| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pancreatic cancer with peritoneal metastases |
| Cancro del pancreas con metastasi peritoneali |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pancreatic cancer with peritoneal metastases |
| Cancro del pancreas con metastasi peritoneali |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059326 |
| E.1.2 | Term | Pancreatic carcinoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the anti-tumoral activity of combined Nabpaclitaxel-PIPAC and systemic Nabpaclitaxel-Gemcitabine chemotherapy for pancreatic cancer peritoneal metastases. |
| Valutare l’attività antitumorale del trattamento combinato Nabpaclitaxel-PIPAC con chemioterapia sistemica Nabpaclitaxel-Gemcitabina per il cancro del pancreas con metastasi peritoneali. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives include the evaluation of the feasibility, the safety, further assessment of the antitumoral activity, the overall and progression free survival, the QoL, the pharmacokinetics of Nabpaclitaxel PIPAC. Furthermore, the study aims to evaluate the patients’ nutritional status and the molecular evolution of PM along treatment with a time-course translational research. |
| Obiettivi secondari includono la valutazione della fattibilità, della sicurezza, ulteriori valutazioni dell’attività antitumorale, valutazione della sopravvivenza globale e libera da progressione, della QoL, e della farmacocinetica della Nabpaclitaxel-PIPAC. Inoltre, lo studio si propone di valutare lo stato nutrizionale dei pazienti e l'evoluzione molecolare delle metastasi peritoneali durante il trattamento tramite una ricerca traslazionale. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
¿ Age = 18 years;
¿ Willing and able to provide written and informed consent;
¿ Histological or cytological proof of pancreatic cancer;
¿ Metastatic disease with peritoneal carcinomatosis determined by the treating physician, based on abdominal CT or MR and/or diagnostic laparotomy or laparoscopy;
¿ Evaluable disease defined by RECIST 1.1 criteria
¿ Eastern Cooperative Oncology Group (ECOG) performance status =2;
¿ Life expectancy of at least 3 months;
¿ No contraindication for laparoscopy;
¿ No contraindication for drugs used in the study;
¿ Adequate bone marrow function: Absolute neutrophil count = 1500 cell./mm3; Platelets = 100000 cell./mm3;
¿ Hemoglobin = 9 g/dl
¿ Adequate renal function (serum creatinine up to 1.5 times the maximal limit of the local laboratory) or else based upon clinical evaluation;
¿ Resolution of all toxic effects of prior therapies or surgical procedures to Grade = 1 (except alopecia and peripheral neuropathy);
¿ In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 x the upper limit of normal (ULN). If the patient has liver metastases, ALT and AST should be < 5 x ULN
¿ Total bilirubin = ULN, or total bilirubin 1.5 x ULN with direct bilirubin = ULN of the laboratory in subjects with documented Gilbert's Syndrome
¿ If screening assessments are abnormal, chemistry assessments may be repeated up to two times; subjects may receive appropriate supplementation prior to re-assessment.
¿ Confirmed negative serum pregnancy test (beta-hCG) within 72 hours before starting study treatment for patients with pre- or peri-menopausal status.
Male subject must, even if surgically sterilized (ie, status post-vasectomy): Agree to practice highly effective barrier contraception (use condoms) during the entire study treatment period and through 120 days after the last dose of study drugs. For subjects (who have not undergone vasectomy) with female partners of childbearing potential, the subject and his partner must in addition to condoms, use highly effective contraceptive measures when engaging in sexual intercourse throughout the study, and for at least 120 days after the last dose of study drugs (eg, oral contraceptive and condoms, intrauterine device |
¿ Età = 18 anni;
¿ Paziente disponibile ed in grado di fornire il consenso informato;
¿ Prova istologica o citologica del cancro del pancreas;
¿ Malattia metastatica con carcinosi peritoneale determinata dal curante, sulla base di TC o RM addominale e / o laparotomia o laparoscopia diagnostica;
¿ Malattia valutabile definita dai criteri RECIST 1.1
¿ Performance status dell'Eastern Cooperative Oncology Group (ECOG) =2;
¿ Aspettativa di vita di almeno 3 mesi;
¿ Nessuna controindicazione per la laparoscopia;
¿ Nessuna controindicazione per i farmaci utilizzati nello studio;
¿ Funzione adeguata del midollo osseo: conta assoluta dei neutrofili = 1500 cellule./mm3; Piastrine = 100000 cell./mm3;
¿ Emoglobina = 9 g / dl
¿ Funzionalità renale adeguata (creatinina sierica fino a 1,5 volte il limite massimo) oppure basata su valutazione clinica;
¿ Risoluzione di tutti gli effetti tossici di precedenti terapie o procedure chirurgiche al Grado = 1 (eccetto alopecia e neuropatia periferica);
¿ In assenza di metastasi epatiche, l'alanina aminotransferasi (ALT) e l'aspartato aminotransferasi (AST) devono essere inferiori a 2,5 volte il limite superiore della norma (ULN). Se il paziente ha metastasi epatiche, ALT e AST devono essere <5 x ULN
¿ Bilirubina totale = ULN, o bilirubina totale 1,5 x ULN con bilirubina diretta = ULN del laboratorio in soggetti con sindrome di Gilbert documentata
¿ Se le valutazioni di screening sono anormali, le valutazioni chimiche possono essere ripetute fino a due volte; i soggetti possono ricevere un'adeguata integrazione prima della rivalutazione.
¿ Test di gravidanza siero negativo confermato (beta-hCG) entro 72 ore prima dell'inizio del trattamento in studio per pazienti con stato pre- o peri-menopausale.
¿ Il soggetto di sesso maschile deve, anche se sterilizzato chirurgicamente (ovvero, stato post-vasectomia): Acconsentire a praticare una contraccezione di barriera altamente efficace (usare il preservativo) durante l'intero periodo di trattamento in studio e fino a 120 giorni dopo l'ultima dose di farmaci in studio. Per i soggetti (che non hanno subito la vasectomia) con partner di sesso femminile in età fertile, il soggetto e il suo partner devono, oltre al preservativo, utilizzare misure contraccettive altamente efficaci durante i rapporti sessuali durante lo studio e per almeno 120 giorni dopo l'ultimo dose dei farmaci in studio (p. es., contraccettivi orali e preservativi, dispositivo intrauterino). |
|
| E.4 | Principal exclusion criteria |
¿ Advanced metastatic systemic disease with clinical deterioration;
¿ Symptoms of gastrointestinal occlusion and total parenteral nutritional support;
¿ Patients defined as “refractory” to previous systemic treatment with Nab-paclitaxel and Gemcitabine administered for locally advanced pancreatic cancer (patients treated with Nabpaclitaxel-Gemcitabine for a locally advanced disease may be included if PM developed after at least 6 months from the end of previous chemotherapy);
¿ History of severe and unexpected reactions to Nabpaclitaxel or Gemcitabine derivates?
¿ Known hypersensitivity reaction to drugs chemically related to Nabpaclitaxel, Gemcitabine and their excipients;
¿ Severe cardiac disease (recent myocardial ischemia, severe cardiac arrhythmias, severe cardiac failure);
¿ Clinical disease progression after first 2 months of systemic Nabpaclitaxel Gemcitabine chemotherapy;
¿ Any concurrent severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk of associated with study participation or investigational product administration or may interfere with compliance with study procedures or the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into the study;
¿ Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive beta-hCG laboratory test;
¿ Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment and through 120 days after the last dose of study drug. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the Subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Tubal ligation at least six weeks before taking study treatment. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject. Combination of the following: Placement of an intrauterine device (IUD) or intrauterine system (IUS); Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository. |
