Patients affected by localized/locally advanced GC/GEJC (Siewert I-II-III)/esophageal adenocarcinoma eligible for peri-operative chemotherapy and radical surgery and deemed fit enough to receive the standard treatment with the triplet FLOT (5-fluorouracil, oxaliplatin and docetaxel) will be evaluated for the enrollment into the observational phase of the study during the standard pre-operative therapeutic management according to the best clinical practice and local guidelines at their Centre.
OBSERVATIONAL PHASE The observational phase will include patients with localized/locally advanced HER2-positive GC/GEJC (Siewert I-II-III)/esophageal adenocarcinoma eligible for standard pre-operative chemotherapy with FLOT for 4 cycles and radical surgery. Patients will undergo an exploratory liquid biopsy (LB) to be centrally collected at baseline, i.e. during the baseline disease staging as per standard clinical practice and prior to the start of the pre-operative FLOT treatment, and a second exploratory LB to be centrally collected at the end of the pre-operative FLOT treatment before the standard surgery. Then, a third mandatory exploratory LB will be collected at 2-6 weeks after surgery and, during the same timepoint, the interventional liquid biopsy will be collected and centrally analyzed with the SignateraTM CE-marked assay as pre-screening test ® in order to determine whether post-operative ctDNA is positive or negative (LB#1: interventional for the potential enrollment in the TRINITY study). Patients will be permitted to be enrolled in the observational phase even after the start of pre-operative FLOT or even after surgery, the lack of availability of one or both pre-surgical exploratory LBs will not preclude the enrolment in the interventional study and postoperative SignateraTM will be offered as prescreening assay.
Patients eligible for the interventional TRINITY study will be those who underwent surgery after the completion of the standard FLOT pre-operative treatment, with locally-confirmed HER2 positive status both on archival pre-treatment tumor biopsy and on post-treatment surgical sample and with detected post-operative ctDNA at LB#1.
In any case of non-eligibility for the interventional study for not fulfilling the molecular pre-screening algorithm, patients will continue the standard treatment as per clinical practice with post-operative FLOT for 4 cycles and standard follow up. In this case, patients with prescreening failure will continue to be followed-up in the frame of the observational phase of the study with the collection of serial LBs at specific timepoints at 3, 6 and 12 months from the date of pre-screening failure (date of results of LB#1), respectively, and then in concomitance with follow-up visits scheduled as per standard clinical practice.
INTERVENTIONAL TRINITY STUDY Patients deemed eligible for the Screening in the interventional TRINITY trial will be screened from 2 and 12 weeks after the date of surgery, in order to start the post-operative treatment no later than 12 weeks after surgery, and will undergo all the screening tests comprising a CT scan including high resolution thorax-abdomen CT scan and echocardiography.
Patients fulfilling all the eligibility criteria for the trial will be randomized according to a 1:1 basis to the experimental treatment with T-DXd at the dose of 6.4 mg/kg intravenous every 3 weeks plus either capecitabine 1000 mg/sqm BID orally on days 1-14 or 5-fluorouracil 600 mg/sqm continuous intravenous infusion on days 1-5, as per Investigator's choice, every 3 weeks for 6 cycles versus the control treatment arm with post-operative FLOT with standard dose and schedule and at the same dose used during the last pre-operative cycle, for 4 cycles.
At 3, 6 and 12 months after randomization, additional exploratory LBs will be collected and at 12 months after randomization also the interventional LB#2 will be collected and centrally analysed to detect ctDNA and to assess the occurrence of ctDNA clearance in both arms as per study primary endpoint.
After randomization, patients will undergo a thorax-abdomen CT scan every 3 months for 1 year to monitor the occurrence of clinical disease relapse. In case of disease relapse before the 12-month post-randomization time-point, the interventional LB#2 will not be performed. After 12 months post-randomization, exploratory LBs will be performed longitudinally during follow-up as per standard clinical practice. Importantly, exploratory LB will be always collected at the time of disease relapse.
This study will pre-screen approximately 600 patients, in order to include about 100 patients in the observational phase and enrol a total number of 46 patients in the interventional study, across 20 Italian Centres in the frame of the GONO network.
