KeyLargo: Pembrolizumab + Oxaliplatin + Capecitabine in Gastric Cancer

A Single Arm, Phase II Study of Pembrolizumab, Oxaliplatin, and Capecitabine in the First Line Treatment of Patients With Gastro-esophageal Cancer.

This study will be conducted in two stages: 1) safety validation and 2) dose expansion

1. Safety Validation Cohort: The first portion of the study will preliminarily establish the tolerability of the combination of pembrolizumab, oxaliplatin and capecitabine. Five (5) subjects will be enrolled and their safety data after 21 days of treatment will be reviewed before additional subjects are enrolled. Subjects on this portion of the study will only be enrolled at the Duke Cancer Institute.
2. Dose Expansion Cohort: The second portion of the study (ie. phase II) will enroll 30 subjects. In the dose expansion cohort, the first cycle will be modified to allow one week of pembrolizumab monotherapy before starting capecitabine and oxaliplatin (XELOX) chemotherapy, which will allow analysis of biomarkers related to pembrolizumab. Subjects on this portion of the study will be enrolled at the Duke Cancer institute and select external collaborating institutions.

The primary objective of this trial is to describe the progression free survival (PFS) associated with the combination of pembrolizumab, oxaliplatin and capecitabine (pembrolizumab +XELOX) in all patients with previously untreated metastatic esophagogastric adenocarcinoma.

Study Overview

• Status: Completed
• Conditions: Gastric Cancer; Esophagus Cancer
• Intervention / Treatment: Drug: Oxaliplatin+Capecitabine+Pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Clayton, North Carolina, United States, 27520
      • Johnston Health Services Corporation
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Center, Duke University
    • Henderson, North Carolina, United States, 27536
      • Maria Parham Healthcare Association
    • Laurinburg, North Carolina, United States, 28352
      • Scotland Health Care System
    • Lumberton, North Carolina, United States, 28358
      • Southeastern Regional Medical Center
    • Smithfield, North Carolina, United States, 27577
      • Johnston Health Services Corporation
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Lexington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically and/or cytologically documented and radiographically measurable (by RECIST 1.1) adenocarcinoma of the esophagus or stomach (HER2-positive or negative) that is metastatic/recurrent and not amenable to potentially curative treatment
• No prior chemotherapy for metastatic/recurrent disease. Prior adjuvant or neo-adjuvant treatment with a fluoropyrimidine or fluoropyrimidine based regimen is allowed only if it is completed at least 6 months prior to the start of study drug, whether given alone or with radiation therapy. Patients who have received prior neo-adjuvant therapy (chemotherapy and/or radiation therapy) which did not contain 5-FU or capecitabine and have been diagnosed with metastatic disease (with no previous treatment in the metastatic setting) are eligible. No 6-months window is required for these patients. In the setting of metastatic disease requiring local palliation, only radiosensitizing doses of 5-FU or capecitabine monotherapy are permitted.
• Prior radiation therapy is permitted, provided is completed at least 28 days prior to the start of study drug.
• Age ≥ 18 years with ability to understand and willingness to provide informed consent.
• ECOG performance status of 0 or 1.

• Adequate organ and marrow function as defined below by the following:

  1. Absolute neutrophil count (ANC) ≥ 1500 µl
  2. Platelets ≥ 100,000/µl
  3. Hemoglobin (Hgb) ≥ 9 g/dL
  4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  5. AST/ALT ≤ 2 x ULN without liver metastasis; ≤ 5 x ULN with liver metastasis
  6. Creatinine clearance ≥ 50 cc/min

Exclusion Criteria:

• Prior therapy with an anti-PD-1, anti PD-L1, anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agents.
• Chemotherapy, targeted small molecule therapy, radiotherapy, experimental agents, prior therapy with anti-tumor vaccines or other immune-stimulatory antitumor agents, or biological cancer therapy (including monoclonal antibodies) within 14 days prior to the start of study drug, or not recovered (≤ grade 1 or baseline) from adverse events due to a previously administered agent.
• Known CNS metastases and/or carcinomatous meningitis. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for at least 30 days prior to the start of study drug.
• Documented history of clinically significant autoimmune disease (other than well-controlled hypothyroidism) or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo, type I diabetes mellitus, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Receiving systemic steroid therapy or any form of immunosuppressive therapy within 1 week prior to the start of study drug.
• Received a live vaccine within 4 weeks prior to the start of the study drug.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Known history of HIV seropositivity, hepatitis C virus, acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment. Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or chronic obstructive pulmonary disease) are eligible.
• Pregnant or breastfeeding
• Not willing to use an effective method of birth control
• Concurrent severe and/or uncontrolled medical conditions, which may compromise participation in the study, including impaired heart function or clinically significant heart disease.
• Current use of medication specified by the protocol as prohibited for administration in combination with the study drug. This includes patients with a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to the start of study drug. Inhaled or topical steroids and adrenal replacement doses > 10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Recent or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment within 2 weeks prior to the start of study drug.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the start of study drug (56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study (except fot rhe planned metastatectomy).
• Serious, non-healing wound, ulcer, or bone fracture.
• History of myocardial infarction, NYHA lass III or IV congestive heart failure, arrhythmia requiring therapy, unstable angina, cardia or other vascular stenting, angioplasty, or surgery within 6 months prior to the start of study drug.
• History of other carcinomas within the last five years, except cured non-melanoma skin cancer, curatively treated in-situ cervical cancer, or localized prostate cancer with a current PSA of < 1.0mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to the start of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxaliplatin+Capecitabine+Pembrolizumab	Drug: Oxaliplatin+Capecitabine+Pembrolizumab; For each cycle: Oxaliplatin 130 mg/m2 IV on Day1, Capecitabine 825 or 1000 mg/m2 PO, BID Days on Days1-14, Pembrolizumab 200 mg IV on Day 1. This study has 2 parts: Safety validation part: all Cycles are 21 days in length.; Dose Expansion part: Cycle 1 is 28 days in length. Cycle 2 and beyond are 21 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Months of Progression-free Survival (PFS)	PFS measured from study entry until documented progression or death from any cause. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Patients who have not experienced progression will be censored at the date of the last radiographic assessment. The median PFS will be estimated using the Kaplan-Meier method.	Up to 44 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate as Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	Response rate is calculated as the number of people with a complete response or partial response, divided by the total number of people treated. Complete response is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Up to 44 months
Months of Overall Survival	Overall survival is the amount of time subjects live since starting the study.	Up to 44 months

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Hope Uronis, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2018
• Primary Completion (Actual): February 6, 2023
• Study Completion (Actual): February 6, 2023

Study Registration Dates

• First Submitted: November 10, 2017
• First Submitted That Met QC Criteria: November 10, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: gastric cancer; pembrolizumab; XELOX
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Stomach Neoplasms; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Capecitabine; Oxaliplatin; Pembrolizumab
• Other Study ID Numbers: Pro00080566

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No