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

Sponsor

Federation Francophone de Cancerologie Digestive (Other)

Overall Status

Recruiting

CT.gov ID

NCT03719924

Collaborator

Shire (Industry)

106

Enrollment

Locations

Arms

61.3

Anticipated Duration (Months)

11.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma	Drug: Onivyde Drug: Paclitaxel	Phase 2

Detailed 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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

106 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

All initial characteristics will be described in the overall population and by treatment arm. Evaluation criteria related to efficacy and safety will be described by treatment arm. Initial characteristics of best response and toxicities will be evaluated using usual statistics: for quantitative variables: mean, standard deviation, median, interquartile interval and range and for qualitative variables: frequencies and percentages. For the primary evaluation end point, a one-sided 95% confidence interval (CI) will be calculated in the experimental arm.All initial characteristics will be described in the overall population and by treatment arm. Evaluation criteria related to efficacy and safety will be described by treatment arm. Initial characteristics of best response and toxicities will be evaluated using usual statistics: for quantitative variables: mean, standard deviation, median, interquartile interval and range and for qualitative variables: frequencies and percentages. For the primary evaluation end point, a one-sided 95% confidence interval (CI) will be calculated in the experimental arm.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 7, 2019

Anticipated Primary Completion Date :

Jul 15, 2023

Anticipated Study Completion Date :

Apr 15, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: arm A: ONIVYDE ONIVYDE ONIVYDE will be administered first, followed by folinic acid or L-folinic acid and then 5-FU at D1 and D14 ONIVYDE: 80 mg/m² intravenous over 90 minutes Folinic acid: 400 mg/m² intravenous over 30 minutes or L-folinic acid (racemic form L) 200 mg/m² over 30 minutes 5-FU: 2400 mg/m² over 46 hours	Drug: Onivyde onivyde will be administered first, followed by folinic acid or L-folinic acid and then 5-FU at D1 and D14. Other Names: no other intervention name to add
Active Comparator: Arm B: TAXOL TAXOL Premedication consists of corticosteroids, H1 antihistamines and H2 antagonists during 30 minutes at time 1 hour before chemotherapy One cycle every 28 days (D1=D28) 80 mg/m2 IV over 60 minutes at D1, D8 and D15	Drug: Paclitaxel Paclitaxel : 80 mg/m2 IV during 60 minutes at D1, D8 and D15 Other Names: no other intervention name to add

Arm

Intervention/Treatment

Experimental: arm A: ONIVYDE

ONIVYDE ONIVYDE will be administered first, followed by folinic acid or L-folinic acid and then 5-FU at D1 and D14 ONIVYDE: 80 mg/m² intravenous over 90 minutes Folinic acid: 400 mg/m² intravenous over 30 minutes or L-folinic acid (racemic form L) 200 mg/m² over 30 minutes 5-FU: 2400 mg/m² over 46 hours

Drug: Onivyde

onivyde will be administered first, followed by folinic acid or L-folinic acid and then 5-FU at D1 and D14.

Other Names:

no other intervention name to add

Active Comparator: Arm B: TAXOL

TAXOL Premedication consists of corticosteroids, H1 antihistamines and H2 antagonists during 30 minutes at time 1 hour before chemotherapy One cycle every 28 days (D1=D28) 80 mg/m2 IV over 60 minutes at D1, D8 and D15

Drug: Paclitaxel

Paclitaxel : 80 mg/m2 IV during 60 minutes at D1, D8 and D15

Other Names:

no other intervention name to add

Outcome Measures

Primary Outcome Measures

survival at 9 months [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.

Secondary Outcome Measures

Progression-free survival [5 years]
Clinical Progression-free survival and/or radiological Progression free survival will be evaluated
Overall survival (OS) [1 year]
evaluate the overall survival
Best response rate during treatment [6 months]
Best response rate during treatment according to RECIST 1.1 criteria (according to the investigator and with centralised review)
Toxicity (NCI-CTC v4) [6 months]
all observed toxicities, graded according to NCI-CTC v4 and the SAE
Quality of life (questionnaires) [6 months]
Quality of life (QLQ-C30 questionnaires of EORTC) and OES18 questionnaires of EORTC

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Chu Amiens	Amiens	France
2	Institut Sainte Catherine	Avignon	France
3	Hopital Européen	Marseille	France
4	Ch Le Raincy	Montfermeil	France
5	Chu Saint Louis	Paris	France
6	Ch Perpignan	Perpignan	France
7	Chu de Poitiers	Poitiers	France
8	Chu Rouen	Rouen	France
9	Ch Duchenne	Saint-Malo	France