Evaluation of Trastuzumab Deruxtecan and Fluoropyrimidine Versus Standard Chemotherapy in HER2-Positive Gastric or Gastroesophageal Cancer with Minimal Residual Disease
- Trial ID
- 2023-506662-31-00
- Sponsor
- Fondazione GONO G.I.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the TRINITY study is to evaluate the **clearance of circulating tumor DNA (ctDNA)** in patients receiving adjuvant treatment with trastuzumab deruxtecan (T-DXd) plus capecitabine/5-fluorouracil compared to those continuing with standard FLOT chemotherapy, at one year from randomization. This objective is clinically relevant as ctDNA clearance is a potential biomarker for treatment efficacy and could indicate a reduction in minimal residual disease, which is crucial for improving long-term outcomes in patients with HER2-positive gastric or gastroesophageal cancer.
Secondary objectives include:
- Assessing the efficacy of post-operative T-DXd plus capecitabine/5-fluorouracil treatment versus standard FLOT continuation in terms of overall survival, disease-free survival, and metastases-free survival.
- Evaluating the impact of post-operative T-DXd plus capecitabine/5-fluorouracil treatment versus standard FLOT continuation on patients' quality of life.
Participants
The clinical trial involves participants diagnosed with **gastric or gastroesophageal cancer**, specifically focusing on individuals with localized or locally advanced stages of the disease. The study population includes both male and female subjects, aged 18 years and older, with an **ECOG Performance Status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have a life expectancy of at least 12 weeks. The trial includes individuals who have undergone standard pre-operative chemotherapy with the FLOT regimen followed by radical surgery, and who exhibit HER2 overexpression/amplification. The trial population was selected based on the absence of distant metastases as confirmed by post-operative radiological assessments. The sponsor has not provided the total number of participants involved in the study. Participants' lifestyle considerations include compliance with study procedures and treatments, and they must be accessible for treatment and follow-up at the participating center. The trial also involves a vulnerable population, as indicated by the inclusion of both male and female subjects who are required to adhere to specific contraceptive measures during and after the study period.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **trastuzumab deruxtecan** plus fluoropyrimidine compared to standard chemotherapy in patients with HER2-positive gastric or gastroesophageal cancer. This is a randomized, double-blind, controlled trial with an estimated duration from November 2023 to November 2026. The primary objective is to assess the clearance of circulating tumor DNA (ctDNA) in the treatment arm at one year from randomization. Secondary endpoints include disease-free survival, overall survival, and metastases-free survival.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as HER2 overexpression and adequate organ function. Following randomization, participants will receive treatment and attend regular follow-up visits to monitor their response and any adverse effects. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. The expected length of participant involvement is up to 18 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.
The trial involves the administration of investigational medicinal products via **intravenous infusion** or oral routes, with specific dosing regimens for each product. Participants must comply with all study procedures and treatments, and they are required to use effective contraception during and after the study period. The trial is conducted in accordance with ethical guidelines, ensuring informed consent and data privacy. Participants are expected to have a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Treatment
The clinical trial involves the administration of **trastuzumab deruxtecan**, known by the sponsor product code DS-8201a, which is provided as a **solution for infusion**. This experimental medication is administered via **intravenous infusion** at a dosage of 6.4 mg/kg, with a maximum total dose of 115.2 mg/kg over a treatment period of 18 months. The active substance, trastuzumab deruxtecan, is a protein-based compound developed by Daiichi Sankyo, Inc. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Fluorouracil** is utilized as a comparator treatment in the study. It is administered as a **concentrate for solution for injection/infusion** via **intravenous infusion**. The maximum daily dose is 600 mg/m², with a total dose not exceeding 18,000 mg/m² over 18 months. Fluorouracil is a chemical compound used in chemotherapy, and its administration will be closely monitored to ensure adherence to the protocol.
**Anhydrous docetaxel** is another comparator treatment, provided in the form of **PHF00230MIG** for **intravenous infusion**. The maximum daily dose is 50 mg/m², with a total dose of 200 mg/m² over a treatment period of 8 months. This chemical compound is part of the chemotherapeutic regimen and will be administered according to the study's dosing schedule.
**Calcium folinate**, also known as leucovorin calcium, is included as a comparator treatment. It is administered as **PHF00231MIG** via **intravenous infusion**. The maximum daily dose is 200 mg/m², with a total dose of 800 mg/m² over 8 months. This cytostatic agent is used to enhance the efficacy of chemotherapy and will be administered in accordance with the trial protocol.
**Oxaliplatin** is another comparator treatment, provided in the form of **PHF00230MIG** for **intravenous infusion**. The maximum daily dose is 85 mg/m², with a total dose of 340 mg/m² over 8 months. As a chemotherapeutic agent, oxaliplatin will be administered following the study's guidelines to ensure participant safety and treatment efficacy.
**Capecitabine** is used as a test treatment in the study. It is administered orally in the form of **PHF00009MIG**. The maximum daily dose is 2000 mg/m², with a total dose of 168,000 mg/m² over 18 months. This chemotherapeutic agent is a prodrug that is metabolized into fluorouracil in the body, and its administration will be monitored to ensure compliance with the study protocol.
