Combined Nabpaclitaxel Pressurized IntraPeritoneal Aerosol Chemotherapy With Systemic Nabpaclitaxel-Gemcitabine Chemotherapy for Pancreatic Cancer Peritoneal Metastases

Peritoneal Carcinomatosis Clinical Trial

— Nab-PIPAC  

Official title:

Combined Nabpaclitaxel Pressurized IntraPeritoneal Aerosol Chemotherapy With Systemic Nabpaclitaxel-Gemcitabine Chemotherapy for Pancreatic Cancer Peritoneal Metastases - A Single-arm, Open-label, Phase II Trial: Nab-PIPAC Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05371223
• Other study ID #: 4368
• Status: Recruiting
• Phase: Phase 2
• Start date: March 1, 2022
• Est. completion date: July 30, 2025

Study information

• Verified date: February 2024
• Source: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Contact: Andrea Di Giorgio, MD
• Phone: +393288994872
• Email: andrea.digiorgio[@]policlinicogemelli.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Combined chemotherapy consisting of endovenous Nabpaclitaxel-Gemcitabine and Nabpaclitaxel-PIPAC may be a promising treatment for patients affected by pancreatic cancer PM who are in need of curative options. The purpose of this study is to evaluate the antitumoral activity of combined Nabpaclitaxel-PIPAC and systemic Nabpaclitaxel-Gemcitabine chemotherapy for pancreatic cancer peritoneal metastases. 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.

Description:

Pancreatic carcinoma (PC) is an aggressive neoplasm carrying a high metastatic potential with a 5-year survival rate of 7%. The vast majority of cases already developed locally advanced disease, and distant metastases are present at the time of diagnosis. Furthermore, the recurrence rate is nearly 80% within the first two years after surgery, and about half of these patients show peritoneal relapse. Palliative systemic chemotherapy represents the standard treatment option in case of peritoneal metastases (PM) from PC but roughly reaches a median overall survival of 6-11 months with more than 5% of serious adverse events. Based on the available data, Nabpaclitaxel is indicated in combination with Gemcitabine for the first-line systemic treatment of patients with metastatic adenocarcinoma of the pancreas. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a novel intraperitoneal drug-delivery system of low-dose chemotherapy as a pressurized aerosol. Until now, the combination cisplatin/doxorubicin or oxaliplatin has been administered by PIPAC. Recently, a phase I study (NCT03304210) was conducted to explore the use of intraperitoneal Nabpaclitaxel administered by PIPAC, confirming its safety and preliminary efficacy. The recommended dose to safely start a phase-II study was 112.5 mg/m2.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 38
• Est. completion date: July 30, 2025
• Est. primary completion date: May 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 0 or 1;
• 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;

Exclusion Criteria:

• Advanced metastatic systemic disease with clinical deterioration;
• Patients with extraabdominal tumor spread;
• Patients with a germline or somatic pathogenic variant involving an (Homologous Recombination Repair) HRR-related gene;
• 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;

Related Conditions & MeSH terms

• Carcinoma
• Pancreas Neoplasm
• Pancreatic Neoplasms
• Peritoneal Carcinomatosis
• Peritoneal Neoplasms

Intervention

Drug:
• Combined Nabpaclitaxel Pressurized IntraPeritoneal Aerosol Chemotherapy With Systemic Nabpaclitaxel-Gemcitabine
Each combined course is constituted by two consecutive 28-day cycles of systemic chemotherapy (three adminstrations per cycle: days 1,8 and 15) and one cycle of PIPAC administered within 10-13 days from the last administration of systemic chemotherapy. Between each combined course a 7-10 days pause is observed. The recommended dose of Nabpaclitaxel in combination with Gemcitabine is 125 mg/m2 administered endovenous over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommended dose of Gemcitabine is 1000 mg/m2 administered intravenously over 30 minutes immediately after the completion of Nabpaclitaxel administration on Days 1, 8 and 15 of each 28-day cycle. A pressurized aerosol containing Nabpaclitaxel at the dose of 112,5 mg/m2 diluted in a total volume of 200 ml of NaCl 0.9% is applied through the nebulizer inside the abdominal cavity during laparoscopy.

Locations

Country	Name	City	State
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Rome

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The intravenous area under the curve (AUC) of paclitaxel	The concentration of paclitaxel in peritoneal samples. The penetration of paclitaxel in peritoneal tissues.	Three and a half years
Other	Intra-patient e intra-tumoral heterogeneity	- The germline mutational profile from blood samples	Three and a half years
Other	Identification of pancreatic cancer disease evolution trough pathway analysis a in primary tumor and peritoneal sites during treatments	- The genomic mutational profile of PM biopsies taken during PIPAC;	Three and a half years
Primary	Disease Control Rate (DCR)	The Disease Control Rate (DCR) defined as the combined incidence of complete response (CR), partial response (PR) and stable disease (SD) according to the RECIST v. 1.1 criteria during study treatments and the EOT visit.	Three and a half years
Secondary	The compliance to treatment	- The number of patients unable to undergo six cycles of systemic chemotherapy combined with three PIPAC cycles and reasons for discontinuation.	Three and a half years
Secondary	Toxicity assessed by CTCAE	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 administration.; 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 chemotherapy administration.	Three and a half years
Secondary	Postoperative complication assessed by Clavien-Dindo	-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.	Three and a half years
Secondary	Antitumoral activity assessed by PRGS	-The pathological tumor response, based on the 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; (PRGS 1: Complete regression without cancer cells - PRGS 2: higher response with prevalence of regressive phenomena and only a few residual cancer cells - PRGS 3: minor response with prevalence of residual cancer cells and poor regressive phenomena - PRGS 4: no response to therapy without regressive phenomena A reduction in the PRGS during subsequent biopsies will be considered as a positive response.)	Three and a half years
Secondary	Antitumoral activity assessed by PCI	-The macroscopic tumor response, based on Peritoneal Cancer Index (PCI) recorded during each PIPAC; The PCI index will be calculated according to the Sugarbaker method, which provides the assignment of a score between 0 and 3 based on the size of peritoneal metastases (0 without lesions; 1 if diam. 0.5 cm; 2 if diam. between 0.5 and 5 cm; 3 if diam > 5 cm or coalescent lesions) observed in 12 regions of the peritoneal cavity. The maximum score is 39.	Three and a half years
Secondary	Antitumoral activity assessed by ascites volume	- The macroscopic tumor response, based on ascites volume recorded during each PIPAC	Three and a half years
Secondary	Antitumoral activity assessed by tumor markers	- The biochemical tumor response, based on tumor markers (CEA, Ca 19.9, Ca 125) measured at different time points.	Three and a half years
Secondary	The Progression Free Survival (PFS)	the time between treatment start and one of the following events, whichever comes first: radiologic progression based on RECIST criteria v. 1.1,; clinical progression (eg, bowel occlusion, inability to oral feeding, refractory ascites),; death;	From treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months
Secondary	The Overall Survival (OS)	The Overall Survival (OS) is defined as the time between treatment start and death.	From treatment start to death, assessed up to 12 months