Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis From Gastrointestinal Cancer (PIPAC-NAL-IRI)

Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis From Gastrointestinal Cancer: a Phase I Study

The PIPAC NAL-IRI study is designed to examine the maximal tolerated dose of nanoliposomal irinotecan (Nal-IRI, Onivyde) administered with repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC), in a monocentric, phase I trial.

Study Overview

• Status: Recruiting
• Conditions: Gastric Cancer; Colorectal Cancer; Pancreatic Cancer; Small Bowel Cancer; Bile Duct Cancer; Peritoneal Carcinomatosis; Peritoneal Metastases; Appendix Cancer
• Intervention / Treatment: Drug: PIPAC with Nal-IRI

Detailed Description

Peritoneal metastases (PM) are a common manifestation of gastrointestinal cancer. The prognosis of patients with PM is particularly poor, and response to systemic chemotherapy is worse compared to parenchymal metastatic cancer in the liver or lungs. In addition, patients with PM frequently develop debilitating symptoms such as intractable ascites, bowel obstruction, or ureteric obstruction, resulting in a severely compromised quality of life.

In selected patients with widespread PM, pressurized intraperitoneal aerosol chemotherapy (PIPAC) holds considerable promise. Briefly, PIPAC combines laparoscopy with intraperitoneal (IP) administration of chemotherapy as an aerosol, which is generated by a nebulizer. The pharmacokinetic (PK) and clinical advantages of PIPAC may be further enhanced by using nanosized anticancer drugs. Nal-IRI (Onivyde) is a nanoliposomal formulation of irinotecan (Camptothecin-11 (CPT-11)), with a markedly superior efficacy when compared with free CPT-11 in human breast and colon cancer xenograft models.

This is a phase I clinical study with aerosolized IP Nal-IRI in patients with PM from GI cancer. In this phase I study, dose escalation will be combined with pharmacokinetic/pharmacodynamic modelling which incorporates, in addition to plasma, tumour tissue, and peritoneal drug concentrations, biomarkers of toxicity and efficacy.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Wim P Ceelen, MD, PhD, Prof; Phone Number: +3293326251; Email: wim.ceelen@ugent.be

Study Locations

• Belgium
  • East-Flanders
    • Ghent, East-Flanders, Belgium, 9000
      • Recruiting
      • UZ Ghent
      • Contact: Wim P Ceelen, MD, PhD, Prof; Phone Number: +3293326251; Email: wim.ceelen@ugent.be
      • Contact: Wouter Willaert, MD, PhD, Prof; Phone Number: +3293328950; Email: wouter.willaert@ugent.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Biopsy proven cancer of the pancreas, gallbladder or biliary tract, stomach, small bowel, colon, rectum, or appendix with extensive or irresectable peritoneal carcinomatosis
• Estimated life expectancy > 6 months; > 3 months if primary cancer is pancreatic
• Age ≥ 18 years
• Adequate performance status (Karnofsky index > 60% and WHO performance status < 2)
• Written informed consent obtained prior any act of the research

Exclusion Criteria:

• Concomitant systemic (IV) treatment with irinotecan (either as monotherapy or as part of a combination regimen such as FOLFIRI, CAPIRI, or FOLFOXIRI)
• Pregnancy or breastfeeding during the clinical study
• Patients of childbearing age unable or unwilling to provide effective contraception during the study and until the end of relevant exposure (extended by 30 days (female participants) or 120 days (male participants) since the IMP is genotoxic).
• Known allergy or intolerance to irinotecan
• Significant amount of ascites detectable (exceeding 3l in volume)
• Intestinal or urinary tract obstruction
• Extensive hepatic and/or extra-abdominal metastatic disease
• Impaired renal function (serum creatinine > 1.5 mg/dl or calculated GFR (CKD-EPI) < 60 mL/min/1.73 m²
• Impaired liver function (serum total bilirubin > 1.5 mg/dl, except for known Gilbert's disease)
• Platelet count < 100.000/µl
• Hemoglobin < 9g/dl
• Neutrophil granulocytes < 1.500/ml

