Adjuvant TRastuzumab Deruxtecan for HER2-positive Gastroesophageal Cancer With Persistence of miNImal Residual Disease

NCT06253650 | Recruiting Phase 2 DMC

• 1 other identifier: 2023-506662-31-00
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Gastric Cancer; HER2-positive Gastric Cancer

Keywords

Trastuzumab-Deruxtecan; Gastric Cancer; HER2-positive Gastric Cancer; Liquid biopsy; Minimal residual disease

Outcome Measures

Primary Outcomes (1)

• 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.

  1 year

Secondary Outcomes (7)

• Disease-free survival

  3 years

• Overall survival

  3 years

• Metastases-free survival

  3 years

• Quality of life - PRO EORTC-QLQ-C30

  during adjuvant treatment phase

• Quality of life - EORTC QLQ-STO22

  during adjuvant treatment phase

Other Outcomes (1)

• Translational analyses

  3 years

Study Arms (2)

Experimental

EXPERIMENTAL

treatment with T-DXd (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 for 6 cycles.

Drug: Experimental

Control

ACTIVE COMPARATOR

treatment with post-operative FLOT for 4 cycles as per standard of care and using the doses previously adopted in the last cycle of the preoperative phase, i.e. 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).

Drug: Control

Interventions

Experimental DRUG

6 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

Experimental

Control DRUG

4 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.

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Life expectancy of at least 12 weeks.
• Resected gastric or gastroesophageal junction (Siewert I-II-III) cancer/esophageal adenocarcinoma, after the completion of pre-operative chemotherapy with FLOT, as per standard clinical practice.
• Absence of distant metastases as defined by post-operative radiological assessments (contrast-enhanced CT scan of the thorax and abdomen or, in case of contraindications, non-contrast-enhanced chest CT scan and abdomen Magnetic Resonance Imaging)
• Presence of locally determined HER2 overexpression/amplification on the post-treatment surgical tissue specimen defined as IHC 3+ or 2+/ISH amplified.
• Positivity of the post-operative liquid biopsy, performed 2-6 weeks after the radical surgery.
• LVEF ≥ 50% within 28 days before randomization/enrolment.
• Adequate bone marrow and organ function within 14 days before randomization/enrolment as described below:
• Neutrophil count ≥ 1.5 x 10\^3/μL
• Platelet count ≥ 100 x 10\^6/μL
• Haemoglobin ≥ 9 g/dL
• Total bilirubin lower than 1.5 time the upper-normal limits (ULN) of the Institutional normal values

You may not qualify if:

• 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.
• Patients with a medical history of myocardial infarction (MI) within 6 months before randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
• Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \>450 msec (males) based on average of the screening triplicate12-lead ECG.
• History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
• Lung criteria:
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.)
• Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for patients who are included in the study.
• Prior pneumonectomy (complete)
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection not under adequate disease control (that is defined as the presence of all the following conditions: receiving stable regimen of highly active anti-retroviral therapy for at least 4 weeks prior to study enrollment, CD4+ count above 250 cells/μL, undetectable viral load on standard polymerase chain reaction-based tests, absence of any HIV-related opportunistic infections for at least 4 weeks prior to study enrollment and no requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections), or active hepatitis B or C infection (HBsAg, anti-HBs, anti-HBc, anti-HCV). Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients who are anti-HBc positive and HBsAg negative or patients with HBsAg positive have to dose HBV-DNA. If HBV DNA is undetectable (\<10UL/ml or under the limit of detection per local lab standard) are considered as HBV negative. Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board (IRB)/ethics committee (EC).
• Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to \>Grade 2 for at least 3 months prior to \[randomization/enrollment/Cycle 1 Day 1\] and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as: chemotherapy-induced neuropathy and fatigue.

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Milan, 20133, Italy

RECRUITING

Related Publications (1)

• Nasca V, Bergamo F, Foltran L, Antonuzzo L, Bencardino K, Dell'Aquila E, Corallo S, Spallanzani A, Brunetti O, Spada D, Tamberi S, Cella CA, Avallone A, Fornaro L, Di Donato S, Strippoli A, Puccini A, Tamburini E, Palermo F, Morano F, Pietrantonio F, Raimondi A. Adjuvant TRastuzumab deruxtecan plus fluoropyrimidine versus standard chemotherapy in HER2-positive gastric or gastroesophageal cancer patients with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: the multicentre, phase II randomized TRINITY trial. BMC Cancer. 2025 Apr 8;25(1):633. doi: 10.1186/s12885-025-14063-6.

  PMID: 40200187 DERIVED

MeSH Terms

Conditions

Stomach Neoplasms; Neoplasm, Residual

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Filippo Pietrantonio, MD

  Fondazione IRCCS - Istituto Nazionale dei Tumori di Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Filippo Pietrantonio, MD

CONTACT

+39 0223903807; filippo.pietrantonio@istitutotumori.mi.it

Federica Palermo

CONTACT

+39 0223903835; federica.palermo@istitutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2024
• First Posted: February 12, 2024
• Study Start: March 1, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2028
• Last Updated: June 13, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)