Oxaliplatin ± Nivolumab in Combination With Trifluridine/Tipiracil or 5-fluorouracile in Frail Patients With Advanced, Recurrent or Metastatic Gastric, Oesophageal or Gastroesophageal Junction Cancer

Phase 2

Recruiting

• Conditions: Gastric Adenocarcinoma; Esophagus Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma
• Interventions: Drug: FOLFOX regimen; Drug: Trifluridine/Tipiracil; Drug: Nivolumab; Drug: Oxaliplatin

• Registration Number: NCT05476796
• Lead Sponsor: UNICANCER

Brief Summary

Oxaliplatin ± nivolumab in combination with trifluridine/tipiracil or 5-fluorouracile (5-FU) in frail patients with advanced, recurrent or metastatic gastric, oesophageal or gastroesophageal junction cancer.

Detailed Description

Randomised Phase II Study Evaluating Trifluridine/Tipiracil Plus Oxaliplatin ± Nivolumab Versus FOLFOX ± Nivolumab in Patients With HER2 Negative Locally Advanced, Recurrent or Metastatic Gastric, Oesophageal or Oesogastric Junction Adenocarcinoma

Study Timeline

• Study First Submitted: 2022-07-26
• Study First Submitted QC: 2022-07-26
• Study First Posted: 2022-07-27
• Study Start: 2023-06-23
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-22
• Last Update Posted: 2024-10-24
• Primary Completion: 2026-01
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 118

Inclusion Criteria

1. Histologically confirmed locally advanced, recurrent or metastatic non resectable adenocarcinoma of the stomach, oesophagus or gastroesophageal junction (GEJ) ineligible to curative treatment.

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 combined positive scor (CPS) PD-L1 score (result in % with the name of the method used). The microsatellite and mismatch repair (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 eligible for FOLFOX chemotherapy

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

Exclusion Criteria

1. Patient with a performance status ECOG PS >2.
2. Other current or previous malignancy within the past 3 years (with the exception of squamous cell carcinoma of the skin treated by surgery).
3. Adjuvant chemotherapy or radio-chemotherapy completed for less than 6 months.
4. Peripheral neuropathy of NCI-CTCAE grade ≥2 at baseline.
5. Patients with known allergy or severe hypersensitivity to any of the trial drugs or any of the trial drug excipients.
6. 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.
7. Previous treatment with trifluridine/tipiracil.
8. Known Human Immunodeficiency Virus (HIV) infection.
9. Active Hepatitis B virus (HBV, defined as having a positive hepatitis B surface antigen [HBsAg] test prior to inclusion) or hepatitis C virus (HCV).
10. Interstitial lung disease.
11. Prior pneumonitis requiring systemic corticosteroid therapy.
12. Active infections.
13. Pregnant or breastfeeding woman.
14. Participation in another therapeutic trial within the 30 days prior to randomisation.
15. Persons deprived of their liberty or under protective custody or guardianship.
16. Clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia (for men: QTc ≥450 msec, for women: QTc ≥470 msec)
17. Active systemic autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
18. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first study drug administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
FOLFOX ± nivolumab	FOLFOX regimen	Folinic Acid 400 mg/m² (or 200 mg/m² if L-folinic acid) + oxaliplatin 85 mg/m² (infusion duration: 2 hours) followed by 5-FU bolus 400 mg/m² and then 5-FU 2400 mg/m² as a 46-hour continuous infusion. Treatment repeated every 14 days. In case of limiting-oxaliplatin neuropathy and in all cases after 8 cycles, oxaliplatin will be stopped and 5-FU (simplified LV5FU2 regimen) or capecitabine (1000 mg/m² BID during 2 weeks every 3 weeks) will be continued alone until disease progression or intolerable toxicity. ± nivolumab 240 mg (infusion duration 30 minutes, every 2 weeks) until disease progression or intolerable toxicity for a maximum of 2 years.
FOLFOX ± nivolumab	Nivolumab	Folinic Acid 400 mg/m² (or 200 mg/m² if L-folinic acid) + oxaliplatin 85 mg/m² (infusion duration: 2 hours) followed by 5-FU bolus 400 mg/m² and then 5-FU 2400 mg/m² as a 46-hour continuous infusion. Treatment repeated every 14 days. In case of limiting-oxaliplatin neuropathy and in all cases after 8 cycles, oxaliplatin will be stopped and 5-FU (simplified LV5FU2 regimen) or capecitabine (1000 mg/m² BID during 2 weeks every 3 weeks) will be continued alone until disease progression or intolerable toxicity. ± nivolumab 240 mg (infusion duration 30 minutes, every 2 weeks) until disease progression or intolerable toxicity for a maximum of 2 years.
Trifluridine/Tipiracil + Oxaliplatin ± nivolumab	Trifluridine/Tipiracil	Trifluridine/Tipiracil will be administered with a 14-day schedule (35 mg/m² twice-daily \[BID\] for 5 days followed by 9 days of recovery) until disease progression or intolerable toxicity. Oxaliplatin will be administered intravenously on day 1 of each treatment cycle (infusion duration: 2 hours), every 2 weeks. The first cycle will be administered at level -1 (70 mg/m²) and then increased to 85 mg/m² (if feasible) from the cycle 2 to 8 or until disease progression, whatever occurs first. In case of limiting-oxaliplatin neuropathy and in all cases after 8 cycles, oxaliplatin will be stopped and Trifluridine/Tipiracil will be continued alone until disease progression or intolerable toxicity. ± nivolumab 240 mg (infusion duration 30 minutes, every 2 weeks) until disease progression or intolerable toxicity for a maximum of 2 years.
Trifluridine/Tipiracil + Oxaliplatin ± nivolumab	Oxaliplatin	Trifluridine/Tipiracil will be administered with a 14-day schedule (35 mg/m² twice-daily \[BID\] for 5 days followed by 9 days of recovery) until disease progression or intolerable toxicity. Oxaliplatin will be administered intravenously on day 1 of each treatment cycle (infusion duration: 2 hours), every 2 weeks. The first cycle will be administered at level -1 (70 mg/m²) and then increased to 85 mg/m² (if feasible) from the cycle 2 to 8 or until disease progression, whatever occurs first. In case of limiting-oxaliplatin neuropathy and in all cases after 8 cycles, oxaliplatin will be stopped and Trifluridine/Tipiracil will be continued alone until disease progression or intolerable toxicity. ± nivolumab 240 mg (infusion duration 30 minutes, every 2 weeks) until disease progression or intolerable toxicity for a maximum of 2 years.
Trifluridine/Tipiracil + Oxaliplatin ± nivolumab	Nivolumab	Trifluridine/Tipiracil will be administered with a 14-day schedule (35 mg/m² twice-daily \[BID\] for 5 days followed by 9 days of recovery) until disease progression or intolerable toxicity. Oxaliplatin will be administered intravenously on day 1 of each treatment cycle (infusion duration: 2 hours), every 2 weeks. The first cycle will be administered at level -1 (70 mg/m²) and then increased to 85 mg/m² (if feasible) from the cycle 2 to 8 or until disease progression, whatever occurs first. In case of limiting-oxaliplatin neuropathy and in all cases after 8 cycles, oxaliplatin will be stopped and Trifluridine/Tipiracil will be continued alone until disease progression or intolerable toxicity. ± nivolumab 240 mg (infusion duration 30 minutes, every 2 weeks) until disease progression or intolerable toxicity for a maximum of 2 years.

Primary Outcome Measures

Name	Time	Method
Progression free-survival	From randomization to disease progression or death up to 5 years	The progression-free survival (PFS) is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.

Secondary Outcome Measures

Name	Time	Method
Objective response rate	5 years	Objective response rate (ORR) is defined as the percentage of patients with a best response during treatment being either Complete Response (CR) or Partial Response (PR).
Overall survival	From randomization to death from any cause, up to 5 years	The overall survival (OS) is the length of time from randomization that patients enrolled in the study are still alive.
Incidence of Treatment Adverse Events	Throughout study completion, up to 5 years	The tolerance and safety will be evaluated by toxicity (acute \[\<1 months after the end of the trial treatment\] and late \[≥1 month after the end of the trial treatment), assessed using the Common terminology criteria for adverse events version 5.0 (CTCAE v5.0). CTCAE is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.
Time to patient performance status deterioration >2	From randomization to PS deterioration >2, up to 5 years	Time to performance status (PS) deterioration \>2 is defined as the time between patient randomisation and the first date when PS\>2.; The Eastern Cooperative Oncology Group (ECOG) PS, a simple measure of functional status, determines ability of patient to tolerate therapies. It has scores ranging from 0 to 5 (0 = "fully active", 1 = "completely ambulatory", 2 = "\<50% in bed during the day", 3 = "\>50% in bed, but not bedbound", 4 = "bedbound", and 5 = "death").
Quality of life questionnaire - Core 30 (QLQ-C30)	From baseline until disease progression, up to 1 year	Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.; The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.; All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

Trial Locations

Locations (29)

CHU d'Estaing; 🇫🇷 Clermont-Ferrand, France

Institut Andrée Dutreix - Clinique de Flandre; 🇫🇷 Coudekerque-Branche, France

Clinique de l'Europe; 🇫🇷 Amiens, France

Hopital Privé Arras Les Bonnettes; 🇫🇷 Arras, France

Institut Sainte Catherine; 🇫🇷 Avignon, France

Centre Hospitalier de Beauvais; 🇫🇷 Beauvais, France

CHU Besançon - Hôpital Jean Minjoz; 🇫🇷 Besançon, France

CHU Morvan; 🇫🇷 Brest, France

Clinique Pasteur Lanroze; 🇫🇷 Brest, France

CH Cholet; 🇫🇷 Cholet, France

Centre Jean Perrin; 🇫🇷 Clermont-Ferrand, France

Centre Georges François Leclerc; 🇫🇷 Dijon, France

Hôpital Nord-Ouest Villefranche-sur-Saône; 🇫🇷 Gleizé, France

Centre Léon Bérard; 🇫🇷 Lyon, France

Hôpital Saint Joseph; 🇫🇷 Marseille, France

Institut Paoli Calmettes; 🇫🇷 Marseille, France

Hôpital Nord Franche Comté; 🇫🇷 Montbéliard, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Hôpital Saint Louis; 🇫🇷 Paris, France

Hopital Europeen Georges Pompidou; 🇫🇷 Paris, France

GH Diaconesses - Crois St Simon; 🇫🇷 Paris, France

Institut Mutualiste Montsouris; 🇫🇷 Paris, France

CHU de Poitiers; 🇫🇷 Poitiers, France

CHU - Hôpital Robert Debré; 🇫🇷 Reims, France

Institut Jean Godinot; 🇫🇷 Reims, France

CHU Rouen - Charles Nicolle; 🇫🇷 Rouen, France

ICO - Site René Gauducheau; 🇫🇷 Saint-Herblain, France

Institut de cancérologie Strasbourg Europe; 🇫🇷 Strasbourg, France

CHU Nancy - Hôpital Brabois; 🇫🇷 Vandœuvre-lès-Nancy, France