| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with Histologically-confirmed diagnosis of peritoneal malignant mesothelioma and non eligible for cytoreductive surgery |
| Patients avec un diagnostic histologiquement confirmé d’un mésothéliome malin péritonéal non résécable. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patient with Histologically-confirmed diagnosis of peritoneal malignant mesothelioma and non eligible for cytoreductive surgery |
| Patients avec un diagnostic histologiquement confirmé d’un mésothéliome malin péritonéal non résécable. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the overall survival |
| Evaluer la survie globale |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the
- PFS
- Response to treatment
- Safety
- Compliance
- Conversion to resectability
- Quality of life
- Medico-economic |
Evaluer :
- Survie globale sans progression (PFS)
- Réponse au traitement
- Tolérance
- Compliance
- Conversion en résécabilité
- Qualité de vie
- Médico-économique
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1- Role of EGFR and Ras mutations: The objective is to study prognostic value of EGFR and Ras mutations in terms of and recurrence free survival and overall survival.
2- Role of mesothelin, calretinin and CA-125: The objective is to evaluate the predictive value of mesothelin, calretinin and CA-125 expression for tumor response to chemotherapy.
3- Definition of new imaging biomarkers: The objective is to develop a radiomic model predictive of tumor response in mesothelioma on CT and MRI.
Version 1.0 20/09/2019 |
|
| E.3 | Principal inclusion criteria |
1) Age ≥ 18 years to < 75 years ;
2) ECOG Performance Status of 0 to 2;
3) Histologically-confirmed diagnosis of peritoneal malignant mesothelioma;
4) No previous treatment (both medical and surgical oncologic treatments) for peritoneal malignant mesothelioma except for exploratory laparoscopy or diverting stoma;
5) Peritoneal Carcinomatosis Index (PCI)>27 or at least 4 points on the small bowel with serosal involvement contraindicating the cytoreductive surgery because of the impossibility to preserve a length >=1.5 m of uninvolved small bowel;
6) Life expectancy of at least 6 months
7) Adequate bone marrow and hepatic function defined as:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109 / L
b. Platelet count ≥ 100 x 109 / L
c. Creatinine clearance ≥ 60 ml/min
d. The total bilirubin ≤ 1.5 times upper limit of normal
e. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper limit of normal is acceptable if liver has tumour involvement.
8) For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment.
9) Patients with reproductive potential and who are sexually active must agree to have at least one method of contraception for the duration of treatment and 6 months after the last administration of study treatment. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard care.
10) Written and dated informed consent before any study procedure.
11) Affiliated to the French national social security system. |
1) Âge ≥ 18 ans à <75 ans;
2) Indice de performance ECOG de 0 à 2;
3) Diagnostic histologiquement confirmé d’un mésothéliome malin péritonéal;
4) Pas de traitement antérieur (traitements oncologiques à la fois médicaux et chirurgicaux) pour le mésothéliome malin péritonéal, à l'exception d’une cœlioscopie exploratoire ou d’une stomie de dérivation;
5) Indice de carcinose péritonéale (PCI)>27 ou au moins 4 points de l’intestin grêle avec atteinte séreuse, contre-indiquant la chirurgie cytoréductrice en raison de l'impossibilité de conserver une longueur> = 1,5 m de l'intestin grêle non atteint ;
6) Espérance de vie d'au moins 6 mois
7) Bilan hépatique et sanguin adéquat, défini par :
a. Neutrophiles (NAN) ≥ 1,5 x 109 / L
b. Plaquettes ≥ 100 x 109 / L
c. Clairance de la créatinine ≥ 60 ml / min
d. Bilirubine totale ≤ 1,5 fois la limite normale supérieure
(LNS)
e. Phosphatase alcaline (AP), aspartate aminotransférase (AST ou SGOT) et alanine aminotransférase (ALT ou SGPT) ≤ 3 fois la limite normale supérieure. La phosphatase alcaline, l'AST et l'ALT ≤ 5 fois la limite normale supérieure sont acceptables si le foie présente une atteinte tumorale.
8) Pour les femmes en âge de procréer, test de grossesse négatif pour la gonadotrophine chorionique humaine bêta sérique (β-HCG) obtenu dans les 7 jours précédant le début du traitement.
9) Les patients en âge de procréer et sexuellement actives doivent accepter d’avoir au moins une méthode de contraception pendant la durée du traitement et six mois après la dernière administration du traitement à l’étude.
10) Obtention du consentement éclairé signé et ce, avant toute procédure spécifique à l’essai.
11) Patients affiliés à un système de protection sociale français.
|
|
| E.4 | Principal exclusion criteria |
1) Patients eligible for cytoreductive surgery
2) Extra abdominal metastatic disease except for limited extra-peritoneal disease (mediastinal and/or retroperitoneal lymph nodes, oligo-metastatic lung disease);
3) Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease such as:
- progressive active infection, uncontrolled infection
- symptomatic cardiac or coronary insufficiency,
- history of recent myocardial infarction,
- severe renal insufficiency, renal impairment, defined as GFR<60 mL/min per 1.73m2, calculated by the Modification of Diet in Renal Disease (MDRD) abbreviated formula, pre-existing hearing impairment,
- pre-existing cisplatin-induced neuropathy,
- or any other severe medical condition
4) Any contraindication to repeated laparoscopy (eg. Ventriculo-peritoneal shunt without valves, pulmonary hypertension);
5) Complete or partial bowel obstruction non responsive to medical treatment;
6) Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products.
