Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer: A Randomized Phase II Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry
研究概览
简要总结
The OvIP1 study is designed to examine how drug dose and perfusion temperature affect the pharmacokinetics and pharmacodynamics of cisplatin used as (hyperthermic) intraperitoneal chemoperfusion, as an adjunct to surgery, in women with stage III epithelial ovarian cancer.
详细描述
Stage III ovarian cancer (OC) remains an important cause of cancer related mortality in women. After successful initial treatment, most patients eventually develop recurrent peritoneal disease which can only arise from peritoneal minimal residual disease (pMRD) left after primary cytoreductive surgery (CRS). Intensification of locoregional therapy through intraoperative intraperitoneal chemoperfusion (IPEC) immediately following CRS may prevent or delay peritoneal recurrence. Although IPEC, usually under hyperthermic conditions, is increasingly used in OC, its efficacy and the potential benefit of hyperthermia are at present unknown.The primary aim of this study is to assess the pharmacokinetic and pharmacodynamic properties of IP cisplatin administered under normothermic or hyperthermic conditions, and at different dosing schedules. Additional endpoints include surgery related morbidity and mortality, quality of life, overall survival, disease free survival, peritoneal recurrence free survival, peritoneal cytology, and exploration of potential biomarkers.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Tumor type:
- •* Biopsy proven serous epithelial ovarian carcinoma or peritoneal carcinoma
- •Primary or recurrent disease
- •Extent of disease:
- •Positive retroperitoneal lymph nodes and /or microscopic metastasis beyond the pelvis (FIGO stage III, Appendix (47))
- •Stage IV with unilateral pleural fluid allowed
- •Complete or nearly complete macroscopic cytoreduction at the time of surgery (CC-0 or CC-1) deemed possible based on imaging, laparoscopy, or both
- •Second-line patients; platinum sensitive
- •Age over 18 years
- •No major cardiac or respiratory disease
- •Adequate performance status (Karnofsky index > 70%)
- •Adequate mental faculty, allowing to understand the proposed treatment protocol and provide informed consent
- •Expected life expectancy more than 6 months
- •Laboratory data:
- •Serum creatinine ≤ 1.5 mg/dl or a calculated Glomerular Filtration Rate (GFR) (CKD-EPI) ≥ 60 mL/min/1.73 m2
- •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
- •International Normalized Ratio (INR) ≤ 2
- •Absence of alcohol and/or drug abuse
- •No other concurrent malignant disease
- •No inclusion in other clinical trials interfering with the study protocol
- •No concurrent chronic systemic immune or hormone therapy, except neoadjuvant chemotherapy
- •Absence of any severe organ insufficiency
- •No pregnancy or breast feeding
- •Written informed consent
排除标准
- •Severe or uncontrolled cardiac insufficiency, including recent (< 6 months) occurrence of myocardial infarction, the presence of congestive cardiac insufficiency, of symptomatic angor in spite of optimal medical care, of cardiac arrhythmia requiring medical treatment presenting insufficient rhythm control, or uncontrolled arterial hypertension
- •Pregnancy or breast feeding
- •Platinum resistant or refractory disease
- •Active bacterial, viral or fungal infection
- •Active gastro-duodenal ulcer
- •Parenchymal liver disease (any stage cirrhosis)
- •Uncontrolled diabetes mellitus
- •Severe obstructive or restrictive respiratory insufficiency
- •Psychiatric pathology capable of affecting comprehension and judgment faculty
- •Tumor in the presence of obstruction
- •Evidence of extra-abdominal disease (with the exception of unilateral malignant pleural effusion) or extensive liver metastasis
研究组 & 干预措施
low dose, normothermic
CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: Cytoreductive surgery (Procedure)
low dose, normothermic
CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: IPEC with Cisplatin (75mg/m²) (Drug)
high dose, normothermic
CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: Cytoreductive surgery (Procedure)
high dose, normothermic
CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: IPEC with Cisplatin (100mg/m²) (Drug)
low dose, hyperthermic
CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: Cytoreductive surgery (Procedure)
low dose, hyperthermic
CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²) (Drug)
high dose, hyperthermic
CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: Cytoreductive surgery (Procedure)
high dose, hyperthermic
CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
干预措施: HIPEC with Cisplatin (100mg/m²) (Drug)
结局指标
主要结局
Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry
时间窗: 1 tumor nodule will be immediately fixed in liquid nitrogen after cytoreductive surgery and chemoperfusion. Frozen sections will be ablated through study completion
This will be analyzed via laser ablation-inductively coupled plasma- mass spectrometry (LA-ICP-MS)
次要结局
- Surgical morbidity and mortality will be measured using Dindo-Clavien classification(Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion)
- Disease-specific Quality of Life-OV28(3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion)
- Cancer-specific Quality of Life-C30(3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion)
- Maximum perfusate concentration (Cmax) of cisplatin(T=0min (before chemoperfusion), T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion))
- Overall survival(24 months after finishing the adjuvant chemotherapy)
- Disease free survival(24 months after finishing the adjuvant chemotherapy)
- Peritoneal recurrence free survival(24 months after finishing the adjuvant chemotherapy)
- Expression analysis of selected biomarkers = Excision repair cross-complementation group 1 (ERCC1), Methylguanine methyltransferase enzyme (MGMT), Breast cancer gene 1 (BRCA1), Copper transporter 1 (CTR1) using quantitative PCR(1 tumor nodule will be immediately fixed in liquid nitrogen. Histological coupes will be made through study completion)
- Stromal composition and density of tumor tissues via analyzing collagen density, fibroblast Proliferation and DNA-intrastrand adduct formation of Pt-[GG](1 tumor nodule will be immediately fixed in 4% paraformaldehyde. Histological coupes will be made through study completion)
- Maximum plasma concentration (Cmax) and Area Under The Curve (AUC) of cisplatin(T=0min (before chemoperfusion); T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion))
- Pharmacodynamics (PD) of cisplatin will be analyzed by visualizing the amount of DNA double-strand breaks (dsb) via the specific DNA-adduct immunohistochemical Liedert staining(1 tumor nodule will be immediately fixed in 4% paraformaldehyde and immunohistochemical stainings will be done through study completion)