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Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer (OvIP1)

Primary Purpose

Ovarian Cancer, Primary Peritoneal Cancer

Status

Completed

Phase

Phase 2

Locations

Belgium

Study Type

Interventional

Intervention

Cytoreductive surgery

IPEC with Cisplatin (75mg/m²)

IPEC with Cisplatin (100mg/m²)

Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)

HIPEC with Cisplatin (100mg/m²)

About this trial

This is an interventional treatment trial for Ovarian Cancer focused on measuring Cytoreductive surgery, (H)ipec, Ovarian cancer, Cisplatin, Peritoneal carcinomatosis, Pharmacokinetics, Pharmacodynamics

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

UZ Ghent

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

low dose, normothermic

high dose, normothermic

low dose, hyperthermic

high dose, hyperthermic

Arm Description

CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy

CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy

CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy

CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Surgical morbidity and mortality will be measured using Dindo-Clavien classification

This will be estimated with the Dindo-Clavien classification

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

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

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)

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)

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

Overall survival

Calculated from date of surgery until death

Disease free survival

Time interval between date of surgery and disease progression or death

Peritoneal recurrence free survival

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

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]

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

Full Information

NCT ID

NCT02567253

First Posted

September 23, 2015

Last Updated

December 6, 2022

Sponsor

University Hospital, Ghent

1. Study Identification

Unique Protocol Identification Number

NCT02567253

Brief Title

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

Acronym

OvIP1

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

March 2016 (Actual)

Primary Completion Date

December 31, 2020 (Actual)

Study Completion Date

August 25, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Ghent

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ovarian Cancer, Primary Peritoneal Cancer

Keywords

Cytoreductive surgery, (H)ipec, Ovarian cancer, Cisplatin, Peritoneal carcinomatosis, Pharmacokinetics, Pharmacodynamics

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

54 (Actual)

8. Arms, Groups, and Interventions

Arm Title

low dose, normothermic

Arm Type

Experimental

Arm Description

CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy

Arm Title

high dose, normothermic

Arm Type

Experimental

Arm Description

CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy

Arm Title

low dose, hyperthermic

Arm Type

Experimental

Arm Description

CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy

Arm Title

high dose, hyperthermic

Arm Type

Experimental

Arm Description

CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy

Intervention Type

Procedure

Intervention Name(s)

Cytoreductive surgery

Intervention Description

Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer

Intervention Type

Drug

Intervention Name(s)

IPEC with Cisplatin (75mg/m²)

Intervention Description

Intraperitoneal normotherm (37°C) administration of Cisplatin (75mg/m²) , during 90min

Intervention Type

Drug

Intervention Name(s)

IPEC with Cisplatin (100mg/m²)

Intervention Description

Intraperitoneal normotherm (37°C) administration of Cisplatin (100mg/m²), during 90min

Intervention Type

Drug

Intervention Name(s)

Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)

Intervention Description

Intraperitoneal hypertherm (41°C) administration of Cisplatin (75mg/m²), during 90min

Intervention Type

Drug

Intervention Name(s)

HIPEC with Cisplatin (100mg/m²)

Intervention Description

Intraperitoneal hypertherm (41°C) administration of Cisplatin (100mg/m²), during 90min

Primary Outcome Measure Information:

Title

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

Description

This will be analyzed via laser ablation-inductively coupled plasma- mass spectrometry (LA-ICP-MS)

Time Frame

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 Measure Information:

Title

Surgical morbidity and mortality will be measured using Dindo-Clavien classification

Description

This will be estimated with the Dindo-Clavien classification

Time Frame

Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion

Title

Cancer-specific Quality of Life-C30

Description

This will be investigated using the cancer-specific (C30) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires

Time Frame

3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion

Title

Disease-specific Quality of Life-OV28

Description

This will be investigated using the disease-specific (OV28) European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaires

Time Frame

3 weeks before operation, 6 weeks after and 3, 6, 12, 18 and 24 months after surgery and chemoperfusion

Title

Maximum perfusate concentration (Cmax) of cisplatin

Description

Cisplatin (free + bounded) will be measured in perfusate, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)

Time Frame

T=0min (before chemoperfusion), T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion)

Title

Maximum plasma concentration (Cmax) and Area Under The Curve (AUC) of cisplatin

Description

Cisplatin (free + bounded) will be measured in plasma, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)

Time Frame

T=0min (before chemoperfusion); T=15min, T=30min, T=90min (during chemoperfusion); T=2h, T=3h, T=7.5h, T=24h (after start chemoperfusion)

Title

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

Description

Time Frame

1 tumor nodule will be immediately fixed in 4% paraformaldehyde and immunohistochemical stainings will be done through study completion

Title

Overall survival

Description

Calculated from date of surgery until death

Time Frame

24 months after finishing the adjuvant chemotherapy

Title

Disease free survival

Description

Time interval between date of surgery and disease progression or death

Time Frame

24 months after finishing the adjuvant chemotherapy

Title

Peritoneal recurrence free survival

Description

Time interval between date of surgery and peritoneal recurrence or death

Time Frame

24 months after finishing the adjuvant chemotherapy

Title

Description

Gene expression of potential predictive biomarkers using qPCR

Time Frame

1 tumor nodule will be immediately fixed in liquid nitrogen. Histological coupes will be made through study completion

Title

Stromal composition and density of tumor tissues via analyzing collagen density, fibroblast Proliferation and DNA-intrastrand adduct formation of Pt-[GG]

Description

Time Frame

1 tumor nodule will be immediately fixed in 4% paraformaldehyde. Histological coupes will be made through study completion

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Wim P Ceelen, MD, PhD

Organizational Affiliation

University Hospital, Ghent

Official's Role

Principal Investigator

Facility Information:

Facility Name

UZ Ghent

City

Ghent

State/Province

East-Flanders

ZIP/Postal Code

9000

Country

Belgium

12. IPD Sharing Statement

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Citation

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

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