Etude : NAPOLI 3 / D-US-60010-001

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Acronyme / Nom
Situation thérapeutique
Cadre réglementaire
Présentation de l'étude
Acronyme / Nom : NAPOLI 3 / D-US-60010-001

Situation thérapeutique : Métastatique ou localement avancé

Traitement : Chimiothérapie

Cadre réglementaire : RIPH1

Dernière MÀJ : 03/12/2021
CIM10 - Localisation(s)
Informations principales
Titre : Étude de phase III multicentrique, randomisée et en ouvert de l’association irinotécan liposomal pour injection, oxaliplatine, 5-fluorouracile/leucovorine versus l’association nab-paclitaxel plus gemcitabine chez des sujets atteints d’un adénocarcinome du pancréas métastatique n’ayant jamais reçu de chimiothérapie

Spécialité : Organes digestifs
Localisation : C25 - Tumeur maligne du pancréas
Informations complémentaires
Schéma : The purpose of this study is to look at the efficacy and safety of Irinotecan liposome injection in combination with other approved drugs used for cancer therapy, namely 5 fluorouracil/leucovorin (5FU/LV) plus oxaliplatin compared to nab-paclitaxel + gemcitabine treatment in improving the overall survival of patients not previously treated for metastatic pancreatic cancer.

- Experimental: Irinotecan liposome injection + Oxaliplatin + 5-FU/LV
Irinotecan liposome injection, oxaliplatin, 5 FU/LV, will be administered on Days 1 and 15 of each 28-day cycle (until progression or unacceptable toxicity).
* Irinotecan liposome injection is irinotecan in the form of the sucrosofate salt, encapsulated in liposomes for i.v. infusion. It is supplied in sterile, single-use vials containing 10 mL of irinotecan liposome injection at a concentration of 4.3 mg/mL free base equivalent (FBE).
* Oxaliplatin injection, USP is supplied in single-dose vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.
* Fluorouracil injection, USP is a colorless to faint yellow, aqueous, sterile, nonpyrogenic injectable solution available in 50 mL and 100 mL pharmacy bulk package. Each mL contains 50 mg fluorouracil in water for injection, USP.
* Leucovorin Calcium for Injection is supplied in vials ranging from 50-500 mg and available as an injectable solution or lyophilized powder for reconstitution.

- Active Comparator: Nab-paclitaxel + Gemcitabine
Nab-paclitaxel and gemcitabine will be administered on Days 1, 8 and 15 of each 28-day cycle (until progression or unacceptable toxicity).
* Nab-paclitaxel is a lyophilised powder containing 100 or 250 mg of paclitaxel formulated as albumin-bound particles in single-use vials for re-constitution. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
* Gemcitabine for injection is a lyophilised powder for solution for infusion, with each single use vial containing 200 mg, 1 g or 2 g of gemcitabine.

The primary objective of this study is to evaluate the efficacy of the regimen of irinotecan liposome injection + oxaliplatin + 5 fluorouracil (5-FU)/leucovorin (LV) versus nab paclitaxel + gemcitabine in improving overall survival (OS) in subjects who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas.

• To evaluate progression free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 guidelines
• To evaluate the overall response rate (ORR) according to RECIST Version 1.1 guidelines
• To evaluate the safety of this regimen in this patient population.

Phase : III

Stade : Métastatique

Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : (1) Subject has been informed about the nature of the study, and has agreed to participate in the study, and signed the ICF prior to participation in any study-related activities.
(2) Male or non-pregnant and non-lactating female and ≥18 years of age:
a. Females of child-bearing potential (i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) must test negative for pregnancy at the time of screening based on a urine or serum pregnancy test. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Female subjects of reproductive potential must agree to use a highly effective method of birth control, during the study and for 6 months following the last dose of study medication (see also Appendix 4).
b. Male subjects must agree to use condoms during the study and for 6 months following the last dose of study medication.
(3) Histological or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting.
(4) Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to screening.
(5) Subject has one or more metastatic tumours measurable by CT scan (or MRI, if the subject is allergic to CT contrast media) according to RECIST Version 1.1 criteria.
(6) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening and within 7 days prior to randomisation.
(7) Subject has adequate biological parameters as demonstrated by the following blood counts:
a. Absolute neutrophil count (ANC) ≥2000/mm3 without the use of hemopoietic growth factors within the last 7 days prior to randomisation
b. Platelet count ≥100,000/mm3
c. Haemoglobin (Hgb) ≥9 g/dL obtained ≤14 days prior to randomisation.
(8) Adequate hepatic function as evidenced by:
a. Serum total bilirubin ≤1.5x upper limit of normal (ULN) (biliary drainage is allowed for biliary obstruction), and
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN (≤5x ULN is acceptable if liver metastases are present).
(9) Adequate renal function with a creatinine clearance (CLCR) of >30 mL/min. Actual body weight should be used for calculating CLCR using the Cockcroft Gault Equation:
CLCR (mL/min) = ((140–Age [years]) * (Weight [kg]/(Serum Creatinine [mg/dL]*72).
Multiply the result by 0.85 if the subject is female. For subjects with a body mass index (BMI) >30 kg/m2, adjusted body weight should be used instead.
(10) Electrocardiogram (ECG) without any clinically significant findings (QT interval corrected by Fridericia’s formula (QTcF) <450 msec and no known arrhythmias), and per the investigator’s assessment.
(11) Adequate coagulation studies (obtained ≤14 days prior to randomisation) as demonstrated by prothrombin time and partial thromboplastin time within normal limits (≤1.5 x ULN). (Subjects on warfarin or other vitamin K antagonists should be discussed with the sponsor).
(12) Subject has no clinically significant abnormalities in urinalysis results (obtained within the last 7 days prior to randomisation), per the investigator’s assessment.
(13) Subjects infected with human immunodeficiency virus (HIV) are eligible if they meet all the following criteria:
a. CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications
b. Probable long-term survival with HIV if cancer were not present
c. Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study
d. HIV is not multi-drug resistant
e. Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication.