- Malattia sistemica metastatica avanzata con deterioramento clinico;
¿ Sintomi di occlusione gastrointestinale e supporto nutrizionale parenterale totale;
¿ Pazienti definiti "refrattari" al precedente trattamento sistemico con Nab-paclitaxel e Gemcitabina somministrati per il cancro del pancreas localmente avanzato (i pazienti trattati con Nabpaclitaxel-Gemcitabina per la malattia localmente avanzata possono essere inclusi se le metastasi peritoneali si sono sviluppate dopo almeno 6 mesi dalla fine della precedente chemioterapia);
¿ Storia di reazioni gravi e inattese a Nabpaclitaxel o derivati della gemcitabina;
¿ Reazione di ipersensibilità nota a farmaci chimicamente correlati a Nabpaclitaxel, Gemcitabina e ai loro eccipienti;
¿ Grave malattia cardiaca (recente ischemia miocardica, gravi aritmie cardiache, grave insufficienza cardiaca);
¿ Progressione clinica della malattia dopo i primi 2 mesi di chemioterapia sistemica con Nabpaclitaxel Gemcitabina;
¿ Qualsiasi condizione medica o psichiatrica grave, acuta o cronica concomitante o anormalità di laboratorio che può aumentare il rischio di essere associato alla partecipazione allo studio o alla somministrazione di prodotti sperimentali o può interferire con la conformità con le procedure dello studio o l'interpretazione dei risultati dello studio e, a giudizio di lo sperimentatore, renderebbe il soggetto inadeguato per l'ingresso nello studio;
¿ Donne in gravidanza o in allattamento (in allattamento), dove la gravidanza è definita come lo stato di una femmina dopo il concepimento e fino alla fine della gestazione, confermato da un test di laboratorio beta-hCG positivo;
¿ Donne in età fertile, definite come tutte le donne fisiologicamente in grado di rimanere incinta, a meno che non utilizzino metodi contraccettivi altamente efficaci durante la somministrazione del trattamento in studio e fino a 120 giorni dopo l'ultima dose del farmaco in studio. I metodi contraccettivi altamente efficaci includono: Astinenza totale (quando questa è in linea con lo stile di vita preferito e abituale del Soggetto). L'astinenza periodica (ad esempio, metodi di calendario, ovulazione, sintotermici, post-ovulazione) e i rapporti incompleti non sono metodi contraccettivi accettabili. Legatura delle tube almeno sei settimane prima di iniziare il trattamento in studio. Sterilizzazione maschile (almeno 6 mesi prima dello screening). Per i soggetti di sesso femminile nello studio, il partner maschile vasectomizzato dovrebbe essere l'unico partner per quel soggetto. Combinazione dei seguenti: posizionamento di un dispositivo intrauterino (IUD) o di un sistema intrauterino (IUS); Metodi contraccettivi di barriera: preservativo o cappuccio occlusivo (diaframma o cappuccio cervicale / a volta) con schiuma / gel / pellicola / crema / supposta vaginale spermicida. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
The Disease Control Rate (DCR) defined as the combined incidence of complete response (CR), partial response (PR) and stable disease (SD) for = 16 weeks measured according to the RECIST v. 1.1 criteria during study treatments and the EOT visit. |
Endpoint primario:
Il Disease Control Rate (DCR) definito come l'incidenza combinata di risposta completa (CR), risposta parziale (PR) e malattia stabile (SD) per almeno 16 settimane misurata secondo i criteri RECIST v. 1.1 durante il trattamento dello studio e alla visita di fine trattamento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The compliance to treatment will be assessed through the following endpoints:
- The number of patients unable to undergo six cycles of systemic chemotherapy combined with three PIPAC cycles and reasons for discontinuation
- The number of patients who discontinued or postponed beyond 10 days the scheduled standard systemic chemotherapy after each PIPAC cycle.
- The number of patients that reduce the dose of systemic chemotherapy during the study;
- The number of patients that reduce the dose of PIPAC drug during the study;
- The safety and toxicity will be assessed through the following endpoints:
- The number of patients with major toxicity, defined as grade =3 according to Common Terminology Criteria for Adverse Events (CTCAE) V5.0 during the on-study evaluation phase and up to 4 weeks after the last chemotherapy cycleadministration (around 8 months).
- The number of patients with minor toxicity, defined as grade =2 according to CTCAE v5.0 during the treatment period and up to 4 weeks after the last combined coursechemotherapy administration.
- The number of patients with major and minor postoperative complications, defined as grade =3 and grade =2 according to Clavien-Dindo, respectively, during the treatment period and up to 4 weeks after the last PIPAC procedure.
