Esophageal Squamous Cell Carcinoma, HER-2 Gene Amplification, HER-2 Protein Overexpression
Conditions
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).
Interventions
DRUGTrastuzumab
Addition of trastuzumab to standard treatment (fluoropyrimidine/platinum doublet with pembrolizumab)
Sponsors
Odense University Hospital
Aalborg University Hospital
Aarhus University Hospital
Morten Mau-Sørensen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study is a two-staged single arm national phase II trial * Stage 1: 17 patients * Stage 2: 7 patients
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) . | 6 months | PFS according to RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response rate according to RECIST 1.1 | Best response during 6 months follow-up | Partial, complete and overall response rate according to RECIST 1.1 |
| Frequency of AEs assessed by NCI CTCAE, v. 5.0 | During minimum 6 months follow-up | Safety and tolerability of trastuzumab, pembrolizumab and a fluoropyrimidine/platinum assessed by NCI CTCAE, v. 5.0 |
| Overall survival | 6 months | Time to death of all causes |
Other
| Measure | Time frame | Description |
|---|---|---|
| Frequency of germeline Fc Gamma Receptor polymorphisms | During minimum 6 months follow-up | Predictive value of Fc Gamma Receptor polymorphisms in ESCC patients receiving |
| Frequency of PD-L1 status by CPS score | During minimum 6 months follow-up | PD-L1 status by CPS score |
| Change in amplified HER2 in ctDNA during treatment | During mininum 6 months follow-up | Clinical utility of measurements of amplified HER2 in ctDNA as a monitoring tool of treatment with 5-FU platinum, trastuzumab and pembrolizumab |
Countries
Denmark
Contacts
Primary ContactMorten Mau-Sørensen, MD PhD
Backup ContactKristian Egebjerg, MD
Outcome results
None listed