FÉDÉRATION FRANCOPHONE DE CANCÉROLOGIE DIGESTIVE


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PRODIGE 61 - FUNGEMAX



Coordonateurs : Pr TAIEB J., Pr BACHET J.

Étude de Phase II randomisée visant à comparer 5-FU/LV+Nal-IRI, gemcitabine+Nab-paclitaxel ou un schéma thérapeutique séquentiel de 2 mois avec 5-FU/LV+Nal-IRI, suivi de deux mois sous gemcitabine+Nab-paclitaxel, en cas de cancer du pancréas métastatique

Phase : II
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Synopsis

Title

PRODIGE 61 – FFCD 1702 – FUNGEMAX Randomized phase II study comparing 5-FU/LV+Nal-IRI, gemcitabine+Nab-paclitaxel or a sequential regimen of 2 months 5-FU/LV+Nal-IRI followed by two months of gemcitabine+Nab-paclitaxel, in metastatic pancreatic cancer

Sponsor

French Federation of Digestive Oncology (FFCD)

Design

Multicenter randomized phase II comparative open study

Study objectives

Primary objective:
  • Compare the progression free survival at 6 months in experimental arms (arm A: Nal-Iri plus 5FU/LV and Nab-Paclitaxel plus Gemcitabine alternatively, arm B: Nal-Iri plus 5FU/LV) VS the reference arm (arm C: Nab-Paclitaxel plus Gemcitabine) according to the RECIST 1.1 criteria
Secondary objectives:
  • Progression free survival at 6 months (according to central review)
  • Best objective response rate
  • Progression free survival (according to the investigator and central review)
  • Overall survival
  • Time to treatment failure
  • Safety
  • Quality of life (EORTC QLQ-C30)
  • CA 19-9 and CEA monitoring

Inclusion criteria

  • Histopathologically or cytologically proven pancreatic adenocarcinoma (on primitive or metastatic lesion)
  • Metastatic disease at a distance
  • At least one measurable lesion according RECIST v1.1 criteria
  • 18 < age < 75 years
  • Life expectancy > 12 weeks
  • Performance status WHO < 2
  • No prior chemotherapy : adjuvant chemotherapy by gemcitabine +/- capecitabine is allowed if ended at least 12 months before the inclusion and adjuvant or neo-adjuvant FOLRIFINOX chemotherapy is allowed if ended at least 12 month prior the inclusion
  • Pain well controlled before the inclusion of the patient
  • ANC > 1,500 cells/µL (without the use of hematopoietic growth factors); platelet count > 100,000 cells/µL, hemoglobin > 9 g/dL (blood transfusions is permitted for patients with hemoglobin levels below 9 g/dL)
  • Adequate hepatic function as evidenced by: Serum total bilirubin within normal range for the institution (Serum bilirubin < 1,5 UNL) Biliary drainage allowed for biliary obstruction.
  • Albumin levels > 3.0 g/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN (< 5 x ULN acceptable if liver metastases were present)
  • Normal renal function test (creatinine clearance > 50 ml/min)
  • Normal ECG or ECG without any clinically significant findings
  • Patient able to understand and sign an informed consent
  • Females of child-bearing potential are required to test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test.
  • Both male and female patients of reproductive potential were required to agree to use a reliable method of birth control, during the study and for 3 months following the last dose of study drug.
  • Patient affiliated to social security
  • Regular follow-up possible

Non-inclusion criteria

  • Uncontrolled brain or meningeal metastasis, or bone metastasis (no need of systematic CT scan)
  • Prior radiation therapy (except if there is at least one measurable target outside irradiation area)
  • Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > Grade 1
  • History of chronic inflammatory bowel disease
  • Other types of pancreatic tumours, in particular endocrine or acinar cell tumours
  • Ampulloma
  • Gilbert's syndrome
  • Presence of neuropathy > grade 1 according to NCI-CTC
  • History of any second malignancy in the last 5 years; subjects with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they had been continuously disease free for at least 5 years.
  • Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion.
  • NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure.
  • Known hypersensitivity to any of the drugs /constituents or non-lipososomal irinotecan
  • Any other medical or social condition deemed by the investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interferes with the interpretation of the results.
  • Use of CYP3A4/UGT1A inducers/inhibitors
  • Use of strong CYP2C8 inhibitors or inducers, or presence of any other contraindications for nab-paclitaxel or gemcitabine
  • ILD presence
  • Pregnant or breast feeding

