Combination Margetuximab and Pembrolizumab for Advanced, Metastatic HER2(+) Gastric or Gastroesophageal Junction Cancer

• ClinicalTrials.gov Identifier: NCT02689284
• Recruitment Status: Completed
• First Posted: February 23, 2016
• Results First Posted: August 4, 2022
• Last Update Posted: August 4, 2022
• Sponsor: MacroGenics
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): MacroGenics

Tracking Information

• First Submitted Date: January 27, 2016
• First Posted Date: February 23, 2016
• Results First Submitted Date: February 28, 2022
• Results First Posted Date: August 4, 2022
• Last Update Posted Date: August 4, 2022
• Actual Study Start Date: January 2016
• Actual Primary Completion Date: January 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 11, 2022)

• Number of Patients With Dose Limiting Toxicities [ Time Frame: 21 days ]
  Characterize maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of margetuximab when administered in combination with pembrolizumab
• Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs). [ Time Frame: up to 24 months ]
  The number of patients that experience either an AE or a SAE during the study participation
• Number of Patients With a Complete Response (CR) or Partial Response (PR) to Treatment [ Time Frame: 12 months ]
  Investigate the preliminary anti-tumor activity as measured by response to treatment of margetuximab when administered in combination with pembrolizumab, using conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Number of Patients With a Complete Response (CR) or Partial Response (PR) to Treatment Using irRC Criteria [ Time Frame: 12 Months ]
  Investigate the preliminary anti-tumor activity, as measured by objective response rate (ORR) of margetuximab when administered in combination with pembrolizumab, using immune-related response criteria (irRC).
• Duration of Response [ Time Frame: up to 24 months ]
  Duration of response is calculated at the time from CR or PR to relapse or cancer progression.

Original Primary Outcome Measures (submitted: February 18, 2016)

• Determine the recommended expansion phase cohort (Cohort 2) dose of margetuximab in combination with pembrolizumab [ Time Frame: 3 weeks ]
  Characterize maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of margetuximab when administered in combination with pembrolizumab
• Anti-Tumor Activity [ Time Frame: 12 months ]
  Investigate the preliminary anti-tumor activity as measured by response duration of margetuximab when administered in combination with pembrolizumab, using both conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related response criteria (irRC).
• Anti-Tumor Activity [ Time Frame: 12 Months ]
  Investigate the preliminary anti-tumor activity, as measured by objective response rate (ORR) of margetuximab when administered in combination with pembrolizumab, using conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related response criteria (irRC).

Current Secondary Outcome Measures (submitted: July 11, 2022)

• Overall Survival (OS) [ Time Frame: 24 Months ]
  The median length of time between first dose of study medication and death from any cause.
• Progression Free Survival (PFS) [ Time Frame: 24 Months ]
  The interval between the first dose of study medication and progression of disease or death from any cause.
• Change From Baseline in Pharmacodynamic Markers in Whole Blood [ Time Frame: from first dose to the end of treatment, average about 12 months ]
  The planned assessment included examination of markers of T-cell activation
• Analysis of HER2 Tumor Cell Membrane Expression in Biopsy Specimens Before and After Treatment [ Time Frame: from first dose to the end of treatment, average 12 months. ]
• Number of Patients Who Develop Treatment-emergent Anti-drug Antibodies to Margetuximab (Immunogenicity) [ Time Frame: Assessed Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Day 1 of every odd cycle, and end of treatment visit, average 12 months ]
• Maximum Concentration of Margetuximab at Steady State [ Time Frame: At end of infusion on Cycle 1, Day 1. Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit, average 12 months ]
  Measurement of PK characteristics is limited to margetuximab. No analysis of pembrolizumab was conducted.
• Area Under the Concentration Time Curve at Steady State (AUC ss) [ Time Frame: Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit, average 12 months ]
  AUC is a mathematical calculation that describes the variation in drug concentration in the blood over time.
• Clearance [ Time Frame: Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit, average 12 months. ]
  Drug clearance is the amount of drug removed from the bloodstream by the body per unit of time.
• Volume of Distribution at Steady State [ Time Frame: Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit average 12 months . ]
  The volume of distribution is related to a whether how much drug is distributed to body tissues, or remains in the bloodstream.
• Terminal Half-life [ Time Frame: Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit average 12 months . ]
  Terminal half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.

