Back to resultsPressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Associated With Systemic Chemotherapy in Women With Advanced Ovarian Cancer (PIPACOVA)
Primary Purpose
Metastatic Ovarian Carcinoma, Peritoneal Carcinomatosis, Stage III Ovarian Cancer
Status
Recruiting
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Combined PIPAC / IV chemotherapy treatment
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Ovarian Carcinoma focused on measuring Dose escalation, Phase I study, Intravenous Chemotherapy, Intraperitoneal chemotherapy, PIPAC, RP2D, cytoreductive surgery, Ovarian epithelial cancer, peritoneal cancer, doxorubicin, cisplatin, CA-125 antigen, pharmacokinetic
Eligibility Criteria
Inclusion Criteria:
- Age ≥18 years and ≤ 75 years
- ECOG PS 0-2 ;
- High-grade carcinoma of the ovary, fallopian tubes, or peritoneum proven histologically, stage III or IV of the FIGO classification and with history of insufficient tumor response/ after three cycles of previous neoadjuvant systemic carboplatin-paclitaxel chemotherapy as judged by the investigators after discussion and validation in Multidisciplinary Team ;
- Adequate hematologic function
- Absolute Neutrophil Count > 1500 / mm3 (or 1.5 10 9/L)
- Hemoglobin ≥ 9.0 g/dL,
- platelets > 100 G/L,
- Adequate hepatic and renal function:
- Serum creatinine ≤1.5 times upper normal values or glomerular filtration rate ≥ 60 mL/min/1.73 m2 estimated by the CKD-EPI equation
- Total bilirubin ≤1.5 times the upper normal limit,
- ASAT / ALAT ≤1.5 times the upper normal limit (≤5 times upper normal limits for patients with liver metastases);
- Absence of unstable pathologies : myocardial infarction within 6 months prior to the start of the study, congestive heart failure, unstable angina, active cardiomyopathy, unstable rhythm disorder, uncontrolled hypertension, uncontrolled psychiatric disorders, severe infection, peptic ulcer, or any pathology that could be aggravated by treatment or limit compliance (investigator's judgment)
- Patient information given and Written informed consent obtained prior to the initiation of any specific study procedure
- Affiliated to a social insurance regime or similar
Exclusion Criteria:
- Extra-peritoneal metastases (position or number which make the disease unresectable)
- Signs of intestinal obstruction or lesions with risk of intestinal perforation, or signs of inflammatory disease of the digestive tract
- Contraindication to systemic chemotherapy CARBOPLATIN-PACLITAXEL :known allergy to paclitaxel
- Contraindication to the PIPAC procedure:
- Known allergy to cisplatin or other platinum-containing compounds
- Known allergy to doxorubicin or other anthracyclines or anthracenediones;
- Heart failure with myocardial insufficiency
- Uncontrolled coronary insufficiency;
- Patient whose last chemotherapy required administration of G-CSF (Granulocyte-Colony Stimulating Factor)
- Pregnancy or breastfeeding
- Persons deprived of liberty or under guardianship ;
- Major patient protected by the Law;
- Persons participating in other research with an exclusion period still in progress at the time of inclusion or research that may interfere with the results of the present study (investigator's judgment) ;
- Impossibility to submit to the medical follow-up of the trial for geographical, social or psychic reasons (investigator's judgement)
Sites / Locations
- Hôpital Claude Huriez - Chirurgie générale et digestiveRecruiting
- Hôpital Claude Huriez - Oncologie médicaleRecruiting
- Hôpital de la Croix-RousseRecruiting
- Hôpital Lyon Sud - Chirurgie Digestive et OncologiqueRecruiting
- Hôpital Lyon Sud - Chirurgie Gynécologique et oncologique-obstétriqueRecruiting
- Hôpital Lyon Sud - Oncologie MédicaleRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Combined PIPAC / IV chemotherapy treatment
Arm Description
Patients will undergo 3 cycles of combined chemotherapy, consisting of PIPAC (cisplatin-doxorubicin, escalating doses) and systemic chemotherapy (paclitaxel-carboplatine, standard doses). First patient will be treated at the lowest dose: doxorubicin 2.1 mg/m² and cisplatin 10.5 mg/m². Subsequent patients will be treated at the dose recommended by the CRM algorithm in the absence of dose-limiting toxicity. A total of 11 dose levels with a factor between 1 and 3 are considered. The maximum dose considered will be doxorubicin, 6.3 mg/m² and cisplatin, 31.5 mg/m². The doses of intravenous chemotherapy will be defined in a standard way, according to the habits of the investigating clinicians and in accordance with the doses received previously. Each cycle will last 28 days and will begin at day 1 with PIPAC procedure and will be completed at day 8 with systemic chemotherapy. Combined chemotherapy will be repeated every 4 weeks for up to 3 cycles in the absence of unacceptable toxicity.