Study treatment

Arm A (experimental arm): Nal-IRI plus 5-FU/LV and Nab-Paclitaxel plus Gemcitabine alternately every two months

- Nal-IRI at 80 mg/m2 IV over 90 minutes followed by folinic acid (leucovorin 400 mg/m2 IV, or Elvorin 200 mg/m2 IV over 30 minutes) then by 5-FU 2400 mg/m2 IV over 46-hours, every 2 weeks.

According the recommendations of the transparency commission, the systematic determination of UGT1A1*28 polymorphism is recommended before the first cure of Nal-IRI.
Patients known to be homozygous for UGT1A1*28 allele will receive the first cycle of therapy at a reduced Nal-IRI dose of 60 mg/m². If the patient does not experience any drug related toxicity after the first administration of Nal-IRI, the dose is permitted to be increased to 80 mg/m2 from cycle 2 onwards.

- Nab-Paclitaxel + Gemcitabine (6 injections, one injection three weeks out of four; so ˜ 2 months per cycle)
Day 1 (D1): Nab-Paclitaxel plus Gemcitabine at the dose of :
  • Gemcitabine: 1000 mg/m² in 500 ml normal saline infusion at a fixed dose rate of 10 mg/m²/min (i.e. 100 min).
  • Nab-Paclitaxel: 125 mg/m2
This treatment is administered at D1, D8, D15 and at D29, D36, D43.

This therapeutic sequence (5-FU/LV plus Nal-IRI followed by Nab-Paclitaxel + Gemcitabine) will be repeated until disease progression or unacceptable toxicity.
The response or the progression with each treatment will be censored. In case of progression or limiting toxicity with one of these two treatments, the other one will be continued until tumoral progression, limiting toxicity or patient’s refusal.
Clinical, biological and morphological assessments will be done every 2 months

Arm B (experimental arm): Nal-IRI plus 5-FU/LV

Nal-IRI at 80 mg/m2 IV over 90 minutes followed by folinic acid (leucovorin 400 mg/m2 IV, or Elvorin 200 mg/m2 IV over 30 minutes) then by 5-FU 2400 mg/m2 IV over 46-hours, every 2 weeks.

According the recommendations of the transparency commission, the systematic determination of UGT1A1*28 polymorphism is recommended before the first cure of Nal-IRI.
Patients known to be homozygous for UGT1A1*28 allele will receive the first cycle of therapy at a reduced Nal-IRI dose of 60 mg/m2. If the patient does not experience any drug related toxicity after the first administration of Nal-IRI, the dose is permitted to be increased to 80 mg/m2 from cycle 2 onwards.

This treatment will be continued until disease progression (clinical and/or radiological), limiting toxicity or patient’s refusal and evaluation will be performed every 2 months.

Arm C (reference arm): Nab-Paclitaxel plus Gemcitabine
Nab-Paclitaxel + Gemcitabine
(6 courses, one course three weeks out of four; so ˜ 2 months per cycle)
Day 1 (D1): Nab-Paclitaxel + Gemcitabine at the dose of :
  • Gemcitabine: 1000 mg/m² in 500 ml normal saline infusion at a fixed dose rate of 10 mg/m²/min (i.e. 100 min).
  • Nab-Paclitaxel: 125 mg/m2
This treatment is administered at D1, D8, D15 and at D29, D36, D43.

This treatment will be continued until disease progression (clinical and/or radiological), limiting toxicity or patient’s refusal and evaluation will be performed every 2 months.

Randomization

Randomization (1:1:1) of the patient will be done according to a minimization technique and will be stratified according to the following stratification factors:
  • Center
  • WHO/PS 0 versus 1
  • 1 versus >1 metastatic sites

Sample size calculation

The hypotheses used to calculate the sample size are:
  • H0: The rate of patients alive without progression at 6 months is not different between arms.
  • H1: The rate of patients alive without progression at 6 months in experimental arms is different from the rate in standard arm (same hypothesis for the 2 experimental arms).

