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

Sponsor

Yonsei University (Other)

Overall Status

Completed

CT.gov ID

NCT05535569

Collaborator

(none)

Enrollment

Location

Arm

52.2

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent/Metastatic Gastric Cancer	Drug: Nivolumab, Paclitaxel	Phase 1/Phase 2

Detailed Description

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 Design

Study Type:

Interventional

Actual Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 17, 2017

Actual Primary Completion Date :

Nov 22, 2021

Actual Study Completion Date :

Nov 22, 2021

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

(Phase Ib) Maximum Tolerated dose (MTD) [424 weeks]
Maximum Tolerated dose (MTD) as determined by Dose limiting Toxicity (DLT).
(Phase Ib) Recommended phase 2 dose [424 weeks]
Recommended phase 2 dose as determined by Dose limiting Toxicity (DLT).
(Phase II) PFS [424 weeks]
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.

Secondary Outcome Measures

OS [24 weeks]
Overall Survival (OS): the time from the date of first dose and the date of death from any cause
ORR [24 weeks]
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
DCR [24 weeks]
Disease Control Rate (DCR): the proportion of randomized patients achieving a best overall response of CR, PR, or SD.
PFS [24 weeks]
Progression-free survival (PFS): To evaluate the treatment effect of nivolumab and paclitaxel on progression-free survival (PFS) rate at 24 weeks

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.