Evaluation of Trastuzumab and Pertuzumab Addition to Neoadjuvant Chemoradiation in Resectable HER2-Positive Esophageal Adenocarcinoma
- Trial ID
- 2024-513797-22-00
- Sponsor
- Amsterdam UMC Stichting
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether the addition of **trastuzumab** and **pertuzumab** to standard neoadjuvant chemoradiation improves overall survival in patients with resectable **HER2 positive esophageal adenocarcinoma**. This is clinically relevant as enhancing overall survival could significantly impact treatment outcomes for this patient population, potentially offering a more effective therapeutic strategy for managing this aggressive cancer type.
Participants
The clinical trial focuses on patients diagnosed with **HER2 positive esophageal adenocarcinoma**. The study population includes both male and female participants, aged 18 years and older, who are not considered part of a vulnerable population. The sponsor has not provided the total number of participants involved in the trial. Participants were selected based on specific criteria, including histologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction, with tumors classified as T1N+M0 or T2-T4a N0 or N+ M0. The trial requires that the tumor be HER2-positive, as determined by local laboratory assessments, and surgical resectability must be confirmed during a multidisciplinary meeting. Participants must be fit for esophagectomy and possess adequate hematological, renal, and hepatic functions. Additionally, an adequate left ventricular ejection fraction is required. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants must provide written, voluntary informed consent and be accessible for follow-up and management at the treatment center.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of adding **trastuzumab** and **pertuzumab** to standard neoadjuvant chemoradiation in patients with resectable **HER2 positive esophageal adenocarcinoma**. This is a randomized, multi-center, double-blind, controlled Phase III study. The trial aims to assess whether this combination improves overall survival compared to the standard treatment alone. The study is expected to run from January 2022 to January 2037, with participant involvement lasting up to three months, depending on individual treatment response and tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histological and clinical criteria. This includes confirmation of **HER2-positive** status and assessment of surgical resectability. Following the screening, participants will be randomized to receive either the investigational treatment or the control. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. These visits will include assessments of hematological, renal, and hepatic functions, as well as cardiac evaluations to ensure an adequate left ventricular ejection fraction. The end-of-study visit will occur after the completion of the treatment period, where final assessments of overall survival and secondary endpoints, such as quality-adjusted life years and progression-free survival, will be conducted.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, as defined by CTCAE v5.0 criteria, or if they are unable to comply with the study protocol. Additionally, any significant post-operative complications, as classified by the Clavien-Dindo system, may also necessitate early termination. The trial will also evaluate the percentage completion of chemotherapy and radiation treatment, as well as the quality of life throughout the study duration.
Treatment
The clinical trial involves the administration of **Perjeta** (pertuzumab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for infusion, with a concentration of 420 mg. The active substance, pertuzumab, is a protein-based therapeutic agent. The administration route is via **infusion**, with a maximum dosage of 8 mg/kg. The treatment period is limited to a maximum of 3 cycles, with each cycle corresponding to a specific time unit code of 2. The product is manufactured by Roche Registration GmbH and is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
Additionally, the trial includes the use of **Herceptin** (trastuzumab), which is provided as a **powder for concentrate for solution for infusion**. This medication is also administered as a solution for infusion, with a concentration of 150 mg. Trastuzumab, like pertuzumab, is a protein-based therapeutic agent. The route of administration is **intravenous infusion**, with a maximum dosage of 8 mg/kg, similar to Perjeta. The treatment duration is also capped at 3 cycles. Herceptin is produced by Roche Registration GmbH and is not intended for pediatric patients. Participant compliance with the administration schedule is closely monitored to ensure the integrity of the trial data.
Efficacy
The efficacy of the clinical trial titled "The TRAP-2 study" will be assessed by evaluating the primary endpoint of **overall survival** in patients with resectable HER2-positive esophageal adenocarcinoma. Secondary endpoints include quality-adjusted life years, progression-free survival, pathological response according to the Mandard criteria, R0 resection rate, and safety, which will be measured in terms of toxicity as defined by CTCAE v5.0 criteria and post-operative complications according to the Clavien-Dindo classification. Additionally, the percentage completion of chemotherapy and radiation treatment, as well as quality of life, will be assessed.
Inclusion and Exclusion 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. - Patient is fit for esophagectomy.Adequate hematological, renal and hepatic functions defined as: o Neutrophils ≥ 1.5 x 109/L o Platelets ≥ 100 x 109/L o Hemoglobin ≥ 5.6 mmol o Total bilirubin ≤ 1.5 x upper normal limit o Creatinine < 150 μmol l-1 or creatinine clearance (Cockroft) ≥ 50 ml/min - Adequate left ventricular ejection fraction defined as an LVEF of ≥50% 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. - ECOG performance status 3 or higher (cf. Appendix A) - 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Recruiting | 03 Jan 2022 | — |
| Netherlands | — | — | 408 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Herceptin 150 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 8 | 3 | PRD2154035 |
Perjeta 420 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 8 | 3 | PRD2154581 |