| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with gastric, oesophagus or gastroesophageal junction adenocarcinoma locally advanced, recurrent or metastatic, ineligible for triplet chemotherapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Oxaliplatin in combination with trifluridine/tipiracil or 5-fluorouracile in frail patients with advanced, recurrent or metastatic gastric, oesophageal or gastroesophageal junction cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030137 |
| E.1.2 | Term | Oesophageal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001150 |
| E.1.2 | Term | Adenocarcinoma gastric |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066354 |
| E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to evaluate the superiority of trifluridine/tipiracil + oxaliplatin over FOLFOX regimen in terms of Progression-Free Survival (PFS), in first-line palliative setting, in patients with gastric, oesophagus or gastroesophageal junction adenocarcinoma locally advanced, recurrent or
metastatic, ineligible for triplet chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
- The efficacy of the treatments in terms of:
• Objective Response rate (according to RECIST v1.1) (ORR)
• Overall Survival (OS)
- Safety and tolerability of treatment (NCI-CTCAE version 5.0)
- Time to PS deterioration >2
- The effect of treatments on Quality of Life (QoL) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Ancillary studies:
To evaluate prognostic and predictive values of several biological and radiological biomarkers. A correlation with Geriatric Core Dataset (G-CODE) and overall treatment utility (OTU) (Hall’s index) will also be studied in patients ≥70 years old. |
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed locally advanced, recurrent or metastatic adenocarcinoma of the stomach, oesophagus or gastroesophageal junction (GEJ).
2. No dysphagia or difficulty in swallowing.
3. No overexpression/amplification of HER2 (IHC 0 or 1+; if IHC is 2+, HIS must be negative). Known CPS PD-L1 score (result in % with the name of the method used). The microsatellite and MMR status of patient’s tumour (MSI/MSS and pMMR/dMMR) must also be known at the
time of screening (IHC and PCR tests have to be done).
4. At least one evaluable lesion according to RECIST v1.1 outside any previously irradiated area.
5. No prior palliative chemotherapy.
6. Age ≥18 years old.
7. Patient unfit for triplet chemotherapy, defined with ONE of the following criteria:
- ECOG-PS=2
- Age ≥70 year old PLUS one frailty criteria on ADL/IADL score
- Denutrition (defined by albumin <30 g/L)
- Other criterion left at investigator’s discretion (this later must be filled in by the investigator).
8. Adequate organs function:
- Absolute neutrophils count ≥1.5x109/L
- Platelets count ≥100x109/L
- Haemoglobin ≥9 g/L
- Serum bilirubin levels <2 times upper limit of normal (ULN), up to 2.5 times ULN in case of hepatic metastasis (biliary drainage allowed)
- Transaminases <5 times ULN
- Creatinine clearance >40 mL/min
9. No Dihydropyrimidine dehydrogenase (DPD) deficiency (uracilemia <16 ng/ml)
10. Women of childbearing potential must have a negative serum or urine pregnancy test done within 14 days before the first study treatment.
11. Patients must agree to use adequate contraception methods for the duration of study treatment
and within 6 months after completing treatment.
12. Patients must be affiliated to a Social Security System (or equivalent).
13. Patient must have signed and dated a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent.
14. Availability of archived tumour material for ancillary studies |
|
| E.4 | Principal exclusion criteria |
1. Other current or previous malignancy within the past 3 years (with the exception of squamous cell carcinoma of the skin treated by surgery).
2. Adjuvant chemotherapy or radio-chemotherapy completed for less than 6 months.
3. Peripheral neuropathy of NCI-CTCAE grade ≥2 at baseline.
4. Patients with known allergy or severe hypersensitivity to any of the trial drugs or any of the trial drug excipients.
5. Patients unwilling or unable to comply with trial obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the trial.
6. Previous treatment with trifluridine/tipiracil.
7. Known Human Immunodeficiency Virus (HIV) infection.
8. Active Hepatitis B virus (HBV, defined as having a positive hepatitis B surface antigen [HBsAg] test prior to inclusion) or hepatitis C virus (HCV).
9. Interstitial lung disease.
10. Prior pneumonitis requiring systemic corticosteroid therapy.
11. Active infections.
12. Pregnant or breastfeeding woman.
13. Participation in another therapeutic trial within the 30 days prior to randomisation.
14. Persons deprived of their liberty or under protective custody or guardianship.
15. Clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months, or high |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS defined as the time from the date of randomisation to date of disease progression (radiological or clinical) or death from any cause, whichever occurs first. Patients without tumour progression or death at the time of analysis will be censored at the date of their last tumour assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint of the study is the PFS defined as the time from the date of randomisation to date of disease progression (radiological or clinical) or death from any cause, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints:
• ORR (according to RECIST v1.1 criteria) defined as the percentage of patients with Complete Response (CR) or Partial Response (PR). Patients who discontinue treatment without a tumour assessment will be considered non-responders for the analysis
• Overall survival (OS), defined as the time from date of randomisation to the date of death from any cause. If a patient is alive at the database cut-off date, then the patient will be censored at the last date of follow-up.
- Safety and tolerability of treatment (NCI-CTCAE version 5.0) determined through the incidence of adverse events, treatment related adverse events, serious adverse Events (SAE), and death.
- Time to PS deterioration >2 defined as the time between patient randomisation and date when PS>2
- Quality of Life (QoL) according to QLQ-C30 questionnaire
- Ancillary studies will address:
• Specific pathological features and expression of biomarkers: microsatellite status (MS), PD1 and PDL1 expression, TMB, CD8+ cell infiltration, Epstein Barr Virus (assessed by in situ hybridization), TP53, E-cadherin, HER3.
• Circulating DNA and its value for prognosis and treatment monitoring (monitoring of DNA levels at different point during the treatment: pretreatment ctDNA and then every two months during the first year). Genetic changes will also be evaluated in several genes.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Efficacy endpoints:
Evaluation every 8 weeks from D1C5 till disease progression
- Safety and tolerability of treatment (NCI-CTCAE version 5.0)
During all the study
- Quality of Life (QoL) according to QLQ-C30 questionnaire
Every 8 weeks from D1C5 till disease progression
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Predictive values of several biological and radiological biomarkers |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The last visit of the last subject enter |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 60 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 60 |
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