Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer: A Randomized Phase II Trial

Conditions
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Ovarian Cancer, Primary Peritoneal Cancer

Intervention / Treatment
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* Procedure: Cytoreductive surgery
* Drug: IPEC with Cisplatin (75mg/m²)
* Drug: IPEC with Cisplatin (100mg/m²)
* Drug: Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)
* Drug: HIPEC with Cisplatin (100mg/m²)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: low dose, normothermic<br>CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy | Procedure: Cytoreductive surgery<br>* Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer<br>Drug: IPEC with Cisplatin (75mg/m²)<br>* Intraperitoneal normotherm (37°C) administration of Cisplatin (75mg/m²) , during 90min<br>|
| Experimental: high dose, normothermic<br>CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy | Procedure: Cytoreductive surgery<br>* Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer<br>Drug: IPEC with Cisplatin (100mg/m²)<br>* Intraperitoneal normotherm (37°C) administration of Cisplatin (100mg/m²), during 90min<br>|
| Experimental: low dose, hyperthermic<br>CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy | Procedure: Cytoreductive surgery<br>* Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer<br>Drug: Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)<br>* Intraperitoneal hypertherm (41°C) administration of Cisplatin (75mg/m²), during 90min<br>|
| Experimental: high dose, hyperthermic<br>CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy | Procedure: Cytoreductive surgery<br>* Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer<br>Drug: HIPEC with Cisplatin (100mg/m²)<br>* Intraperitoneal hypertherm (41°C) administration of Cisplatin (100mg/m²), during 90min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry | This will be analyzed via laser ablation-inductively coupled plasma- mass spectrometry (LA-ICP-MS) | 1 tumor nodule will be immediately fixed in liquid nitrogen after cytoreductive surgery and chemoperfusion. Frozen sections will be ablated through study completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical morbidity and mortality will be measured using Dindo-Clavien classification | This will be estimated with the Dindo-Clavien classification | Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion | 
| Cancer-specific Quality of Life-C30 | This will be investigated using the cancer-specific (C30) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires | 3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion | 
| Disease-specific Quality of Life-OV28 | This will be investigated using the disease-specific (OV28) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires | 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 | Cisplatin (free + bounded) will be measured in perfusate, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS) | T=0min (before chemoperfusion), T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion) | 
| Maximum plasma concentration (Cmax) and Area Under The Curve (AUC) of cisplatin | Cisplatin (free + bounded) will be measured in plasma, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS) | 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 | PD of cisplatin will be studied via Pt-DNA adduct formation, using the Liedert staining which is specific for Pt-[Guanine, Guanine] adducts (Pt-[GG]) using Mab R-C18. The amount of double-strand breaks (dsb) will be analyzed then via fluorescence microscopy | 1 tumor nodule will be immediately fixed in 4% paraformaldehyde and immunohistochemical stainings will be done through study completion | 
| Overall survival | Calculated from date of surgery until death | 24 months after finishing the adjuvant chemotherapy | 
| Disease free survival | Time interval between date of surgery and disease progression or death | 24 months after finishing the adjuvant chemotherapy | 
| Peritoneal recurrence free survival | Time interval between date of surgery and peritoneal recurrence or death | 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 | Gene expression of potential predictive biomarkers using qPCR | 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] | Analyzing collagen density using the sirius red staining, analyzing fibroblast proliferation using alfa smooth-muscle action (α-SMA) stainings and DNA intrastrand adduct formation of Pt-[GG] with the Liedert staining using Mab R-C18 | 1 tumor nodule will be immediately fixed in 4% paraformaldehyde. Histological coupes will be made through study completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cytoreductive surgery, (H)ipec, Ovarian cancer, Cisplatin, Peritoneal carcinomatosis, Pharmacokinetics, Pharmacodynamics