E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with peritoneal carcinosis of colorectal origin and uncertain resectability with an indication for systemic chemotherapy compatible with the FOLFIRI + bevacizumab combination. |
Patient ayant un cancer colorectal localement avancé ou métastatique compliqué d’une carcinose péritonéale de résécabilité incertaine avec une indication de chimiothérapie systémique compatible avec l’association FOLFIRI + bevacizumab |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or Metastatic colorectal carcinosis |
Cancer colorectal localement avancé ou métastatique |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052171 |
E.1.2 | Term | Peritoneal carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To assess recommended dose (to be used in phase II) and safety of first cycle of intraperitoneal oxaliplatine treatment in combination with systemic chemotherapy FOLFIRI + bevacizumab for patients with peritoneal carcinosis of colorectal origin and uncertain resectability |
Evaluer la tolérance durant le premier cycle de traitement et la dose recommandée pour les essais de phase II de l’administration intra-péritonéale de l’oxaliplatine en association avec une chimiothérapie systémique de type FOLFIRI + bevacizumab chez des patients présentant une CP d’origine colorectale de résécabilité incertaine
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E.2.2 | Secondary objectives of the trial |
To evaluate preliminary clinical efficacy related to the repeated administration of intraperitoneal chemotherapy for patients with peritoneal carcinosis of colorectal origin and uncertain resectability with an indication for systemic chemotherapy compatible with the FOLFIRI + bevacizumab combination To assess patient’s safety throughout the treatment (maximum of 8 cycles or 4 months’ treatment) until the end/patient's study involvement to be able to evaluate cumulative toxicity |
- Obtenir des données préliminaires sur l'efficacité clinique de l'administration IP de l'oxaliplatine donné en combinaison avec une chimiothérapie systémique de type FOLFIRI + bevacizumab chez des patients présentant une CP d'origine colorectale de résécabilité incertaine - Evaluer la tolérance pendant toute la durée du traitement (pour un maximum de 8 cycles, soit 4 mois de traitement) et jusqu'à la fin de participation à l'étude du patient, de l'administration IP de l'oxaliplatine donné en combinaison avec une chimiothérapie systémique de type FOLFIRI + bevacizumab, afin d'évaluer les toxicités cumulées |
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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 |
- To assess pharmacokinetic charactericistics of oxaliplatine in blood and peritoneal liquid - To assess oxaliplatine distribution by peritoneum scanner and its relationship with intraperitoneal treatment response - To assess kinetic decrease of circulating tumor markers by mathematic modelling - Impact of genomic biomeker in chemotherapy response |
- Evaluer les caractéristiques pharmacocinétiques de l’oxaliplatine dans le liquide péritonéal et le sang lorsque celui-ci est administré directement dans la cavité IP - Evaluer par scanner avec péritonéographie la distribution de l’oxaliplatine dans la cavité péritonéale - Evaluer les propriétés cinétiques de la décroissance des marqueurs tumoraux circulants (ACE, CA 19-9, acides nucléiques tumoraux) par modélisImpact d’un panel de biomarqueurs génomiques sur la réponse à la chimiothérapie ation mathématique - |
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E.3 | Principal inclusion criteria |
• ≥18 years old and ≤ 75 years old • ECOG Performance Status (PS) 0-2 • Peritoneal carcinosis with locoregional extension or metastastic of colorectal origin and uncertain resectability • PCI > 20 and / or infiltration of the hepatic pedicle and / or necessary digestive tract resections • Systemic chemotherapy indication, compatible with the FOLFIRI + bevacizumab combination • Satisfactory haematological evaluation: PNN rate greater than 1500 / mm3, platelet count greater than 100 G / l; • Satisfactory renal and hepatic function : serum creatinine ≤1.5 times the normal lower values or creatinine clearance ≥50 ml / min, bilirubin ≤1.25 times lower normal values, AST / ALT ≤1.5 times the lower normal values (≤5 times the lower normal values for patients with liver metastases) • No unstable conditions: myocardial infarction within 6 months prior to the start of the study, congestive heart failure, unstable angina, active cardiomyopathy, unstable rhythm disorder, uncontrolled hypertension, uncontrolled psychiatric disorders, severe infection, peptic ulcer or any condition that could be aggravated by treatment or limit compliance (investigator assessment); • No limitation in the number of previous treatments; • Patients may have received conventional cytotoxic chemotherapy , hormonal or immunological targeted biological agents. They should have recovered from previous grade ≤2 toxicities • Written informed consent • Known RAS status. |