• Patients known to use:

  • CYP3A4 inducers (rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St John's wort)
  • inhibitors of CYP3A4 (clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (atazanavir, gemfibrozil, indinavir, regorafenib)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nal-IRI (Onivyde) - 30mg/m²; PIPAC with Onivyde (30 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.	Drug: PIPAC with Nal-IRI; Nanoliposomal irinotecan (Nal-IRI, Onivyde) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 30 to 90 mg/m². PIPAC will be performed every 4 to 6 weeks for 3 cycles.; Other Names: Onivyde
Experimental: Nal-IRI (Onivyde) - 45mg/m²; PIPAC with Onivyde (45 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.	Drug: PIPAC with Nal-IRI; Nanoliposomal irinotecan (Nal-IRI, Onivyde) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 30 to 90 mg/m². PIPAC will be performed every 4 to 6 weeks for 3 cycles.; Other Names: Onivyde
Experimental: Nal-IRI (Onivyde) - 60mg/m²; PIPAC with Onivyde (60 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.	Drug: PIPAC with Nal-IRI; Nanoliposomal irinotecan (Nal-IRI, Onivyde) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 30 to 90 mg/m². PIPAC will be performed every 4 to 6 weeks for 3 cycles.; Other Names: Onivyde
Experimental: Nal-IRI (Onivyde) - 75mg/m²; PIPAC with Onivyde (75 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.	Drug: PIPAC with Nal-IRI; Nanoliposomal irinotecan (Nal-IRI, Onivyde) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 30 to 90 mg/m². PIPAC will be performed every 4 to 6 weeks for 3 cycles.; Other Names: Onivyde
Experimental: Nal-IRI (Onivyde) - 90mg/m²; PIPAC with Onivyde (90 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.	Drug: PIPAC with Nal-IRI; Nanoliposomal irinotecan (Nal-IRI, Onivyde) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 30 to 90 mg/m². PIPAC will be performed every 4 to 6 weeks for 3 cycles.; Other Names: Onivyde