7) Known positive test for human immunodeficiency virus (HIV), hepatitis B or C virus.
8) Live attenuated vaccines are prohibited 10 days before and during the treatment
9) Other cancer treated within the last 2 years except in situ cervical carcinoma or basocellular carcinoma;
10) Removal of > 10 L of ascites per week;
11) Pregnant or breast-feeding woman;
12) Previously operated patients where laparoscopy is not feasible;
13) Participation in another clinical trial within 30 days prior to study entry
14) Anticancer therapy (e.g chemotherapy, targeted therapy, concomitant systemic immune therapy, or any experimental therapy) within 4 weeks before inclusion.
15) Any other condition or therapy that in the investigator’s opinion may pose a risk to the patient or interfere with the study objectives
16) Persons deprived of liberty or under guardianship or incapable of giving consent;
17) Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule. |
1) Patients éligibles à une chirurgie cytoréductrice
2) Maladie métastatique extra-abdominale, à l'exception d'une maladie extra-péritonéale limitée (ganglions médiastinaux et / ou rétropéritonéaux, maladie oligométastatique pulmonaire);
3) Les sujets considérés comme présentant un faible risque médical en raison d'un trouble médical grave et incontrôlé, d'une maladie systémique non maligne telle que:
- infection active et progressive, une infection non contrôlée,
- insuffisance cardiaque ou coronaire symptomatique,
- antécédents d'infarctus du myocarde récent,
- insuffisance rénale sévère, insuffisance rénale, définie par un GFR <60 mL / min par 1,73 m2, calculée selon la formule MDRD (Modification of diet in renal disease), déficience auditive préexistante,
- neuropathie préexistante induite par le cisplatine,
- ou toute autre condition médicale grave.
4) Toute contre-indication à une laparoscopie répétée (par ex. déviation ventriculo-péritonéal sans valves, hypertension pulmonaire);
5) Occlusion intestinale complète ou partielle ne répondant pas au traitement médical;
6) Hypersensibilité connue à l’un des médicaments à l’étude, aux classes des médicaments de l’étude ou à l’un des composants du produit.
7) Infection connue par HIV, l'hépatite B ou le virus C.
8) Les vaccins vivants atténués sont interdits 10 jours avant et pendant le traitement
9) autres cancers traités au cours des 2 dernières années, à l'exception du carcinome cervical ou du carcinome basocellulaire in situ;
10) Evacuation d'un gros volume d'ascite, > 10 L par semaine;
11) Femme enceinte ou allaite;
12) Patients opérés auparavant pour lesquels la laparoscopie n’est pas réalisable;
13) Participation à un autre essai clinique dans les 30 jours précédant le début de l'étude
14) Traitement anticancéreux (chimiothérapie, traitement ciblé, immunothérapie systémique concomitante ou tout traitement expérimental) dans les 4 semaines précédant l'inclusion.
15) Toute autre condition ou thérapie qui, de l’avis du médecin investigateur, peut présenter un risque pour le patient ou nuire à la réalisation des objectifs de l’étude,
16) Personnes privées de liberté ou sous tutelle ou incapables de donner leur consentement;
17) Toute condition psychologique, familiale, sociologique ou géographique pouvant nuire au respect du protocole d'étude ou du programme de suivi.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The overall survival |
| La survie globale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from the date of randomization to the date of death from any cause. |
| La durée entre la date de la randomisation et la date du décès, quelle que soit la cause. |
|
| E.5.2 | Secondary end point(s) |
1- - Progression free survival (PFS) defined as the time from the date of randomization to the date of any progression or death. PFS will be described with median PFS, 1 and 2y-PFS rate; Progression will be defined as any clinical or radiological change in the patient’s status (a disease related severe symptomatology such as pre-occlusive or occlusive episodes requiring treatment, increasing ascites requiring repeated evacuating ponctions, new radiological targets or significant increase of the existing ones). RECIST v1.1 criteria are difficult to apply and all mesothelioma related studies proposed a radiological evaluation taking into account the thickness of the peritoneum in its most relevant area for each patient. Therefore, the evaluation of PFS has to take into account clinical data.
2-Response to treatment will be defined as either a RECIST response on CT scan for patients with measurable disease, or as a histological response evaluated by peritoneal regression grading score PRGS score based on 4 biopsies (PRGS 1 and 2 are considered as respondants).
3-Safety according to CTCAE V5.0 and Clavien Dindo for surgical complication
4- Compliance of the study treatment defined as the percentage of patients who received 6 cycles of systemic chemotherapy and 4 PIPAC (for experimental arm).
5--Conversion to resectability rate defined as the percentage of patients eligible for cytoreductive surgery and HIPEC at the end of the treatment out of the total number of patients. Patients are eligible for surgery if preservation of at least 1.5 m of small bowel and of at least 2 m of lower gastrointestinal tube is feasible in case of complete cytoreduction. The rate will be calculated for each arm.
6- Quality of life using EORTC QLQ-C30 questionnaire according to EORTC Guidelines.
7- Medico economic using EQ5D-3L questionnaire according to EuroQol Guidelines. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-The time from the date of randomization to the date of any progression or death
2- is assessed at baseline, 21 days after cycle 3 and at the end of the treatment
3- from the date of randomization to the date of any progression or death
4- from the date of randomization to the date of end of study
5- from the date of randomization to the date of end of study
6- at baseline and twice a year during 2 years
7- at baseline and twice a year during 2 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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