaxel in Epstein-Barr Virus(EBV)-Related, or Microsatellite Instability-High (MSI-H), or Programmed Cell Death Ligand 1 (PD-L1) Positive Advanced Gastric Cancer

Study Overview
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Brief Summary
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This is a Phase Ib/II study to identify the recommended dose of paclitaxel and nivolumab for further study, and to assess the safety and clinical efficacy of this combined treatment in EBV-related, MSI-high, or PD-L1 positive advanced gastric cancer after first line treatment.

Detailed Description
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This is a Phase Ib/II study to identify the recommended dose of paclitaxel and nivolumab for further study, and to assess the safety and clinical efficacy of this combined treatment in EBV-related, MSI-high, or PD-L1 positive advanced gastric cancer after first line treatment. Patients who are EBV-related, MSI-high, or PD-L1 positive will be confirmed by immunohistochemistry (IHC) in a central laboratory (Yonsei Cancer Center), and who meet all eligibility criteria will be enrolled to this study and receive treatment with nivolumab and paclitaxel until progressive disease is confirmed or at least 1 discontinuation criterion is met. It was assumed that about 15% of screened patients will be categorized EBV-related, MSI-high, or PD-L1 positive gastric cancer based on previously reported study results. Part 1>> Phase Ib Phase Ib: 6-12 (The actual number of subjects will be determined by the number of dose escalations to identify MTD and RP2D) Part 2>> Phase II - At the RP2D dose level in phase I part, we will expand phase 2 study for a total of 50 patients. Patients will be treated until the time of disease progression, intolerable toxicities, patient's refusal or consent withdrawal. Tumor assessment will be done every 6 weeks.

Official Title
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Phase Ib/II Study to Evaluate the Safety and Efficacy of Nivolumab in Combination With Paclitaxel in Epstein-Barr Virus(EBV)-Related, or Microsatellite Instability-High (MSI-H), or Programmed Cell Death Ligand 1 (PD-L1) Positive Advanced Gastric Cancer

Conditions
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Recurrent/Metastatic Gastric Cancer

Intervention / Treatment
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* Drug: Nivolumab, Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided digned written informed Consent Is male or female ≥19 years of age Has a histologically or cytologically confirmed diagnosis of advanced gastric adenocarcinoma Has documented EBV-related, MSI-high, or PD-L1 positive tumor in primary or metastatic tumor tissue Has a life expectancy of at least 3 months Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Has measurable or evaluable disease as determined by RECIST 1.1. Is able to swallow and retain orally administered medication Has an adequate baseline organ function defined as: White blood cells ≥3000/mm3 and neutrophils ≥1500/mm3 Platelets ≥100000/mm3 Hemoglobin ≥9.0 g/dL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit of normal (ULN) of the study site (or ≤5.0 × ULN in patients with liver metastases) Total bilirubin ≤2.0 × ULN Creatinine≤1.5 × ULN or creatinine clearance (either measured value or estimated value using the Cockcroft-Gault equation) >60ml/min. Exclusion Criteria: Has HER2-positive or indeterminate gastric cancer Have multiple cancers Have a current or past history of severe hypersensitivity to any other antibody products Have concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease Have a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging (preferably CT) or clinical findings Have brain or meninx metastases. Patients may be randomized for the study if they are asymptomatic and require no treatment. Have pericardial fluid, pleural effusion, or ascites requiring treatment Have a history of uncontrollable or significant cardiovascular disease Have systemic infection requiring treatment Are contraindicated for paclitaxel Has had prior treatment with: - Require or, within 28 days before treatment, have received systemic corticosteroids or immunosuppressants Have undergone surgery (any surgery involving general anesthesia) within 28 days before study treatment Have received radiotherapy for gastric cancer within 28 days before treatment or radiotherapy for bone metastases within 14 days before treatment Have a positive test result for human immunodeficiency virus-1 (HIV-1) antibody, Hepatitis B surface protein (HBs) antigen and HBV titer >2000 IU/ml (10,000 copy/ml), or hepatitis C virus (HCV) antibody positive result Are pregnant or breastfeeding, or possibly pregnant Has any unresolved ≥Grade 2 (per CTCAE v4.0) toxicity from previous anti-cancer therapy at the time of enrollment such as neuropathy, except alopecia or anemia Have previously received nivolumab, anti-programmed cell death-1 (PD-1) antibody, anti-PD-L1 antibody, anti-programmed cell death-ligand 2 (PD-L2) antibody, anti-CD137 antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody, or other therapeutic antibodies or pharmacotherapies for the regulation of T-cells Are incapable of providing consent for specific reasons, such as concurrent dementia Are otherwise inappropriate for this study in the investigator's or subinvestigator's opinion.

Ages Eligible for Study
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Minimum Age: 19 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br> | Drug: Nivolumab, Paclitaxel<br>* Increasing dose levels of paclitaxel (70 mg/m2 or 80 mg/m2 on Days 1, 8 and 15 of a 28-day treatment cycle) in combination with a fixed dose of nivolumab (3 mg/kg on Days 1 and 15 of a 28-day treatment cycle) will be explored using a 3+3 design to evaluate the safety and tolerability and to determine a MTD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase Ib) Maximum Tolerated dose (MTD) | Maximum Tolerated dose (MTD) as determined by Dose limiting Toxicity (DLT). | 424 weeks | 
| (Phase Ib) Recommended phase 2 dose | Recommended phase 2 dose as determined by Dose limiting Toxicity (DLT). | 424 weeks | 
| (Phase II) PFS | Progression-free survival (PFS): Defined as the time from start of study treatment until the date of objective disease progression or death (by any cause in the absence of disease progression) Progression is defined in accordance with the RECIST v1.1 criteria. PFS is defined as the interval between the date of first dose and the earliest date of disease progression or death due to any cause. | 424 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall Survival (OS): the time from the date of first dose and the date of death from any cause | 24 weeks | 
| ORR | Overall response rate (ORR): defined as the percentage of subjects with a confirmed CR or PR per RECIST v1.1 relative to the total number of subjects | 24 weeks | 
| DCR | Disease Control Rate (DCR): the proportion of randomized patients achieving a best overall response of CR, PR, or SD. | 24 weeks | 
| PFS | Progression-free survival (PFS): To evaluate the treatment effect of nivolumab and paclitaxel on progression-free survival (PFS) rate at 24 weeks | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epstein-Barr Virus(EBV)-Related, or Microsatellite Instability-High (MSI-H), or Programmed Cell Death Ligand 1 (PD-L1) Positive Advanced Gastric Cancer, Nivolumab