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximally tolerated dose (MTD) of Nal-IRI	Dose limiting toxicities will be monitored.	Within 14 weeks of the start of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended phase 2 dose	Define the dose recommended to use in a follow-up phase 2 trial based on incidence of DLT and toxicity data scored with CTCAE v5.0 for chemotherapy related toxicity.	6 months after last subject's third PIPAC
Surgical morbidity will be measured	This will be estimated with the Dindo-Clavien classification and the comprehensive complication index (CCI).	6 months after third PIPAC
Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed by tumor biopsies.	Tumour samples will be collected at the end of the aerosol delivery after each PIPAC procedure.	T= 30 minutes
Time-to-event endpoints	To evaluate patient's follow-up, several time-to-event endpoints are recorded which include: overall survival (OS), progression free survival (PFS) and peritoneal progression free survival (PPFS).	12 months after last subjects last visit
Quality of Life (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC QLQ-C30)	This will be investigated using the EORTC QLQ-C30 questionnaire. As to question 1 to 28: the scale varies from 1 (not at all) to 4 (very much). A higher value indicates a lower quality of life. The total score will be between 28 and 112. The scale of question 29 and 30 varies from 1 (very poor) to 7 (excellent). The higher the value, the better the quality of life. The total score will be between 2 and 14	Pre-operatively (every PIPAC), week 2 (every PIPAC) and, at 3 months, 6months and 12 months after last PIPAC procedure
Quality of Life (Functional Assessment of Cancer Therapy, FACT-G questionnaire)	This will be investigated using the FACT-G questionnaire. The scale of all questions varies from 0 (not at all) to 4 (very much). The total score will be between 0 and 108. The lower the total score, the better the quality of life.	Pre-operatively (every PIPAC), week 2 (every PIPAC) and, and at 3 months, 6months and 12 months after last PIPAC procedure
Quality of Life (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) score)	This will be investigated using the PRO-CTCAE™ questionnaire. The scale of all questions varies from 0 to 4 or 0 to 1 representing absent/present. PRO-CTCAE scores for each attribute (frequency, severity and/or interference) should be presented descriptively (eg. summary statistics or graphical presentations).	Determined before each PIPAC, every 14th day after PIPAC and at 3 months, 6months and 12 months after last PIPAC procedure
Pain assessment performed by patient (Visual Analog Scale (VAS), Pain )	With this score, pain is assessed on a horizontal line, 100 mm in length, anchored by word descriptors at each end, no pain and very severe pain respectively. The patient marks on the line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimeters from the left-hand end of the line to the point that the patient marks.	Determined before each PIPAC procedure, one day postoperatively, and one week after the procedure.
Overall treatment response	Determined according to the RECIST criteria, if possible (measurable lesions on CT or MRI). When no target lesions available, overall treatment response (stable disease, partial response, or progressive disease) will be determined by incorporating PRGS, clinical signs and symptoms, tumor markers, imaging findings (other than target lesions, e.g. ascites volume).	Determined 8 months after last subject last visit
Maximum concentration (Cmax) of nanoliposomal irinotecan	Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.	Plasma at 10 timepoints: T= pre-dose (0 minutes=start nebulization), T=30 minutes, T=1.5 hour, T=2.5 hours, T=6 hours, T=24 hours, T=72 hours, T=168 hours, T=336 hours, T=504 hours // Tissue: T= pre-dose (0 minutes=start nebulization), T = 30 minutes
Time to reach maximum concentration (Tmax) of nanoliposomal irinotecan	Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.	Plasma at 10 timepoints: T= pre-dose (0 minutes=start nebulization), T=30 minutes, T=1.5 hour, T=2.5 hours, T=6 hours, T=24 hours, T=72 hours, T=168 hours, T=336 hours, T=504 hours // Tissue: T= pre-dose (0 minutes=start nebulization), T = 30 minutes
Area under the curve (AUC0h-24h) of nanoliposomal irinotecan	Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.	Plasma at 10 timepoints: T= pre-dose (0 minutes=start nebulization), T=30 minutes, T=1.5 hour, T=2.5 hours, T=6 hours, T=24 hours, T=72 hours, T=168 hours, T=336 hours, T=504 hours // Tissue: T= pre-dose (0 minutes=start nebulization), T = 30 minutes
Volume of distribution (Vd) of nanoliposomal irinotecan	Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.	Plasma at 10 timepoints: T= pre-dose (0 minutes=start nebulization), T=30 minutes, T=1.5 hour, T=2.5 hours, T=6 hours, T=24 hours, T=72 hours, T=168 hours, T=336 hours, T=504 hours // Tissue: T= pre-dose (0 minutes=start nebulization), T = 30 minutes
Clearance (Cl) of nanoliposomal irinotecan	Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.	Plasma at 10 timepoints: T= pre-dose (0 minutes=start nebulization), T=30 minutes, T=1.5 hour, T=2.5 hours, T=6 hours, T=24 hours, T=72 hours, T=168 hours, T=336 hours, T=504 hours // Tissue: T= pre-dose (0 minutes=start nebulization), T = 30 minutes
Elimination half-life (T1/2) of nanoliposomal irinotecan	Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.	Plasma at 10 timepoints: T= pre-dose (0 minutes=start nebulization), T=30 minutes, T=1.5 hour, T=2.5 hours, T=6 hours, T=24 hours, T=72 hours, T=168 hours, T=336 hours, T=504 hours // Tissue: T= pre-dose (0 minutes=start nebulization), T = 30 minutes
Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed with the Peritoneal regression grading score (PRGS)	Evaluated on tumor biopsies to determine histological treatment response	T= pre-dose (0 minutes= start nebulization)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcome: DNA topoisomerase I (TOP-1) gene copy number	This will be determined in plasma and tissue samples. This outcome evaluates anti-cancer efficacy.	8 months after last subject last visit
Exploratory outcome: Expression of human carboxylesterase 2 (hCE2)	This will be determined in plasma and tissue samples. This outcome evaluates conversion of CPT-11 to SN-38 between patients.	8 months after last subject last visit

