Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients (HERES)

HERES Trial: Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients

The study aims to determine the efficacy of trastuzumab added to standard treatment (fluoropyrimidine/platinum doublet with pembrolizumab) in patients with HER2 positive Esophageal squamous cell carcinoma (ESCC) determined by 6 months progression free survival (PFS) (RECIST 1.1).

Study Overview

• Status: Recruiting
• Conditions: Esophageal Squamous Cell Carcinoma; HER-2 Gene Amplification; HER-2 Protein Overexpression
• Intervention / Treatment: Drug: Trastuzumab

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Morten Mau-Sørensen, MD PhD; Phone Number: 0045 35450879; Email: paul.morten.mau-soerensen@regionh.dk
• Study Contact Backup: Name: Kristian Egebjerg, MD; Email: kristian.egebjerg.02@regionh.dk

Study Locations

• Denmark
  • Region H
    • Copenhagen, Region H, Denmark, DK-2100
      • Recruiting
      • Dept of Oncology, Rigshospitalet
      • Contact: solvej Thanh Le Truong, Nurse; Phone Number: +45 3545 6329; Email: solvej.thao.thanh.le.truong@regionh.dk
      • Principal Investigator: Jon Bjerregaard, MD PhD
  • Region Syd
    • Odense, Region Syd, Denmark, 5000
      • Recruiting
      • Onkologisk Afdeling R, Odense University Hospital
      • Contact: Mette Falbe-Hansen, Nurse; Phone Number: +45 29658926
      • Principal Investigator: Per Pfeiffer, MD PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Signed informed consent
2. Age ≥18 years
3. Inoperable locally advanced or metastatic squamous cell carcinoma of the esophagus not amenable for curative intended therapy
4. HER2 positive defined as IHC2+ and FISH amplification ratio ≥2 or IHC3+
5. ECOG PS <2
6. Baseline left ventricular ejection fraction > 50% measured by echocardiography or MUGA

7. Adequate bone marrow function and organ function:

   1. Hematopoietic function:
   2. Leucocytes > 3.0 x 109/l, neutrocytes > 1.5 x 109/l and thrombocytes > 100 x 109/l
   3. Serum bilirubin < 1.5 × upper limit of normal (ULN); and AST/ALT < 2.5 × ULN (or < 5 × ULN in patients with liver metastases).
8. Creatinine clearance > 30 ml/min

Exclusion Criteria:

1. Prior systemic treatment with non-curative intent including HER2-targeting drugs. Prior neoadjuvant and adjuvant therapies as well as palliative radiotherapy are allowed
2. Significant medical illness that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study treatment
3. Congestive heart failure (New York Heart Association (NYHA) class 3+4); uncontrolled angina pectoris; poorly controlled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg); or high-risk uncontrollable arrhythmias.
4. Patients with severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
5. Patients with known hypersensitivity to trastuzumab or any of the study drugs, murine proteins, or to any of the excipients
6. Symptomatic brain metastases uncontrolled by corticosteroids or carcinomatous meningitis
7. Homozygosity or compound heterozygosity for more than one gene variant of dihydropyrimidine dehydrogenase (DPD) known to cause major reduced metabolism of 5-FU derivates OR plasma uracil > 150 ng/ml are not eligible. Patients with minor DPD insufficiency are allowed provided that local guidelines for administration of 5-FU are followed.
8. Any other cancer (excluding low risk prostate cancer, carcinoma in situ and radically operated localised squamous skin cancer) with clinical activity within the last 2 years
9. Other current cancer treatments except for anti-hormone and anti-resorptive treatment of bone metastasis.
10. Allopurinol, phenytoin, warfarin treatment is not allowed. Non vitamin K oral anticoagulants (NOAK) and low molecular weight (LMW) heparin is allowed
11. Pregnancy or breast-feeding
12. Positive serum pregnancy test in women of childbearing potential.
13. Subjects with reproductive potential not willing to use an effective method of contraception under and 3 months after participation in this study

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: Treatment arm	Drug: Trastuzumab; Addition of trastuzumab to standard treatment (fluoropyrimidine/platinum doublet with pembrolizumab)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) .	PFS according to RECIST 1.1	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate according to RECIST 1.1	Partial, complete and overall response rate according to RECIST 1.1	Best response during 6 months follow-up
Frequency of AEs assessed by NCI CTCAE, v. 5.0	Safety and tolerability of trastuzumab, pembrolizumab and a fluoropyrimidine/platinum assessed by NCI CTCAE, v. 5.0	During minimum 6 months follow-up
Overall survival	Time to death of all causes	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in amplified HER2 in ctDNA during treatment	Clinical utility of measurements of amplified HER2 in ctDNA as a monitoring tool of treatment with 5-FU platinum, trastuzumab and pembrolizumab	During mininum 6 months follow-up
Frequency of germeline Fc Gamma Receptor polymorphisms	Predictive value of Fc Gamma Receptor polymorphisms in ESCC patients receiving	During minimum 6 months follow-up
Frequency of PD-L1 status by CPS score	PD-L1 status by CPS score	During minimum 6 months follow-up

Collaborators and Investigators

• Sponsor: Morten Mau-Sørensen
• Collaborators: Odense University Hospital; Aarhus University Hospital; Aalborg University Hospital
• Investigators: Principal Investigator: Lene Baeksgaard, MD PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Anticipated): January 1, 2025
• Study Completion (Anticipated): January 1, 2025

Study Registration Dates

• First Submitted: November 24, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 27, 2021

Study Record Updates

• Last Update Posted (Actual): August 12, 2022
• Last Update Submitted That Met QC Criteria: August 10, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab
• Other Study ID Numbers: 2021-003415-26

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
• product manufactured in and exported from the U.S.: No