Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis From Gastrointestinal Cancer
- Conditions
- Gastric CancerPancreatic CancerPeritoneal MetastasesColorectal CancerSmall Bowel CancerAppendix CancerBile Duct CancerPeritoneal Carcinomatosis
- Interventions
- Drug: PIPAC with Nal-IRI
- Registration Number
- NCT05277766
- Lead Sponsor
- University Hospital, Ghent
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 45
- 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
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Concomitant systemic (IV) treatment with irinotecan (either as monotherapy or as part of a combination regimen such as FOLFIRI, CAPIRI, or FOLFOXIRI)
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Pregnancy or breastfeeding during the clinical study
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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).
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Known allergy or intolerance to irinotecan
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Significant amount of ascites detectable (exceeding 3l in volume)
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Intestinal or urinary tract obstruction
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Extensive hepatic and/or extra-abdominal metastatic disease
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Impaired renal function (serum creatinine > 1.5 mg/dl or calculated GFR (CKD-EPI) < 60 mL/min/1.73 m²
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Impaired liver function (serum total bilirubin > 1.5 mg/dl, except for known Gilbert's disease)
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Platelet count < 100.000/µl
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Hemoglobin < 9g/dl
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Neutrophil granulocytes < 1.500/ml
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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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Nal-IRI (Onivyde) - 30mg/m² PIPAC with Nal-IRI PIPAC with Onivyde (30 mg/m²) will be administered every 4 to 6 weeks for 3 cycles. Nal-IRI (Onivyde) - 75mg/m² PIPAC with Nal-IRI PIPAC with Onivyde (75 mg/m²) will be administered every 4 to 6 weeks for 3 cycles. Nal-IRI (Onivyde) - 45mg/m² PIPAC with Nal-IRI PIPAC with Onivyde (45 mg/m²) will be administered every 4 to 6 weeks for 3 cycles. Nal-IRI (Onivyde) - 60mg/m² PIPAC with Nal-IRI PIPAC with Onivyde (60 mg/m²) will be administered every 4 to 6 weeks for 3 cycles. Nal-IRI (Onivyde) - 90mg/m² PIPAC with Nal-IRI PIPAC with Onivyde (90 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.
- Primary Outcome Measures
Name Time Method Maximally tolerated dose (MTD) of Nal-IRI Within 14 weeks of the start of the treatment Dose limiting toxicities will be monitored.
- Secondary Outcome Measures
Name Time Method Recommended phase 2 dose 6 months after last subject's third PIPAC 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.
Area under the curve (AUC0h-24h) of nanoliposomal irinotecan 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 Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.
Clearance (Cl) of nanoliposomal irinotecan 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 Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.
Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed by tumor biopsies. T= 30 minutes Tumour samples will be collected at the end of the aerosol delivery after each PIPAC procedure.
Quality of Life (Functional Assessment of Cancer Therapy, FACT-G questionnaire) Pre-operatively (every PIPAC), week 2 (every PIPAC) and, and at 3 months, 6months and 12 months after last PIPAC procedure 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.
Overall treatment response Determined 8 months after last subject last visit 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).
Maximum concentration (Cmax) of nanoliposomal irinotecan 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 Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.
Time to reach maximum concentration (Tmax) of nanoliposomal irinotecan 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 Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.
Time-to-event endpoints 12 months after last subjects last visit 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).
Volume of distribution (Vd) of nanoliposomal irinotecan 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 Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.
Elimination half-life (T1/2) of nanoliposomal irinotecan 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 Determined for CPT-11, SN-38 and SN-38G in plasma and tumor tissue using UPLC-MS/MS.
Surgical morbidity will be measured 6 months after third PIPAC This will be estimated with the Dindo-Clavien classification and the comprehensive complication index (CCI).
Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed with the Peritoneal regression grading score (PRGS) T= pre-dose (0 minutes= start nebulization) Evaluated on tumor biopsies to determine histological treatment response
Quality of Life (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC QLQ-C30) Pre-operatively (every PIPAC), week 2 (every PIPAC) and, at 3 months, 6months and 12 months after last PIPAC procedure 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 14Quality of Life (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) score) Determined before each PIPAC, every 14th day after PIPAC and at 3 months, 6months and 12 months after last PIPAC procedure 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).
Pain assessment performed by patient (Visual Analog Scale (VAS), Pain ) Determined before each PIPAC procedure, one day postoperatively, and one week after the procedure. 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.
Trial Locations
- Locations (1)
UZ Ghent
🇧🇪Ghent, East-Flanders, Belgium