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 TRINITY study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Feb 2024 → ongoing

Decision date (initial)

2024-01-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The clearance of ctDNA in T-DXd plus capecitabine/5-fluorouracil arm versus standard FLOT continuation at 1 year from randomization

Secondary objectives 2

1. To assess 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
2. To assess the impact of of post-operative T-DXd plus capecitabine/5-fluorouracil treatment versus standard FLOT continuation on patients’ quality of life

Conditions and MedDRA coding

Gastric or gastroesophageal cancer

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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)
2. 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)
3. Age ≥ 18 years old (Observational and Interventional Phase)
4. ECOG Performance Status 0-1 (Observational and Interventional Phase)
5. Life expectancy of at least 12 weeks (Observational and Interventional Phase)
6. 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)
7. 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)
8. 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)
9. Presence of locally determined HER2 overexpression/amplification on the archival pre-treatment tissue specimen defined as IHC 3+ or 2+/ISH amplified (Observational Phase)
10. Presence of locally determined HER2 overexpression/amplification on the post-treatment surgical tissue specimen defined as IHC 3+ or 2+/ISH amplified (Interventional Phase)
11. Positivity of the post-operative liquid biopsy, performed 2-6 weeks after the radical surgery (Interventional Phase)
12. LVEF ≥ 50% within 28 days before randomization/enrolment (Interventional Phase)
13. Adequate bone marrow and organ function within 14 days before randomization/enrolment as described in Table 1 (Interventional Phase)
14. 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)
15. 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)
16. 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)
17. 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 22

1. 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)
2. Previous enrolment in the present study (Observational Phase)
3. Participation in another clinical study with an investigational product during the last 12 months (Observational and Interventional Phase)
4. Signs of distant metastases (Observational and Interventional Phase)
5. 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)
6. 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)
7. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG (Interventional Phase)
8. 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)
9. 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)
10. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals (Interventional Phase)
11. 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)
12. 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)
13. 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)
14. Known allergy or hypersensitivity to study treatment or any of the study drug excipients (Interventional Phase)
15. History of severe hypersensitivity reactions to other monoclonal antibodies (Interventional Phase)
16. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant (Interventional Phase)
17. 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)
18. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART) (Interventional Phase)
19. LVEF< 50% within 28 days before enrolment (Interventional Phase)
20. Prior treatment with an anti-HER2 agent (Interventional Phase)
21. Absence of locally determined HER2 overexpression/amplification on the surgical specimen defined as IHC 0 or 1+ or 2+/ISH not amplified (Interventional Phase)
22. Negativity of ctDNA at the post-operative liquid biopsy (Interventional Phase)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The rate of patients with ctDNA clearance after adjuvant T-DXd plus capecitabine/5-fluorouracil versus post-operative FLOT continuation treatment at 1 year from randomization in the intention-to-treat population. Patients with disease relapse or death before the 12-month post-randomization timepoint will be considered in the intention-to-treat population as not having achieved ctDNA clearance.

Secondary endpoints 3

1. Disease-free survival, defined as 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
2. Overall survival, defined as time from the randomization in the study to the occurrence of death
3. Metastases-free survival, defined as 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 1

Locations

1 EU/EEA country · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications