Pembrolizumab, Trastuzumab, HER2 Positive Gastric Cancer

A Phase Ib/II Study of First Line Pembrolizumab in Combination With Trastuzumab, Capecitabine, and Cisplatin in HER2 Positive Gastric Cancer

Gastric cancer is one of the major health problems worldwide, and one of the leading cause of death especially in Asia. Though the cytotoxic chemotherapy is the main treatment option, newer and molecularly targeted agents are recently incorporated to improve the survival outcome. Human epidermal growth factor receptor 2 (HER2, ErbB2) is a transmembrane tyrosine kinase receptor and is overexpressed or amplified in 10-20% of gastric cancer. Recently, Trastuzumab for Gastric Cancer (ToGA) study reported the clinical benefit of trastuzumab for HER2 positive gastric cancer patients. However, because the majority of patients develop intrinsic or acquired resistance within 1 year, elucidating the molecular mechanisms for trastuzumab resistance is warranted to improve the survival outcome of HER2 positive gastric cancer patients.

A growing body of preclinical and clinical evidence shows that the immune system contributes substantially to the therapeutic effects of "monoclonal antibody, trastuzumab" in solid tumors. Pembrolizumab is a potent and highly selective humanized monoclonal antibody designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

Based on strong rationale in exploring the impact of combining trastuzumab with anti-PD-1 inhibitor in HER2 positive cancer, we suggest multicenter phase IB/II study to determine antitumor activity and safety of pembrolizumab in combination with standard treatment (trastuzumab, capecitabine, and cisplatin) in patients with HER2 positive gastric cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Trastuzumab; Drug: Capecitabine; Drug: Cisplatin

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System

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. HER2 positive advanced gastric cancer
2. Be willing and able to provide written informed consent/assent for the trial.
3. Be 19 years of age on day of signing informed consent.
4. Have measurable disease based on RECIST 1.1.
5. performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Scale.
6. Demonstrate adequate organ function
7. Female subject of childbearing potential should have a negative urine or serum pregnancy or be willing to use birth control.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has a known history of active Bacillus Tuberculosis
4. Hypersensitivity to pembrolizumab or any of its excipients.
5. Has had a prior anti-cancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from adverse events due to a previously administered agent.
7. Has a known additional malignancy that is progressing or requires active treatment within 3 years.
8. Has known active central nervous system metastases and/or carcinomatous meningitis.
9. Has active autoimmune disease that has required systemic treatment in the past 2 years
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
12. Has known active Hepatitis B or Hepatitis C
13. Has received a live vaccine within 30 days of planned start of study therapy.

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: 4 combination; pembrolizumab 200mg, IV, q3weeks, Day 1 trastuzumab 6mg/kg (8mg loading dose), IV, q3weeks, Day 1 capecitabine 1000mg/m2, PO, BID, Day 1-14 cisplatin 80mg/m2 (level 1), IV, q3weeks, Day 1	Drug: Pembrolizumab; 200mg, IV, q3weeks, Day 1; Drug: Trastuzumab; 6mg/kg (8mg loading dose), IV, q3weeks, Day 1; Drug: Capecitabine; 1000mg/m2, PO, BID, Day 1-14; Drug: Cisplatin; 80mg/m2 (level 1), IV, q3weeks, Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The recommended dose of phase II	4 weeks
The overall response rate using RECIST 1.1	6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Duration of response	1 year
Time to response	6 weeks

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2017
• Primary Completion (Actual): October 31, 2020
• Study Completion (Anticipated): October 1, 2021

Study Registration Dates

• First Submitted: September 11, 2016
• First Submitted That Met QC Criteria: September 14, 2016
• First Posted (Estimate): September 15, 2016

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: April 1, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab; Cisplatin; Capecitabine; Pembrolizumab
• Other Study ID Numbers: 4-2016-0190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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