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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent/Metastatic Gastric Cancer
• Intervention / Treatment: Drug: Nivolumab, Paclitaxel

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Yonsei University Health System, Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Has provided digned written informed Consent
2. Is male or female ≥19 years of age
3. Has a histologically or cytologically confirmed diagnosis of advanced gastric adenocarcinoma
4. Has documented EBV-related, MSI-high, or PD-L1 positive tumor in primary or metastatic tumor tissue
5. Has a life expectancy of at least 3 months
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Has measurable or evaluable disease as determined by RECIST 1.1.
8. Is able to swallow and retain orally administered medication

9. 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:

1. Has HER2-positive or indeterminate gastric cancer
2. Have multiple cancers
3. Have a current or past history of severe hypersensitivity to any other antibody products
4. Have concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease
5. Have a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging (preferably CT) or clinical findings
6. Have brain or meninx metastases. Patients may be randomized for the study if they are asymptomatic and require no treatment.
7. Have pericardial fluid, pleural effusion, or ascites requiring treatment
8. Have a history of uncontrollable or significant cardiovascular disease
9. Have systemic infection requiring treatment
10. Are contraindicated for paclitaxel

11. Has had prior treatment with:

    - Require or, within 28 days before treatment, have received systemic corticosteroids or immunosuppressants

12. Have undergone surgery (any surgery involving general anesthesia) within 28 days before study treatment
13. Have received radiotherapy for gastric cancer within 28 days before treatment or radiotherapy for bone metastases within 14 days before treatment
14. Have a positive test result for human immunodeficiency virus-1 (HIV-1) antibody,
15. Hepatitis B surface protein (HBs) antigen and HBV titer >2000 IU/ml (10,000 copy/ml), or hepatitis C virus (HCV) antibody positive result
16. Are pregnant or breastfeeding, or possibly pregnant
17. 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
18. 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
19. Are incapable of providing consent for specific reasons, such as concurrent dementia
20. Are otherwise inappropriate for this study in the investigator's or subinvestigator's opinion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Experimental	Drug: Nivolumab, Paclitaxel; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 17, 2017
• Primary Completion (ACTUAL): November 22, 2021
• Study Completion (ACTUAL): November 22, 2021

Study Registration Dates

• First Submitted: September 7, 2022
• First Submitted That Met QC Criteria: September 9, 2022
• First Posted (ACTUAL): September 10, 2022

Study Record Updates

• Last Update Posted (ACTUAL): September 10, 2022
• Last Update Submitted That Met QC Criteria: September 9, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Nivolumab; Epstein-Barr Virus(EBV)-Related, or Microsatellite Instability-High (MSI-H), or Programmed Cell Death Ligand 1 (PD-L1) Positive Advanced Gastric Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Virus Diseases; Infections; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; DNA Virus Infections; Tumor Virus Infections; Herpesviridae Infections; Genomic Instability; Stomach Neoplasms; Epstein-Barr Virus Infections; Microsatellite Instability; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Paclitaxel; Nivolumab
• Other Study ID Numbers: 4-2017-0277

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No