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

Overview

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

• Drug Trastuzumab
  Intravenous administration of study drug
• Drug Pertuzumab
  Intravenous administration of study drug
• Drug Paclitaxel
  Intravenous administration of study drug
• Drug Carboplatin
  Intravenous administration of study drug

Primary outcome measures

• Overall survival [Time frame: 5.5. years (maximum follow-up time)]

Secondary outcome measures (5)

• Progression free survival [Time frame: 5.5. years (maximum follow-up time)]
• Adverse events [Time frame: 15 weeks (duration of neoadjuvant treatment)]
• Surgical complications [Time frame: 30 days after surgery]
• Left Ventricular Systolic Dysfunction [Time frame: 5.5. years]
• General quality of life [Time frame: 5.5. years]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• Academic Medical Center — Amsterdam

Identifiers

NCT: NCT05188313 · NL79276.018.21

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