Critères de non-inclusion : (1) Any other medical or social condition deemed by the investigator to be likely to interfere with a subject’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
(2) Unwilling or unable to comply with study procedures and/or study visits
(3) Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy:
a.Palliative radiotherapy is permitted
b.Placement of biliary stent/tube is permitted
c.Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant setting, except those where at least 12 months have elapsed since completion of the last dose and no persistent treatment-related toxicities are present
(5) Subject has only localised advanced disease
(6) Documented serum albumin <3 g/dL within 7 days prior to randomisation
(7) Known history of central nervous system (CNS) metastases. (Subjects on a stable or decreasing dose of steroids and deemed clinically stable as per the investigator’s assessment are eligible)
(8) Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, diarrhoea >Grade 1, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease or partial bowel obstruction
(9) History of any second malignancy in the last 2 years; subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Subjects with a history of other malignancies are eligible if they have been continuously disease free for at least 2 years prior to screening. Subjects who have a concurrent malignancy that is clinically stable and does not require tumour-directed treatment are eligible
(10) Known hypersensitivity to any of the components of irinotecan liposome injection, other liposomal products, or any components of 5-FU, LV or oxaliplatin
(11) Known hypersensitivity to any of the components of nab-paclitaxel or gemcitabine
(12) Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease, including:
a.Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before screening
b.High cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year prior to screening
c.New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
d.Known historical or active infection with hepatitis B, or active infection with hepatitis C (note that subjects with hepatitis C who have been clinically cured, defined as persistent absence of hepatitis C ribonucleic acid (RNA) detected by polymerase chain reaction (PCR) test in serum 12 weeks after completing antiviral treatment, are eligible for this study)
(13) Active infection or an unexplained fever >38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, subjects with tumour fever may be enroled), which in the investigator’s opinion might compromise the subject’s participation in the study or affect the study outcome
(14) Major surgery, other than diagnostic surgery, within 4 weeks prior to randomisation
(15) Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1 (please refer to Appendix 1). Subjects are ineligible if:
- they are unable to discontinue the use of strong inhibitors of CYP3A, CYP2C8 and UGT1A1 at least 1 week prior to randomisation
- they are unable to discontinue the use of strong CYP3A and CYP2C8 inducers at least 2 weeks prior to randomisation
(16) There is presence of any contraindications outlined in the Contraindications or Warnings and Precautions sections of the investigator brochure (IB) for irinotecan liposome injection, or in the prescribing information for 5-FU, LV or oxaliplatin
(17) There is presence of any contraindications outlined in the Contraindications or Special Warnings and Precautions sections of the product prescribing information for nab paclitaxel or gemcitabine.
(18) Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma
(19) Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of screening
(20) History of systemic tissue disorders (e.g. lupus, scleroderma, arteritis nodosa)
(21) History of interstitial lung disease, history of slowly progressive dyspnoea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies
(22) History of peripheral artery disease (e.g. claudication, Leo Buerger's disease)
(23) Subjects who have received a live vaccine within 4 weeks prior to randomisation
(24) Known low or absent dihydropyrimidine dehydrogenase (DPD) activity. Where required by local regulations, testing for DPD deficiency must be performed using a validated method which is recommended by local health authorities
Informations relatives au promoteur
Promoteur :
Type de sponsor : Industriel

Coordonnateur :
Centre investigateur
Informations relatives aux investigateurs
Centre investigateur :
Centre Oscar Lambret - 3 Rue Frédéric Combemale - 59000 LILLE

Investigateur :
Docteur Farid EL HAJBI

Unité Intégrée de Recherche Clinique

Statut de l'essai : CLOS

MAJ : 06/09/2021