TRINITY is designed as a multicentre, randomized, open-label, interventional phase II study aimed at investigating the activity, efficacy and safety of trastuzumab-deruxtecan (T-DXd) plus capecitabine/5-fluorouracil as a post-operative treatment in localized/locally advanced gastric or gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma patients with HER2 overexpression/amplification and positive post-operative ctDNA after pre-operative 5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) regimen followed by radical surgery.
Written informed consent and any locally required authorization (such as the European Union [EU] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
Compliance with all the study procedures and treatments. Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating Centre.
Age ≥ 18 years old.
Eastern Cooperative Oncology group (ECOG) Performance Status 0-1.
Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
Participation in another clinical study with an investigational product during the last 12 months
Signs of distant metastases at any site.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, renal disease, neurological disease or peripheral neuropathy, serious chronic gastrointestinal conditions associated with diarrhea, or substance abuse or any other medical or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirement, interfere with the subject's participation in the clinical study, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent or interfere with the evaluation of the clinical study results.
Parallel
Experimental
Drug6 cycles of: T-DXd at the dose of 6.4 mg/kg intravenous every 3 weeks plus capecitabine 1000 mg/sqm BID orally on days 1-14 every 3 weeks or 5-fluorouracil 600 mg/m2/day continuous intravenous infusion on days 1-5 every 3 weeks as per Investigator's choice
Control
Drug4 cycles of: 5-fluorouracil 2600 mg/m2 continuous intravenous infusion day 1 for 24 hours every 2 weeks, leucovorin 200 mg/m2 intravenous infusion on day 1 every 2 weeks, oxaliplatin 85 mg/m2 intravenous infusion on day 1 every 2 weeks, and docetaxel 50 mg/m2 intravenous infusion on day 1 every 2 weeks.
ctDNA clearance (negative ctDNA status) at 1 year
The clearance of ctDNA in T-DXd plus capecitabine/5-fluorouracil arm versus standard FLOT continuation at 1 year from randomization.
Disease-free survival
time from the randomization in the study to the occurrence of disease relapse (local and/or distant), second GC/GEJC primary, or death from any cause
Overall survival
time from the randomization in the study to the occurrence of death.
Metastases-free survival
time from the randomization in the study to the first evidence of metastases according to the radiological and clinical assessments detailed in the procedures or death from any cause.
Quality of life - PRO EORTC-QLQ-C30
Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EORTC QLQ-C30 For questions 1-28 of EORTC QLQ-C30 a 4-point scale is used. It scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit")and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. For the questions 29 and 30 of EORTC QLQ-C30 a 7-points scale is used. It scores from 1 to 7: 1 ("very poor") to 7 ("excellent"). Half points are not allowed. The range is 6. First of all, raw score has to be calculated with mean values. Afterwards linear transformation is performed to be comparable. More points are considered to have a better outcome.
Translational analyses
To conduct exploratory translational analyses aimed at identifying which subgroup of patients may derive the highest benefit from a post-operative targeted treatment with T-DXd as compared to FLOT continuation after pre-operative FLOT and radical surgery.
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