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Collaborators: University Ghent; Kom Op Tegen Kanker
• Investigators: Principal Investigator: Wim P Ceelen, MD, PhD, Prof, University Hospital, Ghent

Publications and helpful links

General Publications

• Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006 Mar 15;66(6):3271-7. doi: 10.1158/0008-5472.CAN-05-4007.
• Demtroder C, Solass W, Zieren J, Strumberg D, Giger-Pabst U, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis. Colorectal Dis. 2016 Apr;18(4):364-71. doi: 10.1111/codi.13130.
• Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics. 2000 Dec;56(4):1177-82. doi: 10.1111/j.0006-341x.2000.01177.x.
• Peixoto RD, Speers C, McGahan CE, Renouf DJ, Schaeffer DF, Kennecke HF. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. Cancer Med. 2015 Aug;4(8):1171-7. doi: 10.1002/cam4.459. Epub 2015 Apr 18.
• Ahn BJ, Choi MK, Park YS, Lee J, Park SH, Park JO, Lim HY, Kang WK, Ko JW, Yim DS. Population pharmacokinetics of CPT-11 (irinotecan) in gastric cancer patients with peritoneal seeding after its intraperitoneal administration. Eur J Clin Pharmacol. 2010 Dec;66(12):1235-45. doi: 10.1007/s00228-010-0885-3. Epub 2010 Sep 9.
• Alyami M, Hubner M, Grass F, Bakrin N, Villeneuve L, Laplace N, Passot G, Glehen O, Kepenekian V. Pressurised intraperitoneal aerosol chemotherapy: rationale, evidence, and potential indications. Lancet Oncol. 2019 Jul;20(7):e368-e377. doi: 10.1016/S1470-2045(19)30318-3.
• Chabot GG. Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet. 1997 Oct;33(4):245-59. doi: 10.2165/00003088-199733040-00001.
• Dai J, Chen Y, Gong Y, Wei J, Cui X, Yu H, Zhao W, Gu D, Chen J. The efficacy and safety of irinotecan +/- bevacizumab compared with oxaliplatin +/- bevacizumab for metastatic colorectal cancer: A meta-analysis. Medicine (Baltimore). 2019 Sep;98(39):e17384. doi: 10.1097/MD.0000000000017384.
• Dakwar GR, Shariati M, Willaert W, Ceelen W, De Smedt SC, Remaut K. Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis - Mission possible? Adv Drug Deliv Rev. 2017 Jan 1;108:13-24. doi: 10.1016/j.addr.2016.07.001. Epub 2016 Jul 13.
• Di Giorgio A, Sgarbura O, Rotolo S, Schena CA, Bagala C, Inzani F, Russo A, Chiantera V, Pacelli F. Pressurized intraperitoneal aerosol chemotherapy with cisplatin and doxorubicin or oxaliplatin for peritoneal metastasis from pancreatic adenocarcinoma and cholangiocarcinoma. Ther Adv Med Oncol. 2020 Jul 24;12:1758835920940887. doi: 10.1177/1758835920940887. eCollection 2020.
• Gockel I, Jansen-Winkeln B, Haase L, Niebisch S, Moulla Y, Lyros O, Lordick F, Schierle K, Wittekind C, Thieme R. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in patients with peritoneal metastasized colorectal, appendiceal and small bowel cancer. Tumori. 2020 Feb;106(1):70-78. doi: 10.1177/0300891619868013. Epub 2019 Aug 30.
• Kerscher AG, Chua TC, Gasser M, Maeder U, Kunzmann V, Isbert C, Germer CT, Pelz JO. Impact of peritoneal carcinomatosis in the disease history of colorectal cancer management: a longitudinal experience of 2406 patients over two decades. Br J Cancer. 2013 Apr 16;108(7):1432-9. doi: 10.1038/bjc.2013.82. Epub 2013 Mar 19.