We expected a difference of 15% at 6 months in favor of experimental arms vs standard arm (from 30% to 45%): HR=0.66
With a two-sided a risk of 5% and a power of 80%, it will be necessary to observe 182 events (progression or death), (estimated sample sizes for two-sample comparison of survivor functions Log-rank test, Schoenfeld method).
Taking into account an assumption of 2 years of recruitment, a patient's follow-up of 3 years and with a percentage of patients lost to follow-up of 5%, it will be necessary to randomize 192 patients (96 patients in each compared arm meaning 288 patients overall = 96 patients*3 arms).

Statistical analysis (generality)

Baseline characteristics will be described using descriptive statistics as percentages (with 95% CI) for categorical and ordinal variables and mean (with standard deviation), median (with interval Inter-quartiles and Min-max) for continuous variables. The results will be presented by treatment group and on the overall population.
Comparisons by treatment arm will be performed for the quantitative variables, using a Student or Wilcoxon test (according to the distribution of the variables) and for qualitative variables, using a Chi² test or a Fisher exact test.
For the primary analysis, the statistical method to demonstrate the superiority of experimental arms against standard arm will be the step-down procedure.
Progression free survival and overall survival (OS) will be measured from the date of randomization and will be estimated using Kaplan-Meier method. The median times and rates at different temporalities shall be described as well as their confidence intervals at 95%.
Treatment arms comparisons will be done using log-rank test.
Toxicities, doses received will be described by treatment arms.
A more detailed Statistical Analysis Plan (SAP) will be written before the database lock.

Ancillary study

Blood and tissue will be collected prospectively at the biological resource center of FFCD for future translational projects There will be at least analysis of circulating tumor DNA before treatment to look for predictive factors.

Number of patients

288 patients

Duration of inclusion and length of participation for each patient

Theoretical rate of inclusion: 10 patients per month
Number of centers: 40
Theoretical start of inclusion: Q3 2018
Theoretical end of inclusion: Q4 2021
End of the trial (primary and secondary endpoint analysis): Q4 2024

Administration information

Principal Investigator (FFCD): Prof. Julien Taieb
HOPITAL EUROPEEN G. POMPIDOU
Service d'Hépato-gastro-entérologie
20 Rue Leblanc
75015 PARIS
Tel. : +33(0)1 56 09 50 42 - Fax : +33(0)1 56 09 35 29
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Co-Principal Investigator (GERCOR): Pr Jean Baptiste Bachet
Groupe Hospitalier Pitié Salpêtrière
Service d’Hépato-gastroentérologie & Oncologie Digestive
47-83 boulevard de l’Hôpital 75013 Paris ; France
Tel. : +33 (0)1 42 16 10 41– Fax : +33 (0)1 42 16 12 38
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PROTOCOL WRITING COMMITTEE Jean-Baptiste Bachet (Paris, La Pitié Salpêtrière), Jérémie Bez (Dijon), Christelle De La Fouchardière (Lyon, Léon Bérard), Claire Gallois (Paris HEGP), Karine Le Malicot (Dijon), Carole Montérymard (Dijon), Julien Taieb (Paris HEGP).

BIOLOGICAL COMMITTEE Pierre Laurent-Puig (Paris HEGP), Julien Taieb (Paris HEGP), Claire Gallois (Paris HEGP), Jean-François Emile (Paris)

SPONSOR AND DATA CENTER: Fédération Francophone de Cancérologie Digestive (FFCD), Faculté de Médecine, 7, Boulevard Jeanne d’Arc, BP 87900, 21079 Dijon Cedex, France

Executive director: Cécile GIRAULT
Tel: +33 (0)3 80 66 80 13 – Fax: +33 (0)3 80 38 18 41
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Statistician: Carole MONTERYMARD
Tel: +33 (0)3 80 39 34 84 – Fax: +33 (0)3 80 38 18 41
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Project manager: Daniel GONZALEZ
Tél. : +33 (0)3 80 39 34 04 – Fax: +33 (0) 3 80 38 18 41
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