Clinical trial NCT05170256: Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients
Official title: HERES Trial: Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Esophageal Squamous Cell Carcinoma
HER-2 Protein Overexpression
HER-2 Gene Amplification
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Aalborg University Hospital
name: Aarhus University Hospital
First posted: 2021-12-27
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The study is a two-staged single arm national phase II trial

* Stage 1: 17 patients
* Stage 2: 7 patients
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Progression free survival (PFS) .
timeFrame: 6 months
Secondary outcomes:
measure: Response rate according to RECIST 1.1
timeFrame: Best response during 6 months follow-up
measure: Frequency of AEs assessed by NCI CTCAE, v. 5.0
timeFrame: During minimum 6 months follow-up
measure: Overall survival
timeFrame: 6 months
Other outcomes:
measure: Change in amplified HER2 in ctDNA during treatment
timeFrame: During mininum 6 months follow-up
measure: Frequency of germeline Fc Gamma Receptor polymorphisms
timeFrame: During minimum 6 months follow-up
measure: Frequency of PD-L1 status by CPS score
timeFrame: During minimum 6 months follow-up
Locations:
city: Copenhagen
country: Denmark
facility: Dept of Oncology, Rigshospitalet
state: Region H
city: Odense
country: Denmark
facility: Onkologisk Afdeling R, Odense University Hospital
state: Region Syd
Study officials:
affiliation: Rigshospitalet, Denmark
name: Lene Baeksgaard, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: