Esophageal Adenocarcinoma, Esophageal Cancer
Conditions
Keywords
HER2
Brief summary
Despite treatment according to the CROSS-regimen, median overall survival is less than four years (2.3 QALYs). The burden of disease is within the highest category (0.71 to 1.0). Also, no targeted treatment options are currently available, hampering personalized treatment for this patient population. TRAP-2 aims to address these needs by investigating whether addition of trastuzumab and pertuzumab to standard of care improves survival of patients with resectable HER2 positive esophageal adenocarcinoma (HER2+ EAC). Patients with HER2+ EAC will be randomised to neoadjuvant chemoradiation according to the CROSS regimen or CROSS + TRAstuzumab and Pertuzumab. Primary outcome is overall survival.
Interventions
DRUGTrastuzumab
Intravenous administration of study drug
DRUGPertuzumab
Intravenous administration of study drug
DRUGPaclitaxel
Intravenous administration of study drug
DRUGCarboplatin
Intravenous administration of study drug
Sponsors
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven adenocarcinoma of the esophagus or gastroesophageal junction, T1N+M0; or T2-T4a N0 or N+ M0). * HER2-positive tumor defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed by the local laboratory on a primary tumor biopsy. HER2 status needs to be confirmed by the central laboratory, but does not affect start of treatment. * Surgical resectability, as determined during multidisciplinary meeting. Tumors that cannot be passed with an endoscope for endoscopic ultrasound are eligible if all other criteria are fulfilled. * If the tumor extends below the gastroesophageal (GE) junction into the proximal stomach, the bulk of the tumor must involve the esophagus or GE junction. * Age ≥ 18. * ECOG performance status 0 or 1 (cf. Appendix A). * Adequate hematological, renal and hepatic functions defined as: * Neutrophils ≥ 1.5 x 109/L * Platelets ≥ 100 x 109/L * Hemoglobin ≥ 5.6 mmol * Total bilirubin ≤ 1.5 x upper normal limit * Creatinine clearance (Cockroft) \> 60 ml/min * Adequate left ventricular ejection fraction defined as an LVEF of ≥55% determined by transthoracic echocardiography or MUGA. * Written, voluntary informed consent * Patients must be accessible to follow up and management in the treatment center
Exclusion criteria
* T1N0 tumors or in situ carcinoma. * Past (within 5 years) or current history of malignancy other than entry diagnosis which has a worse expected prognosis than the current esophageal cancer. * Previous chemotherapy, radiotherapy, treatment with an anti-HER2 antibody or with small molecule HER2 inhibitors for esophageal cancer or for any other cancer within 6 months of diagnosis of esophageal cancer. * Previous radiation to the mediastinum precluding full dose radiation of the currently present esophageal tumor. * Invasion of the tracheobronchial tree or presence of tracheoesophageal fistula. * Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation. * Not willing to use highly effective methods of contraception (per institutional standard) during treatment (male or female) and for 6 months after the end of treatment. * Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) precluding major surgery. * Pulmonary fibrosis and/or severely impaired lung function (FEV1 \< 1,5L) precluding major surgery. * Serious underlying medical condition which would impair the ability of the patient to receive the planned treatment, including prior allergic reactions to drugs containing Cremophor, such as teniposide or cyclosporine. * Dementia or altered mental status that would prohibit the understanding and giving of informed consent * Inadequate caloric- and/or fluid intake despite consultation of a dietician and/or tube feeding. * Evidence of interstitial lung disease or active, non-infectious pneumonitis. * Active infection requiring systemic therapy which has not resolved 3 days (simple infection such as cystitis) to 7 days (severe infection such as pyelonephritis) prior to the first dose of trial treatment. * Evidence of acute or chronic infection with hepatitis B, C or HIV. * History of prior allogeneic stem cell or solid organ transplantation. * Pre-existing motor or sensory neurotoxicity greater than or equal to CTC AE grade 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | 5.5. years (maximum follow-up time) | Overall survival will be calculated from the date of randomization to death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival | 5.5. years (maximum follow-up time) | Progression free survival will be calculated from the date of randomization to death or progression. |
| Adverse events | 15 weeks (duration of neoadjuvant treatment) | Treatment toxicity according |
| Surgical complications | 30 days after surgery | Surgical complications according to Clavien Dindo |
| Left Ventricular Systolic Dysfunction | 5.5. years | ≥ 10 percentage points decrease from baseline to an absolute value \< 50% |
| General quality of life | 5.5. years | Quality of life |
Countries
Netherlands
Outcome results
None listed