- The procedures-related characteristics of PIPAC (eg, intraoperative complications, amount of adhesions, procedure-related mistakes and difficulties, operating time).
- The hospital stay, defined as the number of days between PIPAC and initial discharge.
- The number of readmissions, defined as any hospital admission after discharge, up to 4 weeks after the last PIPAC procedure.
- The antitumoral activity of the proposed treatment will be assessed also through:
- The pathological tumor response, based on review of peritoneal biopsies collected during each PIPAC, performed by a pathologist blinded to clinical outcomes using the Peritoneal Regression Grading Score (PRGS). A patient will be considered a responder if any reduction in the PRGS during subsequent biopsies will be recorded;
- The radiological tumor response, based on review of thoracoabdominal CT-scan and MR at baseline and after every 8 weeks, performed by a radiologist blinded to clinical outcomes according to RECIST criteria.
- The macroscopic tumor response, based on Peritoneal Cancer Index (PCI) and ascites volume recorded during each PIPAC;.
- The biochemical tumor response, based on tumor markers (CEA, Ca 19.9, Ca 125) measured at different time points (Table 4);
- The quality of life of the population will be assessed through the
- The potential changes in Quality of life scores extracted from the questionnaire QLQ-C30 at different time points (Table 4);
- The Time to Progression (TTP)Progression Free Survival (PFS) is defined as , defined as the time between screening treatment start and clinical progression (eg, bowel occlusion, inability to oral feeding, refractory ascites) or one of the following events, whichever comes first:
- radiologic response progression based on RECIST criteria v. 1.1,
- clinical progression (eg, bowel occlusion, inability to oral feeding, refractory ascites),
- death;.
- The Overall Survival (OS) is, defined as the time between study screeningtreatment start and death.
Exploratory endpoints
- The intravenous area under the curve (AUC) of paclitaxel. The concentration of paclitaxel in peritoneal samples. The penetration of paclitaxel in peritoneal tissues.
- Nutritional parameters collected along the study period by blood samples, anthropometric and bio-impedancemetric evaluations, and body composition analysis based on CT scan images.
- The germline mutational profile from blood samples
- The genomic mutational profile of PM biopsies taken during PIPAC;
- The transcriptomic profile of PM biopsies taken during PIPAC;
- The tumor cells and tissue microenvironments, including immune system cells;
- The circulating cytokines and immune cells profiles. |
Endpoint secondari:
- La compliance al trattamento valutato attraverso i seguenti endpoints:
- Il numero di pazienti non in grado di sottoporsi a sei cicli di chemioterapia sistemica combinati con tre cicli PIPAC e i motivi per l'interruzione
- Il numero di pazienti che hanno interrotto o posticipato oltre 10 giorni la chemioterapia sistemica standard programmata dopo ogni ciclo PIPAC;
- Il numero di pazienti che riducono la dose di chemioterapia sistemica durante lo studio;
- Il numero di pazienti che riducono la dose del farmaco PIPAC durante lo studio.
- La sicurezza e la tossicità valutati attraverso i seguenti endpoints:
- Il numero di pazienti con tossicità maggiore, definito come grado =3 secondo i Common Terminology Criteria for Adverse Events (CTCAE) V5.0 durante il periodo di trattamento dello studio e fino a un mese successivo all’ultimo ciclo di chemioterapia (circa 8 mesi);
- Il numero di pazienti con tossicità minore, definito come grado =2 secondo CTCAE v5.0 durante il periodo di trattamento e fino a 4 settimane dopo l'ultimo ciclo combinato
- Parametri nutrizionali raccolti durante il periodo di studio da campioni di sangue, valutazioni antropometriche e bioimpedenziometriche e analisi della composizione corporea sulla base di immagini TC.
- Il profilo mutazionale della linea germinale da campioni di sangue
- Il profilo mutazionale genomico delle biopsie dei noduli peritoneali effettuate durante PIPAC;
- Il profilo trascrittomico delle biopsie dei noduli peritoneali effettuate durante PIPAC;
- Le cellule tumorali e i microambienti dei tessuti, comprese le cellule del sistema immunitario;
- Le citochine circolanti e i profili delle cellule immunitarie. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