Outcomes
Primary Outcome Measures
Dose-limiting toxicities
Dose-limiting toxicities will be defined as any of the following events observed during the first cycle of treatment and judged by the investigator to be possibly related to the treatment, based on the classification of the National Cancer Institute Common Criteria for Adverse Events Terminology (NCI CTCAE) Version 5.0 :
Grade 4 Neutropenia (absolute neutrophil count <500 /mm3 (or 0.5 109/L)) ≥7 consecutive days;
Neutropenia of grade ≥ 3 (absolute neutrophil count <1000 /mm3 (or 1 109/L)) and temperature ≥ 38.5°C ;
Thrombocytopenia grade 4 (<25,000/mm3 platelets (or 25 109/L)) or grade 3 (< 50,000/mm3 (or 50 109/L)) associated with bleeding ;
Non-hematological toxicity of grade ≥3 (excluding non-life-threatening toxicities such as alopecia, asymptomatic hypophosphatemia, etc.) despite adequate medical intervention judged by the investigator
Secondary Outcome Measures
Rate of complete surgical resection
Assessed during cytoreductive surgery by the Completeness Cytoreduction (CC) score after the 3 cycles of combined chemotherapy.
Complete cytoreduction refers to a CC-0 or CC-1 score whereas a CC-2 or 3 score is classified as incomplete ; CC-0 score indicates no evidence of macroscopic disease after cytoreduction, a CC-1 score indicates persisting microscopic disease (tumour nodules are < 2.5 mm), a CC-2 score indicates persisting macroscopic disease (residual tumour nodules between 2.5 mm and 2.5 cm) and finally a CC-3 score indicates tumour nodules > 2.5 cm or a confluence of unresected tumour.
Proportion of complete, partial or stabilized tumor response
Assessed according to the Response Evaluation Criteria in Solid Tumor (RECIST) criteria version 1.1, on thoracic abdominal pelvic imaging (scanner or MRI in case of contraindication).
Peritoneal cancer index (PCI) evolution
PCI index will be evaluated under videosurveillance during laparoscopy. PCI is determined according to Sugarbaker, based on lesion size and distribution. Using a pictorial of the abdomen, each location of a 13 point list receives a peritoneal cancer grade ranging from 0 to 3. The counts for all 13 locations are then summarized as PCI.
Area under the curve (AUC) for plasma concentration of DOXORUBICIN and CISPLATIN
The plasma biodisponibility of the PIPAC doxorubicin and CISPLATIN (total and ultrafilterable platinum) chemotherapeutic compound will be assessed by reporting the Area under the plasma concentration- time curve.
Change in CA-125 concentration
CA-125 evolution profile will be monitored during chemotherapy and before surgery of reevaluation at post-treatment visit. Then, mathematical modeling of CA-125 elimination rate KELIM will be calculated from individual CA-125 levels.
Rates of adverse events and operative complications
Adverse events according to the NCI CTCAE v5.0 classification (including toxicities) and per- and post-operative complications according to the Clavien-Dindo classification.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04811703
Brief Title
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Associated With Systemic Chemotherapy in Women With Advanced Ovarian Cancer
Acronym
PIPACOVA
Official Title
Phase I Dose Escalation Study Evaluating the Safety of Adding Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) With Cisplatin-doxorubicin to the Systemic Chemotherapy, and the Recommended Phase II Dose, in Women With Insufficient Response to Carboplatin-paclitaxel for Advanced Epithelial Cancer of the Ovary, Fallopian Tubes or Peritoneum
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 30, 2021 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
January 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Women with history of tumor response insufficient to allow complete cytoreductive surgery after three cycles of previous neoadjuvant systemic carboplatin-paclitaxel chemotherapy will be prospectively recruited in this trial. After signed consent and if unresectability is confirmed, patients will undergo three cycles of doxorubicin-cisplatin PIPAC chemotherapy associated with systemic carboplatin-paclitaxel chemotherapy (alternating PIPAC and intravenous chemotherapy sessions over 3 cycles of 4 weeks).
The primary objective of the study is to determine the maximum tolerated dose (MDT).
During cycle 1, limiting dose toxicity must be collected as soon as it is known. Each patients will be treated at the dose recommended by the CRM (Continual Reassessment Method ) algorithm conditional on dose-limiting toxicity during Cycle 1.
The dose escalation will be guided by CRM to determine the recommended dose of PIPAC chemotherapy for phase II trial.
Secondary objectives are :
to evaluate the anatomopathological response, the radiologic tumoral response and the evolution of the peritoneal cancer extent, to the combined chemotherapy
to describe the pharmacokinetic of the PIPAC chemotherapy
to investigate the KELIM parameter as a predictive marker in the response sensitivity of the combined chemotherapy treatment
and to evaluate the safety of the combined chemotherapy. During the first day of the first cycle, blood samples will be collected to measure doxorubicin and cisplatin (pharmacokinetic study). Along these 3 cycles, the dose of antigen CA-125 will be performed before each chemotherapies (intraperitoneal or intravenous).
At the end of combined chemotherapy treatment, patients will undergo radiologic tumoral response by imaging assessment (scanner or MRI) and a last dosage of CA-125 will be realized..
In case of a complete / partial response / stabilization (RECIST criteria v.1.) on the imaging, re-evaluation for resectability will be done. If resectable disease, cytoreductive surgery will be programmed and a post-operative visit 1 month later will be realized. Otherwise for patients with progress disease or unresectable the participation in the study will be finished.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Ovarian Carcinoma, Peritoneal Carcinomatosis, Stage III Ovarian Cancer, Stage IV Ovarian Cancer, Stage III Fallopian Tube Cancer, Stage IV Fallopian Tube Cancer, Metastatic Malignant Neoplasm in the Peritoneum
Keywords
Dose escalation, Phase I study, Intravenous Chemotherapy, Intraperitoneal chemotherapy, PIPAC, RP2D, cytoreductive surgery, Ovarian epithelial cancer, peritoneal cancer, doxorubicin, cisplatin, CA-125 antigen, pharmacokinetic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Combined PIPAC / IV chemotherapy treatment
Arm Type
Experimental
Arm Description
Patients will undergo 3 cycles of combined chemotherapy, consisting of PIPAC (cisplatin-doxorubicin, escalating doses) and systemic chemotherapy (paclitaxel-carboplatine, standard doses). First patient will be treated at the lowest dose: doxorubicin 2.1 mg/m² and cisplatin 10.5 mg/m². Subsequent patients will be treated at the dose recommended by the CRM algorithm in the absence of dose-limiting toxicity. A total of 11 dose levels with a factor between 1 and 3 are considered. The maximum dose considered will be doxorubicin, 6.3 mg/m² and cisplatin, 31.5 mg/m². The doses of intravenous chemotherapy will be defined in a standard way, according to the habits of the investigating clinicians and in accordance with the doses received previously. Each cycle will last 28 days and will begin at day 1 with PIPAC procedure and will be completed at day 8 with systemic chemotherapy. Combined chemotherapy will be repeated every 4 weeks for up to 3 cycles in the absence of unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Combined PIPAC / IV chemotherapy treatment
Intervention Description
Addition of cisplatin-doxorubicin PIPAC sessions to carboplatin-paclitaxel systemic Chemotherapy
Primary Outcome Measure Information:
Title
Dose-limiting toxicities
Description
Dose-limiting toxicities will be defined as any of the following events observed during the first cycle of treatment and judged by the investigator to be possibly related to the treatment, based on the classification of the National Cancer Institute Common Criteria for Adverse Events Terminology (NCI CTCAE) Version 5.0 :
Grade 4 Neutropenia (absolute neutrophil count <500 /mm3 (or 0.5 109/L)) ≥7 consecutive days;
Neutropenia of grade ≥ 3 (absolute neutrophil count <1000 /mm3 (or 1 109/L)) and temperature ≥ 38.5°C ;
Thrombocytopenia grade 4 (<25,000/mm3 platelets (or 25 109/L)) or grade 3 (< 50,000/mm3 (or 50 109/L)) associated with bleeding ;
Non-hematological toxicity of grade ≥3 (excluding non-life-threatening toxicities such as alopecia, asymptomatic hypophosphatemia, etc.) despite adequate medical intervention judged by the investigator
Time Frame
First cycle of combined chemotherapy = day 1 up to day 28 of the first cycle
Secondary Outcome Measure Information:
Title
Rate of complete surgical resection
Description
Assessed during cytoreductive surgery by the Completeness Cytoreduction (CC) score after the 3 cycles of combined chemotherapy.
Complete cytoreduction refers to a CC-0 or CC-1 score whereas a CC-2 or 3 score is classified as incomplete ; CC-0 score indicates no evidence of macroscopic disease after cytoreduction, a CC-1 score indicates persisting microscopic disease (tumour nodules are < 2.5 mm), a CC-2 score indicates persisting macroscopic disease (residual tumour nodules between 2.5 mm and 2.5 cm) and finally a CC-3 score indicates tumour nodules > 2.5 cm or a confluence of unresected tumour.
Time Frame
During cytoreductive surgery performed at the end of cycle 3 of combined chemotherapy (each cycle is 28 days), and at a maximum of 12 weeks after the third cycle of PIPAC
Title
Proportion of complete, partial or stabilized tumor response
Description
Assessed according to the Response Evaluation Criteria in Solid Tumor (RECIST) criteria version 1.1, on thoracic abdominal pelvic imaging (scanner or MRI in case of contraindication).
Time Frame
After completing chemotherapy treatment, at 4 to 5 weeks after the third cycle of post PIPAC (each cycle is 28 days)
Title
Peritoneal cancer index (PCI) evolution
Description
PCI index will be evaluated under videosurveillance during laparoscopy. PCI is determined according to Sugarbaker, based on lesion size and distribution. Using a pictorial of the abdomen, each location of a 13 point list receives a peritoneal cancer grade ranging from 0 to 3. The counts for all 13 locations are then summarized as PCI.
Time Frame
At day 1 of the beginning of each cycle during PIPAC procedure, at 4 to 5 weeks post PIPAC cycle 3 (each cycle is 28 days) and during post-treatment laparoscopy and/or during cytoreductive surgery (12 weeks max post PIPAC cycle 3)]
Title
Area under the curve (AUC) for plasma concentration of DOXORUBICIN and CISPLATIN
Description
The plasma biodisponibility of the PIPAC doxorubicin and CISPLATIN (total and ultrafilterable platinum) chemotherapeutic compound will be assessed by reporting the Area under the plasma concentration- time curve.
Time Frame
During day 1 of the first cycle of PIPAC chemotherapy (at 0, 30 minute, 1 hour, 2 hours, 4 hours, 6 hours, 7/8 hours and 24 hours post PIPAC for the both chemotherapeutic compound and 48 hours only for DOXORUBICIN), each cycle being 28 days.
Title
Change in CA-125 concentration
Description
CA-125 evolution profile will be monitored during chemotherapy and before surgery of reevaluation at post-treatment visit. Then, mathematical modeling of CA-125 elimination rate KELIM will be calculated from individual CA-125 levels.
Time Frame
Pharmacokinetic blood samples for each cycle, each cycle being 28 days (at day 1 for PIPAC chemotherapy; at day 8 for systemic chemotherapy) and before post-treatment laparoscopy at 4-5 weeks after the third PIPAC)
Title
Rates of adverse events and operative complications
Description
Adverse events according to the NCI CTCAE v5.0 classification (including toxicities) and per- and post-operative complications according to the Clavien-Dindo classification.