- Age : ≥18 ans et 75 ans ; - ECOG PS 0-2 ; - Cancer colorectal localement avancé ou métastatique compliqué d’une carcinose péritonéale de résécabilité incertaine : - PCI > 20 Et/ou - Infiltration pédicule hépatique - Résections digestives étendues nécessaires - Indication de chimiothérapie systémique, compatible avec l’association FOLFIRI + bevacizumab - Bilan hématologique satisfaisant : - Taux de Polynuclaires Neutrophiles (PNN) supérieur à 1500 / mm3 - Taux de plaquettes supérieur à 100 G/l - Bilans rénal et hépatique satisfaisants : - Créatinine sérique ≤1.5 fois les valeurs normales inférieures ou clairance de la créatinine ≥ 50 ml/mn - Bilirubine totale ≤1.25 fois limites normales inférieures - ASAT/ALAT ≤1.5 fois les limites normales inférieures (≤5 fois les limites normales inférieures pour les patients avec métastases hépatiques) - Absence de pathologies instables : infarctus du myocarde dans les 6 mois précédant le début de l’étude, insuffisance cardiaque congestive, angor instable, cardiomyopathie active, trouble du rythme instable, hypertension artérielle non contrôlée, troubles psychiatriques non contrôlés, infection sévère, ulcère peptique, ou toute pathologie qui pourrait être aggravée par le traitement ou limiter la compliance (jugement de l’investigateur) ; - Pas de limitation dans le nombre antérieur de traitements ; - Les patients peuvent avoir reçu des chimiothérapies cytotoxiques conventionnelles, des agents biologiques immunologiques hormonaux ou ciblés. Ils doivent avoir récupéré des toxicités antérieures avec un grade ≤2 ; - Consentement éclairé, écrit et signé après information ; - Statut RAS connu |
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E.4 | Principal exclusion criteria |
Extraperitoneal metastases for which the site or number preclude potentially curative surgery at any moment during the course of the disease • Sign of bowel obstruction or lesions whose topography indicates a risk of intestinal perforation or inflammatory bowel disease • ECOG PS 3-4 • Contraindication to the placement of a intraperitoneal central line • Contraindication specifically related to intraperitoneal administration of oxaliplatin • known history of hypersensitivity to oxaliplatin or to the excipients • peripheral sensory neuropathy grade ≥2 • Pregnant or lactating women • Unable to give consent • Patient under legal protection measures • Refusal to participate in the study
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Extraperitoneal metastases for which the site or number preclude potentially curative surgery at any moment during the course of the disease • Sign of bowel obstruction or lesions whose topography indicates a risk of intestinal perforation or inflammatory bowel disease • ECOG PS 3-4 • Contraindication to the placement of a intraperitoneal central line • Contraindication specifically related to intraperitoneal administration of oxaliplatin • known history of hypersensitivity to oxaliplatin or to the excipients • peripheral sensory neuropathy grade ≥2 • Pregnant or lactating women • Unable to give consent • Patient under legal protection measures • Refusal to participate in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The safety of intraperitoneal (IP) administration of oxaliplatin in combination with systemic chemotherapy FOLFIRI + bevacizumab will be evaluated during the first cycle of therapy according to NCI CTCAE version 4.0 The safety of intraperitoneal (IP) administration of oxaliplatin in combination with systemic chemotherapy FOLFIRI + bevacizumab will be evaluated during the first cycle of therapy according to Dose Limiting Toxicities
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La tolérance de l’administration intra-péritonéale (IP) de l’oxaliplatine en association avec une chimiothérapie systémique de type FOLFIRI + bevacizumab sera évaluée durant le premier cycle du traitement par la mesure des effets indésirables évalués d’après le NCI CTCAE version 4.0. Les Doses Limite de Toxicité sont définies comme n’importe quel évènement suivant observé durant le premier cycle du traitement et jugé selon l’investigateur comme étant possiblement lié au traitement en cours |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
First Cycle 1 |
Premier Cycle 1 |
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E.5.2 | Secondary end point(s) |
1. Overall response rate according to RECIST 2. Clinical efficacy of intraperitoneal (IP) administration of oxaliplatin in combination with systemic FOLFIRI + bevacizumab assessed by the overall response rate according to RECIST version 1.1 criteria assessed by imaging (TAP scanner and / or MRI if contraindication) 4. Peritoneal Cancer Index (PCI) Clinical efficacy of intraperitoneal (IP) administration of oxaliplatin in combination with systemic FOLFIRI + bevacizumab assessed by Peritoneal Cancer Index (PCI) performed after 4 cycles, and / or after 8 cycles 5. Adverse events (NCI CTCAE v4.0) [Time Frame: up to 5 months] [Safety Issue: No] The safety of intraperitoneal (IP) administration of oxaliplatin in combination with systemic chemotherapy FOLFIRI + bevacizumab will be evaluated throughout the duration of treatment (4 months) and until the end of patient follow up (1 month after treatment discontinuation) according to NCI CTCAE version 4.0 |
- Taux de réponse globale suivant les critères RECIST version 1.1 évalué par imageries (scanner TAP et/ou IRM en cas de contre-indication) - Effets indésirables évalués d’après le NCI CTCAE version 4.0 durant toute la durée du traitement et jusqu’à la fin de participation à l’étude du patient ; - Peritoneal Cancer Index (PCI) total mesuré selon l’Index de Sugarbaker lors de la coelioscopie (ou laparotomie) de réévaluation faite en cas de réponse complète/partielle/stabilisation au scanner TAP |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Performed after 4 cycles, and / or after 8 cycles |
Après 4 cycles et/ou 8 cycles |
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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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Determination of Recommended dose with Safety of Intraperitoneal administration of oxaliplatin |
Détermination de la dose recommandée et de la tolérance de l’administration Intra-péritonéale |
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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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 6 |
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
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LVLS |
dernière Visite dernier patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |