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

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ClinicalTrials.gov Identifier: NCT02567253
Recruitment Status : Recruiting
First Posted : October 2, 2015
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Ovarian Cancer Primary Peritoneal Cancer 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) Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Intraoperative Intraperitoneal Chemoperfusion to Treat Peritoneal Minimal Residual Disease in Stage III Ovarian Cancer: A Randomized Phase II Trial
Study Start Date : March 2016
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer

Arm Intervention/treatment
Experimental: low dose, normothermic
CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
Procedure: Cytoreductive surgery
Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer

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

Experimental: high dose, normothermic
CRS + normothermic (37°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
Procedure: Cytoreductive surgery
Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer

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

Experimental: low dose, hyperthermic
CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 75mg/m² Cisplatin during 90min + adjuvant chemotherapy
Procedure: Cytoreductive surgery
Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer

Drug: Hypertherm IntraPEritoneal Chemotherapy with Cisplatin (75mg/m²)
Intraperitoneal hypertherm (41°C) administration of Cisplatin (75mg/m²), during 90min

Experimental: high dose, hyperthermic
CRS + hyperthermic (41°C) intraoperative intraperitoneal chemoperfusion, with 100mg/m² Cisplatin during 90min + adjuvant chemotherapy
Procedure: Cytoreductive surgery
Complete or nearly complete (CC-0 or CC-1) macroscopic cytoreduction at the time of surgery of peritoneal carcinomatosis from ovarian cancer

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




Primary Outcome Measures :
  1. Tissue penetration distance of cisplatin in peritoneal tumor tissue nodules using laser-ablation inductively couples plasma mass spectrometry [ 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 ]
    This will be analyzed via laser ablation-inductively coupled plasma- mass spectrometry (LA-ICP-MS)


Secondary Outcome Measures :
  1. Surgical morbidity and mortality will be measured using Dindo-Clavien classification [ Time Frame: Within 30 days after surgery and intraoperative intraperitoneal chemoperfusion ]
    This will be estimated with the Dindo-Clavien classification

  2. Cancer-specific Quality of Life-C30 [ Time Frame: 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

  3. Disease-specific Quality of Life-OV28 [ Time Frame: 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

  4. Maximum perfusate concentration (Cmax) of cisplatin [ 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) ]
    Cisplatin (free + bounded) will be measured in perfusate, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)

  5. Maximum plasma concentration (Cmax) and Area Under The Curve (AUC) of cisplatin [ 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) ]
    Cisplatin (free + bounded) will be measured in plasma, using high performance liquid chromatography coupled to an inductively coupled plasma- mass spectrometry (HPLC-ICP-MS)

  6. 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 [ Time Frame: 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

  7. Overall survival [ Time Frame: 24 months after finishing the adjuvant chemotherapy ]
    Calculated from date of surgery until death

  8. Disease free survival [ Time Frame: 24 months after finishing the adjuvant chemotherapy ]
    Time interval between date of surgery and disease progression or death

  9. Peritoneal recurrence free survival [ Time Frame: 24 months after finishing the adjuvant chemotherapy ]
    Time interval between date of surgery and peritoneal recurrence or death

  10. 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 [ Time Frame: 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

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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02567253


Contacts
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Contact: Wim P Ceelen, MD, PhD +32 9 332 62 51 wim.ceelen@ugent.be
Contact: Charlotte Carlier, MSc + 32 9 332 55 24 charlotte.carlier@ugent.be

Locations
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Belgium
UZ Ghent Recruiting
Ghent, East-Flanders, Belgium, 9000
Contact: Wim P Ceelen, MD, PhD, FACS    09 332 62 51    wim.ceelen@ugent.be   
Contact: Wouter Willaert, MD, PhD    09 332 8950    wouter.willaert@ugent.be   
Sponsors and Collaborators
University Hospital, Ghent
Investigators
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Principal Investigator: Wim P Ceelen, MD, PhD University Hospital, Ghent

Publications:

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Responsible Party: University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT02567253     History of Changes
Other Study ID Numbers: AGO/2015/002
First Posted: October 2, 2015    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Keywords provided by University Hospital, Ghent:
Cytoreductive surgery
(H)ipec
Ovarian cancer
Cisplatin
Peritoneal carcinomatosis
Pharmacokinetics
Pharmacodynamics
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Neoplasm, Residual
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Cisplatin
Antineoplastic Agents