Clinical trial NCT05188313: TRAstuzumab and Pertuzumab for HER2+ Resectable Oesophageal Cancer
Official title: The Efficacy of the Addition of TRAstuzumab and Pertuzumab to Neoadjuvant Chemoradiation: a Randomized Multi-center Study in Resectable HER2 Overexpressing Adenocarcinoma of the Esophagus or Gastroesophageal Junction. The TRAP-2 Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Esophageal Cancer
Esophageal Adenocarcinoma
Keywords: HER2
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
First posted: 2022-01-12
Enrollment: 376
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival
timeFrame: 5.5. years (maximum follow-up time)
Secondary outcomes:
measure: Progression free survival
timeFrame: 5.5. years (maximum follow-up time)
measure: Adverse events
timeFrame: 15 weeks (duration of neoadjuvant treatment)
measure: Surgical complications
timeFrame: 30 days after surgery
measure: Left Ventricular Systolic Dysfunction
timeFrame: 5.5. years
measure: General quality of life
timeFrame: 5.5. years
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
Study officials:
References: