Nal-iri/lv5-fu Versus Paclitaxel as Second Line Therapy in Patients With Metastatic Oesophageal Squamous Cell Carcinoma

Squamous Cell Carcinoma Clinical Trial

— OESIRI  

Official title:

Nal-IRI/LV5-FU VERSUS PACLITAXEL AS SECOND-LINE THERAPY IN PATIENTS WITH METASTATIC OESOPHAGEAL SQUAMOUS CELL CARCINOMA A Multi-centre, Randomized, Non-comparative Phase II Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03719924
• Other study ID #: PRODIGE 62 - OESIRI
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 7, 2019
• Est. completion date: April 15, 2025

Study information

• Verified date: December 2023
• Source: Federation Francophone de Cancerologie Digestive
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of our study is to evaluate the efficacy and safety of NALIRI plus 5FU versus paclitaxel as a second-line therapy in patients with locally advanced or metastatic ESCC who had failed to cisplatin- or oxaliplatin-based first-line chemotherapy.

The hypotheses are as follows:

H0: the percentage of patients alive at 9 months of 40% is not useful. H1: the percentage of patients alive at 9 months of 60% is expected.

Description:

Principal objective:

• To evaluate the survival of patients at 9 months

Secondary objectives:

• Progression-free survival (PFS) (clinical and/or radiological)

• Overall survival (OS)

• Best response rate during treatment according to RECIST 1.1 criteria (according to the investigator and the centralised review committee)

• Toxicity (NCI CTC 4.0)

• Quality of life (QLQ-C30 and OES18 questionnaires of the EORTC)

Arm A (experimental arm): Nal IRI plus LV5-FU (D1=D28) Nal-IRI: 80 mg/m² intravenous over 90 minutes Followed by intravenous folinic acid 400 mg/m² over 30 minutes or L-folinic acid: 200 mg/m² over 30 minutes And then 5-FU 2,400 mg/m² over 46 hours on D1 to D14 Patients known to be homozygous for the UGT1A1*28 allele who are to be randomized to the Nal-IRI/5-FU Arm receive the first cycle of therapy with a reduced dose of Nal IRI of 60 mg/m2. If the patient does not present any toxicity related to the medicinal product after the first administration of Nal IRI, the dose can be increased to 80 mg/m2 starting with cycle 2.

Arm B (control arm): PACLITAXEL (D1=D28) Paclitaxel: 80 mg/m² at D1, D8 and D15

Patients will be randomized in a 1:1 ratio using the minimisation technique. Randomisation will be stratified based on the following factors:

• Centre

• WHO performance status: 0/1 versus 2

An analysis of circulating tumour DNA (using genetic mutations, in particular, TP53, and DNA methylation analyses) will be performed before the 1st cycle of treatment and at D28, in order to look for factors predictive of response to treatment (decrease in unbound DNA).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 106
• Est. completion date: April 15, 2025
• Est. primary completion date: April 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven metastatic oesophageal squamous cell carcinoma

• Patient in failure with 1st-line treatment with oxaliplatin or cisplatin. Patients presenting with resectable disease treated with surgery or neoadjuvant or adjuvant chemotherapy with oxaliplatin or cisplatin (with or without radiotherapy) can be included if a recurrence has occurred less than 6 months after the end of treatment

• Age = 18 years

• Unresectable disease, measurable or not, according to RECIST 1.1 criteria

• WHO performance status = 2

• Neutrophils = 1500/mm3 (without use of haematopoietic growth factors), platelets = 100 000/mm3, haemoglobin = 9 g/dl (blood transfusions are authorised for patients with a haemoglobin less than 9 g/dl)

• Total bilirubin = 2 x ULN (biliary drainage is authorised in case of a biliary obstruction); albumin = 25 g/L; AST = 2.5 x ULN, and ALT = 2.5 x ULN (= 5 x ULN in case of hepatic metastases)

• Creatinine clearance = 50 ml/min according to MDRD formula

• A normal ECG or ECG with no clinically significant findings

• Patient able to understand and to sign the informed consent form (or who has a legal guardian able to do so for him/him)

• Women of childbearing potential must have a negative pregnancy blood or urine test within 7 days prior to inclusion

• Women of childbearing potential, as well as men (who have sexual relations with women of childbearing potential) must agree to use an effective method of contraception throughout this study and during the 6 months following administration of the last dose of the study medicinal product

• Patient who is a beneficiary of the Social security system

• Patient for whom regular follow-up is possible.

Exclusion Criteria:

• Known brain or bone metastases

• Clinically significant gastrointestinal disorders, including hepatic, haemorrhagic, inflammatory, obstructive disorders or diarrhoea > grade 1

• History of chronic inflammatory bowel disease

• Gilbert's syndrome

• Interstitial lung disease

• Treatment with St John's Wort

• Medical history of Whipple procedure

• Body mass index < 18.5 kg/m2

• Combination with sorivudine and others analogues as brivudine (irreversibly inhibits the enzyme dihydropyrimidine dehydrogenase)

• History of progressive cancer or in remission of less than 3 years duration (patients who present with a cancer in situ or basal cell or squamous cell skin cancer during the last 3 years are eligible).

• Severe arterial thromboembolic events (myocardial infarction, unstable angina, stroke) less than 3 months before inclusion

• NYHA class III or IV congestive heart failure, ventricular arrhythmia or uncontrolled blood pressure

• Significant neuropathy = grade 2 according to NCI CTCAE criteria (National Cancer Institute Common Terminology Criteria for Adverse Events) v.4.0.

• Known hypersensitivity or allergy to a component of the medicinal products used in the study.

• Known DPD deficiency

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Esophageal Squamous Cell Carcinoma
• Squamous Cell Carcinoma

Intervention

Drug:
• Onivyde
onivyde will be administered first, followed by folinic acid or L-folinic acid and then 5-FU at D1 and D14.
• Paclitaxel
Paclitaxel : 80 mg/m2 IV during 60 minutes at D1, D8 and D15

Locations

Country	Name	City	State
France	Chu Amiens	Amiens
France	Institut Sainte Catherine	Avignon
France	Hopital Européen	Marseille
France	Ch Le Raincy	Montfermeil
France	Chu Saint Louis	Paris
France	Ch Perpignan	Perpignan
France	Chu de Poitiers	Poitiers
France	Chu Rouen	Rouen
France	Ch Duchenne	Saint-Malo

Sponsors (2)

Lead Sponsor	Collaborator
Federation Francophone de Cancerologie Digestive	Shire

Country where clinical trial is conducted

France, 

References & Publications (1)

Randrian V, Adenis A, Desrame J, Barbier E, Di Fiore F, Lievre A, Dahan L, Laurent-Puig P, Mineur L, Breysacher G, Roquin G, Louafi S, Lopez A, Louvet C, Borg C, Metges JP, Faroux R, Gaba L, Manfredi S, Tougeron D. Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI)-PRODIGE 62: A multicentre, randomised, non-comparative phase II study. Dig Liver Dis. 2020 Mar;52(3):347-350. doi: 10.1016/j.dld.2019.11.014. Epub 2019 Dec 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	survival at 9 months	The principal objective is to evaluate survival at 9 months in patients presenting with metastatic oesophageal squamous cell carcinoma (OSC) treated with Nal-IRI/LV5-FU or with paclitaxel.	9 months
Secondary	Progression-free survival	Clinical Progression-free survival and/or radiological Progression free survival will be evaluated	5 years
Secondary	Overall survival (OS)	evaluate the overall survival	1 year
Secondary	Best response rate during treatment	Best response rate during treatment according to RECIST 1.1 criteria (according to the investigator and with centralised review)	6 months
Secondary	Toxicity (NCI-CTC v4)	all observed toxicities, graded according to NCI-CTC v4 and the SAE	6 months
Secondary	Quality of life (questionnaires)	Quality of life (QLQ-C30 questionnaires of EORTC) and OES18 questionnaires of EORTC	6 months