Original Secondary Outcome Measures (submitted: February 18, 2016)

• Overall Survival (OS) [ Time Frame: 24 Months ]
  To investigate the preliminary effect of the combination treatment on OS
• Progression Free Survival (PFS) [ Time Frame: 24 Months ]
  To investigate the preliminary effect of the combination treatment on PFS

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combination Margetuximab and Pembrolizumab for Advanced, Metastatic HER2(+) Gastric or Gastroesophageal Junction Cancer
• Official Title: A Phase 1b/2, Open Label, Dose Escalation Study of Margetuximab in Combination With Pembrolizumab in Patients With Relapsed/Refractory Advanced HER2+ Gastroesophageal Junction or Gastric Cancer
• Brief Summary: This main purpose of this clinical study is to learn about the safety and activity of margetuximab and pembrolizumab combination treatment in patients with HER2+ gastric and gastroesophageal junction cancer.
• Detailed Description: Detailed Description: Both margetuximab and pembrolizumab are monoclonal antibodies used in combination to treat HER2+ gastric and gastroesophageal junction cancer. This study has two parts: Dose Escalation and Dose Expansion. The Dose Escalation phase of the study will evaluate safety of escalating doses of the combination treatment. The Dose Expansion phase will evaluate safety and activity of the combination in patients with gastric or gastroesophageal cancer once the final dose and schedule are defined. In addition, a cohort of patients with HER2+ 3+ gastric cancer patients will be enrolled in the Dose Expansion Phase.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Gastric Cancer
• Stomach Cancer
• Esophageal Cancer

Intervention

• Biological: Margetuximab 10 mg/kg
  Margetuximab treatment is administered intravenously (IV) once every 21-day cycle
  Other Name: MGAH22
• Biological: Margetuximab 15 mg
  Margetuximab treatment is administered IV once every 21-day cycle
  Other Name: MGAH22
• Biological: Pembrolizumab
  Pembrolizumab treatment is administered IV once every 21-day cycle
  Other Name: MK-3475

Study Arms

• Experimental: Cohort 1: Margetuximab 10 mg/kg plus pembrolizumab 200 mg
  margetuximab administered in combination with pembrolizumab
  Interventions:

  • Biological: Margetuximab 10 mg/kg
  • Biological: Pembrolizumab
• Experimental: Cohort 2: Margetuximab 15 mg/kg plus pembrolizumab 200 mg
  margetuximab administered in combination with pembrolizumab
  Interventions:

  • Biological: Margetuximab 15 mg
  • Biological: Pembrolizumab

• Publications *: Catenacci DVT, Kang YK, Park H, Uronis HE, Lee KW, Ng MCH, Enzinger PC, Park SH, Gold PJ, Lacy J, Hochster HS, Oh SC, Kim YH, Marrone KA, Kelly RJ, Juergens RA, Kim JG, Bendell JC, Alcindor T, Sym SJ, Song EK, Chee CE, Chao Y, Kim S, Lockhart AC, Knutson KL, Yen J, Franovic A, Nordstrom JL, Li D, Wigginton J, Davidson-Moncada JK, Rosales MK, Bang YJ; CP-MGAH22-5 Study Group. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial. Lancet Oncol. 2020 Aug;21(8):1066-1076. doi: 10.1016/S1470-2045(20)30326-0. Epub 2020 Jul 9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 16, 2019): 95
• Original Estimated Enrollment (submitted: February 18, 2016): 52
• Actual Study Completion Date: January 2021
• Actual Primary Completion Date: January 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Signed written informed consent.
2. Age ≥ 18 years old (or minimum age based upon local regulations)
3. Unresectable locally advanced or metastatic histologically proven HER2+ gastroesophageal junction (GEJ) or gastric cancer. Gastric Cancer Expansion Phase will include only gastric cancer patients with 3+ HER2 positivity.
4. HER2+ as 3+ (as defined in AJCC staging manual 8th edition) by IHC or in-situ hybridation (ISH) amplified.
5. Have received prior treatment with trastuzumab.
6. Have received treatment with at least one or more lines of cytotoxic chemotherapy in the metastatic setting.
7. Resolution of chemotherapy, immunotherapy or radiation-related toxicities.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Life expectancy ≥ 12 weeks.
10. Measurable disease as per RECIST 1.1 criteria.

Exclusion Criteria:

1. Patients with symptomatic central nervous system (CNS) metastases.
2. Patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment.
3. History of prior allogeneic bone marrow, stem-cell or solid organ transplantation.
4. Treatment with any systemic anti-neoplastic therapy, or investigational therapy within the 3 weeks prior to the initiation of study drug.
5. Treatment with radiation therapy within 3 weeks prior to the initiation of study drug administration.
6. Treatment with corticosteroids (≥10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days prior to the initiation of study drug administration.
7. History of clinically-significant cardiovascular disease.
8. Clinically-significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation.
9. History of (non-infectious) pneumonitis that required steroids or presence of active pneumonitis
10. Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis.
11. Evidence of active viral, bacterial, or systemic fungal infection.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Korea, Republic of, Singapore, Taiwan, United States

Administrative Information

• NCT Number: NCT02689284
• Other Study ID Numbers: CP-MGAH22-05
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: MacroGenics
• Original Responsible Party: Same as current
• Current Study Sponsor: MacroGenics
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Study Director: Stephen L Eck, M.D., PhD; MacroGenics

• PRS Account: MacroGenics
• Verification Date: May 2022