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

Phase 2

Completed

• Conditions: Ovarian Cancer; Primary Peritoneal Cancer
• Interventions: 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)

• Registration Number: NCT02567253
• Lead Sponsor: University Hospital, Ghent

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2015-09-23
• Study First Submitted QC: 2015-10-01
• Study First Posted: 2015-10-02
• Study Start: 2016-03
• Primary Completion: 2020-12-31
• Study Completion: 2021-08-25
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-24
• Last Update Posted: 2023-11-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 56

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
low dose, normothermic	Cytoreductive surgery	CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
low dose, normothermic	IPEC with Cisplatin (75mg/m²)	CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
high dose, normothermic	Cytoreductive surgery	CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
high dose, normothermic	IPEC with Cisplatin (100mg/m²)	CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
low dose, hyperthermic	Cytoreductive surgery	CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
low dose, hyperthermic	Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)	CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
high dose, hyperthermic	Cytoreductive surgery	CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
high dose, hyperthermic	HIPEC with Cisplatin (100mg/m²)	CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy

Primary Outcome Measures

Name	Time	Method
Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry	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)

Secondary Outcome Measures

Name	Time	Method
Surgical morbidity and mortality will be measured using Dindo-Clavien classification	Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion	This will be estimated with the Dindo-Clavien classification
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	This will be investigated using the cancer-specific (C30) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires
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)	Cisplatin (free + bounded) will be measured in perfusate, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)
Overall survival	24 months after finishing the adjuvant chemotherapy	Calculated from date of surgery until death
Disease free survival	24 months after finishing the adjuvant chemotherapy	Time interval between date of surgery and disease progression or death
Peritoneal recurrence free survival	24 months after finishing the adjuvant chemotherapy	Time interval between date of surgery and peritoneal recurrence or death
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	Gene expression of potential predictive biomarkers using qPCR
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	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
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	This will be investigated using the disease-specific (OV28) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires
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)	Cisplatin (free + bounded) will be measured in plasma, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)
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	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

Trial Locations

Locations (1)

UZ Ghent; 🇧🇪 Ghent, East-Flanders, Belgium