Time Frame
Up to 8 months after inclusion
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥18 years and ≤ 75 years
ECOG PS 0-2 ;
High-grade carcinoma of the ovary, fallopian tubes, or peritoneum proven histologically, stage III or IV of the FIGO classification and with history of insufficient tumor response/ after three cycles of previous neoadjuvant systemic carboplatin-paclitaxel chemotherapy as judged by the investigators after discussion and validation in Multidisciplinary Team ;
Adequate hematologic function
Absolute Neutrophil Count > 1500 / mm3 (or 1.5 10 9/L)
Hemoglobin ≥ 9.0 g/dL,
platelets > 100 G/L,
Adequate hepatic and renal function:
Serum creatinine ≤1.5 times upper normal values or glomerular filtration rate ≥ 60 mL/min/1.73 m2 estimated by the CKD-EPI equation
Total bilirubin ≤1.5 times the upper normal limit,
ASAT / ALAT ≤1.5 times the upper normal limit (≤5 times upper normal limits for patients with liver metastases);
Absence of unstable pathologies : myocardial infarction within 6 months prior to the start of the study, congestive heart failure, unstable angina, active cardiomyopathy, unstable rhythm disorder, uncontrolled hypertension, uncontrolled psychiatric disorders, severe infection, peptic ulcer, or any pathology that could be aggravated by treatment or limit compliance (investigator's judgment)
Patient information given and Written informed consent obtained prior to the initiation of any specific study procedure
Affiliated to a social insurance regime or similar
Exclusion Criteria:
Extra-peritoneal metastases (position or number which make the disease unresectable)
Signs of intestinal obstruction or lesions with risk of intestinal perforation, or signs of inflammatory disease of the digestive tract
Contraindication to systemic chemotherapy CARBOPLATIN-PACLITAXEL :known allergy to paclitaxel
Contraindication to the PIPAC procedure:
Known allergy to cisplatin or other platinum-containing compounds
Known allergy to doxorubicin or other anthracyclines or anthracenediones;
Heart failure with myocardial insufficiency
Uncontrolled coronary insufficiency;
Patient whose last chemotherapy required administration of G-CSF (Granulocyte-Colony Stimulating Factor)
Pregnancy or breastfeeding
Persons deprived of liberty or under guardianship ;
Major patient protected by the Law;
Persons participating in other research with an exclusion period still in progress at the time of inclusion or research that may interfere with the results of the present study (investigator's judgment) ;
Impossibility to submit to the medical follow-up of the trial for geographical, social or psychic reasons (investigator's judgement)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Frederic SCHELL, MD
Phone
04 78 86 23 71
Ext
+33
Email
frederic.schell@chu-lyon.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Naoual BAKRIN, MD
Phone
04 78 86 23 71
Ext
+33
Email
naoual.bakrin@chu-lyon.fr
Facility Information:
Facility Name
Hôpital Claude Huriez - Chirurgie générale et digestive
City
Lille
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clarisse EVENO, MD
Email
Clarisse.EVENO@CHRU-LILLE.FR
First Name & Middle Initial & Last Name & Degree
Clarisse EVENO, MD
Facility Name
Hôpital Claude Huriez - Oncologie médicale
City
Lille
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anne PLOQUIN, MD
Email
anne.ploquin@CHRU-LILLE.FR
First Name & Middle Initial & Last Name & Degree
Anne PLOQUIN, MD
Facility Name
Hôpital de la Croix-Rousse
City
Lyon
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sophie DUPLOMB, MD
Phone
04 26 73 26 12
Ext
+33
Email
sophie.duplomb@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Sophie DUPLOMB, MD
Facility Name
Hôpital Lyon Sud - Chirurgie Digestive et Oncologique
City
Pierre-Bénite
ZIP/Postal Code
69495
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Naoual BAKRIN, MD
Phone
04 78 86 23 71
Email
naoual.bakrin@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Frederic SCHELL, MD
Facility Name
Hôpital Lyon Sud - Chirurgie Gynécologique et oncologique-obstétrique
City
Pierre-Bénite
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Naoual BAKRIN, MD
Email
naoual.bakrin@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Witold GERTYCH, MD
Facility Name
Hôpital Lyon Sud - Oncologie Médicale
City
Pierre-Bénite
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Naoual BAKRIN, MD
Email
naoual.bakrin@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Benoit YOU, MD
12. IPD Sharing Statement
Learn more about this trial
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Associated With Systemic Chemotherapy in Women With Advanced Ovarian Cancer
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