TRAstuzumab and Pertuzumab for HER2+ Resectable Oesophageal Cancer (TRAP-2)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Esophageal Cancer; Esophageal Adenocarcinoma
• Intervention / Treatment: Drug: Paclitaxel; Drug: Carboplatin; Drug: Trastuzumab; Drug: Pertuzumab

• Study Type: Interventional
• Enrollment (Anticipated): 376
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Recruiting
    • Academic Medical Center
    • Contact: H. WM van Laarhoven, M.D., PhD; Phone Number: 31 20 5665955; Email: secr-onco@amc.uva.nl
    • Principal Investigator: H. WM van Laarhoven, M.D., PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chemoradiation according to the CROSS regimen; Paclitaxel 50 mg/m2 and carboplatin AUC = 2 will be given by intravenous infusion on days 1, 8, 15, 22 and 29. A total dose of 41.4 Gy will be given in 23 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy.	Drug: Paclitaxel; Intravenous administration of study drug; Drug: Carboplatin; Intravenous administration of study drug
Experimental: Chemoradiation according to the CROSS regimen combined with trastuzumab and pertuzumab; Paclitaxel 50 mg/m2 and carboplatin AUC = 2 will be given by intravenous infusion on days 1, 8, 15, 22 and 29. A total dose of 41.4 Gy will be given in 23 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy. Pertuzumab will be administered intravenously first, on Day 1, 22, 43, 64, and 85 using a fixed dose of 840 mg. Trastuzumab will be administered intravenously on Day 1 of each treatment cycle, using an initial dose of 4 mg/kg on day 1, followed by doses of 2 mg/kg weekly up to week 6. From week 7 onwards trastuzumab will be administered at a dose of 6 mg/kg, every three weeks.	Drug: Paclitaxel; Intravenous administration of study drug; Drug: Carboplatin; Intravenous administration of study drug; Drug: Trastuzumab; Intravenous administration of study drug; Drug: Pertuzumab; Intravenous administration of study drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival will be calculated from the date of randomization to death.	5.5. years (maximum follow-up time)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Progression free survival will be calculated from the date of randomization to death or progression.	5.5. years (maximum follow-up time)
Adverse events	Treatment toxicity according	15 weeks (duration of neoadjuvant treatment)
Surgical complications	Surgical complications according to Clavien Dindo	30 days after surgery
Left Ventricular Systolic Dysfunction	≥ 10 percentage points decrease from baseline to an absolute value < 50%	5.5. years
General quality of life	Quality of life	5.5. years

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2022
• Primary Completion (Anticipated): July 1, 2027
• Study Completion (Anticipated): February 1, 2037

Study Registration Dates

• First Submitted: December 27, 2021
• First Submitted That Met QC Criteria: December 27, 2021
• First Posted (Actual): January 12, 2022

Study Record Updates

• Last Update Posted (Actual): June 24, 2022
• Last Update Submitted That Met QC Criteria: June 18, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: HER2
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Carboplatin; Paclitaxel; Trastuzumab; Pertuzumab
• Other Study ID Numbers: NL79276.018.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No