• Kurtz F, Struller F, Horvath P, Solass W, Bosmuller H, Konigsrainer A, Reymond MA. Feasibility, Safety, and Efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastasis: A Registry Study. Gastroenterol Res Pract. 2018 Oct 24;2018:2743985. doi: 10.1155/2018/2743985. eCollection 2018.
• Lamb YN, Scott LJ. Liposomal Irinotecan: A Review in Metastatic Pancreatic Adenocarcinoma. Drugs. 2017 May;77(7):785-792. doi: 10.1007/s40265-017-0741-1.
• Nielsen M, Graversen M, Ellebaek SB, Kristensen TK, Fristrup C, Pfeiffer P, Mortensen MB, Detlefsen S. Next-generation sequencing and histological response assessment in peritoneal metastasis from pancreatic cancer treated with PIPAC. J Clin Pathol. 2021 Jan;74(1):19-24. doi: 10.1136/jclinpath-2020-206607. Epub 2020 May 8.
• Ploug M, Graversen M, Pfeiffer P, Mortensen MB. Bidirectional treatment of peritoneal metastasis with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) and systemic chemotherapy: a systematic review. BMC Cancer. 2020 Feb 10;20(1):105. doi: 10.1186/s12885-020-6572-6.
• Shariati M, Willaert W, Ceelen W, De Smedt SC, Remaut K. Aerosolization of Nanotherapeutics as a Newly Emerging Treatment Regimen for Peritoneal Carcinomatosis. Cancers (Basel). 2019 Jun 28;11(7):906. doi: 10.3390/cancers11070906.
• Taibi A, Geyl S, Salle H, Salle L, Mathonnet M, Usseglio J, Durand Fontanier S. Systematic review of patient reported outcomes (PROs) and quality of life measures after pressurized intraperitoneal aerosol chemotherapy (PIPAC). Surg Oncol. 2020 Dec;35:97-105. doi: 10.1016/j.suronc.2020.08.012. Epub 2020 Aug 20.
• Yi SY, Park YS, Kim HS, Jun HJ, Kim KH, Chang MH, Park MJ, Uhm JE, Lee J, Park SH, Park JO, Lee JK, Lee KT, Lim HY, Kang WK. Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer. Cancer Chemother Pharmacol. 2009 May;63(6):1141-5. doi: 10.1007/s00280-008-0839-y. Epub 2008 Oct 7.
• Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-557. doi: 10.1016/S0140-6736(15)00986-1. Epub 2015 Nov 29. Erratum In: Lancet. 2016 Feb 6;387(10018):536. doi: 10.1016/S0140-6736(15)01306-9.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2022
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: February 18, 2022
• First Submitted That Met QC Criteria: March 11, 2022
• First Posted (Actual): March 14, 2022

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Colorectal cancer; pharmacokinetics; pharmacodynamics; Pancreatic cancer; Cholangiocarcinoma; Stomach cancer; Peritoneal carcinomatosis; PIPAC; safety and efficacy; Onivyde; Nal-IRI; dose-finding study; Primary gastrointestinal cancer; Small bowel cancer; Appendix cancer; dose-escalation study; Peritoneal metastases
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Biliary Tract Diseases; Neoplasms, Glandular and Epithelial; Colonic Diseases; Peritoneal Diseases; Bile Duct Diseases; Abdominal Neoplasms; Biliary Tract Neoplasms; Cecal Neoplasms; Cecal Diseases; Carcinoma; Colorectal Neoplasms; Pancreatic Neoplasms; Gastrointestinal Neoplasms; Bile Duct Neoplasms; Peritoneal Neoplasms; Appendiceal Neoplasms
• Other Study ID Numbers: ONZ-2022-0120

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No