Efficacy
Efficacy in the clinical trial will be assessed primarily through the evaluation of **ctDNA clearance** in patients receiving adjuvant trastuzumab deruxtecan plus capecitabine/5-fluorouracil compared to those continuing with post-operative FLOT treatment. The primary endpoint is the rate of patients achieving ctDNA clearance at one year from randomization in the intention-to-treat population. Patients experiencing disease relapse or death before the 12-month post-randomization timepoint will be considered as not having achieved ctDNA clearance.
Secondary endpoints include disease-free survival, overall survival, and metastases-free survival. Disease-free survival is defined as the time from randomization to the occurrence of disease relapse, second gastric or gastroesophageal cancer primary, or death from any cause. Overall survival is defined as the time from randomization to death from any cause. Metastases-free survival is defined as the time from randomization to the first evidence of metastases or death from any cause, as determined by radiological and clinical assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 (Observational and Interventional Phase)
- 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 (Observational and Interventional Phase)
- Age ≥ 18 years old (Observational and Interventional Phase)
- ECOG Performance Status 0-1 (Observational and Interventional Phase)
- Life expectancy of at least 12 weeks (Observational and Interventional Phase)
- Diagnosis of localized/locally advanced gastric or gastroesophageal junction cancer (Siewert I-II-III)/esophageal adenocarcinoma eligible for standard pre-operative chemotherapy with FLOT regimen followed by radical surgery, as per standard clinical practice (Observational Phase)
- 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 (Interventional Phase)
- 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) (Observational and Interventional Phase)
- Presence of locally determined HER2 overexpression/amplification on the archival pre-treatment tissue specimen defined as IHC 3+ or 2+/ISH amplified (Observational Phase)
- Presence of locally determined HER2 overexpression/amplification on the post-treatment surgical tissue specimen defined as IHC 3+ or 2+/ISH amplified (Interventional Phase)
- Positivity of the post-operative liquid biopsy, performed 2-6 weeks after the radical surgery (Interventional Phase)
- LVEF ≥ 50% within 28 days before randomization/enrolment (Interventional Phase)
- Adequate bone marrow and organ function within 14 days before randomization/enrolment as described in Table 1 (Interventional Phase)
- Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of IMP. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause (Interventional Phase)
- Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 2. from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP. Complete heterosexual abstinence for the duration of the study and drug TRINITY Study – Protocol Version 1.1 dated 27th September, 2022 44 washout period is an acceptable contraceptive method if it is line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable (Interventional Phase)
- Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period, as described in Table 2. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of randomisation/enrolment, throughout the study and for 4 months after the last dose of IMP. Preservation of sperm should be considered prior to enrollment in this study (Interventional Phase)
- Female subjects must not donate, or retrieve for their own use, ova from the time of randomization/enrolmentand throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study (Interventional Phase)
Exclusion Criteria
- Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site) (Observational and Interventional Phase)
- Previous enrolment in the present study (Observational Phase)
- Participation in another clinical study with an investigational product during the last 12 months (Observational and Interventional Phase)
- Signs of distant metastases (Observational and Interventional Phase)
- 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 (Interventional Phase)
- 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 (Interventional Phase)
- Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG (Interventional Phase)
- 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 (Interventional Phase)
- Lung criteria: a) 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.) b) 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. c) Prior pneumonectomy (complete) (Interventional Phase)
- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals (Interventional Phase)
- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, 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 TRINITY Study – Protocol Version 1.1 dated 27th September, 2022 46 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) (Interventional Phase)
- 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 (Interventional Phase)
- 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 (Interventional Phase)
- Known allergy or hypersensitivity to study treatment or any of the study drug excipients (Interventional Phase)
- History of severe hypersensitivity reactions to other monoclonal antibodies (Interventional Phase)
- Pregnant or breastfeeding female patients, or patients who are planning to become pregnant (Interventional Phase)
- Multiple primary malignancies within 3 years, except for: a) adequately resected non-melanoma skin cancer b) curatively treated in-situ disease c) other solid tumors curatively treated (Interventional Phase)
- A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART) (Interventional Phase)
- LVEF< 50% within 28 days before enrolment (Interventional Phase)
- Prior treatment with an anti-HER2 agent (Interventional Phase)
- Absence of locally determined HER2 overexpression/amplification on the surgical specimen defined as IHC 0 or 1+ or 2+/ISH not amplified (Interventional Phase)
- Negativity of ctDNA at the post-operative liquid biopsy (Interventional Phase)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 01 Nov 2023 | 46 |
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 |
|---|---|---|---|---|---|---|
CALCIUM LEVOFOLINATE | Comparator | PHF00231MIG | INTRAVENOUS INFUSION | 200 | 8 | SCP150594 |
FLUOROURACIL | Test | PHF00230MIG | INTRAVENOUS INFUSION | 600 | 18 | SCP7587892 |
OXALIPLATIN | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 85 | 8 | SCP1891954 |
DOCETAXEL | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 50 | 8 | SCP725130 |
DS-8201a | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 6.4 | 18 | PRD5308994 |
CAPECITABINE | Test | PHF00009MIG | ORAL | 2000 | 18 | SCP2172075 |
FLUOROURACIL | Comparator | — | INTRAVENOUS INFUSION | 2600 | 8 | SUB07721MIG |