Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis From Gastrointestinal Cancer: a Phase I Study
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 45
- 试验地点
- 2
- 主要终点
- Maximally tolerated dose (MTD) of Nal-IRI
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Nal-IRI (Onivyde) - 30mg/m²
PIPAC with Onivyde (30 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.
干预措施: PIPAC with Nal-IRI (Drug)
Nal-IRI (Onivyde) - 45mg/m²
PIPAC with Onivyde (45 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.
干预措施: PIPAC with Nal-IRI (Drug)
Nal-IRI (Onivyde) - 60mg/m²
PIPAC with Onivyde (60 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.
干预措施: PIPAC with Nal-IRI (Drug)
Nal-IRI (Onivyde) - 75mg/m²
PIPAC with Onivyde (75 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.
干预措施: PIPAC with Nal-IRI (Drug)
Nal-IRI (Onivyde) - 90mg/m²
PIPAC with Onivyde (90 mg/m²) will be administered every 4 to 6 weeks for 3 cycles.
干预措施: PIPAC with Nal-IRI (Drug)
结局指标
主要结局
Maximally tolerated dose (MTD) of Nal-IRI
时间窗: Within 14 weeks of the start of the treatment
Dose limiting toxicities will be monitored.
次要结局
- Recommended phase 2 dose(6 months after last subject's third PIPAC)
- 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)
- 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)
- Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed by tumor biopsies.(T= 30 minutes)
- 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)
- Overall treatment response(Determined 8 months after last subject last visit)
- 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)
- 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)
- Time-to-event endpoints(12 months after last subjects last visit)
- 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)
- 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)
- Surgical morbidity will be measured(6 months after third PIPAC)
- Pharmacodynamics (PD) of nanoliposomal irinotecan will be analysed with the Peritoneal regression grading score (PRGS)(T= pre-dose (0 minutes= start nebulization))
- 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)
- Quality 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)
- Pain assessment performed by patient (Visual Analog Scale (VAS), Pain )(Determined before each PIPAC procedure, one day postoperatively, and one week after the procedure.)