Clinical trial NCT05277766: Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis from Gastrointestinal Cancer
Official title: Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis from Gastrointestinal Cancer: a Phase I Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Peritoneal Carcinomatosis
Peritoneal Metastases
Colorectal Cancer
Small Bowel Cancer
Appendix Cancer
Gastric Cancer
Pancreatic Cancer
Bile Duct Cancer
Keywords: PIPAC
Nal-IRI
Peritoneal carcinomatosis
dose-finding study
pharmacokinetics
pharmacodynamics
safety and efficacy
Onivyde
Primary gastrointestinal cancer
Colorectal cancer
Small bowel cancer
Appendix cancer
Stomach cancer
Pancreatic cancer
Cholangiocarcinoma
dose-escalation study
Peritoneal metastases
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
Collaborators: name: Kom Op Tegen Kanker
name: University Ghent
First posted: 2022-03-14
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase I study with dose escalation according to two-stage time-to-event continual reassessment method (TITE-CRM): 3x30 - 3x45 - 4x60 - 4x 75 - 16x90 mg/m2 (number of patients x assigned dose). Dose escalation is continued until dose-limiting toxicity (DLT) is observed. Only DLTs that take place within 14 weeks of the start of the treatment are considered.

From that moment, TITE-CRM updates an initial prior estimate of the probabilities of DLT based on all available information, including patients with incomplete follow-up. Newly accrued patients are assigned the dose whose estimated probability of DLT at that time is closest to target probability. This method allows for continuous, staggered accrual of patients. The target-probability of DLT is 30%. The estimated MTD will be the dose whose estimated posterior probability of DLT is closest to that targeted probability.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Maximally tolerated dose (MTD) of Nal-IRI
timeFrame: Within 14 weeks of the start of the treatment
Secondary outcomes:
measure: Recommended phase 2 dose
timeFrame: 6 months after last subject's third PIPAC
measure: Surgical morbidity will be measured
timeFrame: 6 months after third PIPAC
measure: Maximum concentration (Cmax) of nanoliposomal irinotecan
timeFrame: 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
measure: Time to reach maximum concentration (Tmax) of nanoliposomal irinotecan
timeFrame: 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
measure: Area under the curve (AUC0h-24h) of nanoliposomal irinotecan
timeFrame: 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
measure: Volume of distribution (Vd) of nanoliposomal irinotecan
timeFrame: 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
measure: Clearance (Cl) of nanoliposomal irinotecan
timeFrame: 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
measure: Elimination half-life (T1/2) of nanoliposomal irinotecan
timeFrame: 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
measure: Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed with the Peritoneal regression grading score (PRGS)
timeFrame: T= pre-dose (0 minutes= start nebulization)
measure: Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed by tumor biopsies.
timeFrame: T= 30 minutes
measure: Time-to-event endpoints
timeFrame: 12 months after last subjects last visit
measure: Quality of Life (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC QLQ-C30)
timeFrame: Pre-operatively (every PIPAC), week 2 (every PIPAC) and, at 3 months, 6months and 12 months after last PIPAC procedure
measure: Quality of Life (Functional Assessment of Cancer Therapy, FACT-G questionnaire)
timeFrame: Pre-operatively (every PIPAC), week 2 (every PIPAC) and, and at 3 months, 6months and 12 months after last PIPAC procedure
measure: Quality of Life (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) score)
timeFrame: Determined before each PIPAC, every 14th day after PIPAC and at 3 months, 6months and 12 months after last PIPAC procedure
measure: Pain assessment performed by patient (Visual Analog Scale (VAS), Pain )
timeFrame: Determined before each PIPAC procedure, one day postoperatively, and one week after the procedure.
measure: Overall treatment response
timeFrame: Determined 8 months after last subject last visit
Other outcomes:
measure: Exploratory outcome: DNA topoisomerase I (TOP-1) gene copy number
timeFrame: 8 months after last subject last visit
measure: Exploratory outcome: Expression of human carboxylesterase 2 (hCE2)
timeFrame: 8 months after last subject last visit
Locations:
city: Ghent
country: Belgium
facility: UZ Ghent
state: East-Flanders
Study officials:
affiliation: University Hospital, Ghent
name: Wim P Ceelen, MD, PhD, Prof
role: PRINCIPAL_INVESTIGATOR
References: