Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Associated With Systemic Chemotherapy in Women With Advanced Ovarian Cancer

Phase 1RecruitingNCT04811703

Hospices Civils de Lyon15 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥18 years and ≤ 75 years * ECOG PS 0-2 ; * Epithelial stage IIb to IVa 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; * 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)

Locations (6)

Hôpital Claude Huriez - Chirurgie générale et digestive

Lille, France

RECRUITING

Hôpital Claude Huriez - Oncologie médicale

Lille, France

RECRUITING

Hôpital de la Croix-Rousse

Lyon, France

RECRUITING

Hôpital Lyon Sud - Chirurgie Digestive et Oncologique

Pierre-Bénite, France

RECRUITING

Hôpital Lyon Sud - Chirurgie Gynécologique et oncologique-obstétrique

Pierre-Bénite, France

RECRUITING

Hôpital Lyon Sud - Oncologie Médicale

Pierre-Bénite, France

RECRUITING

Outcomes

Primary Outcomes

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

Time frame: First cycle of combined chemotherapy = day 1 up to day 28 of the first cycle

Secondary Outcomes

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.

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

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).

Time frame: After completing chemotherapy treatment, at 4 to 5 weeks after the third cycle of post PIPAC (each cycle is 28 days)

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.

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)]

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.

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.

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.

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)

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.

Time frame: Up to 8 months after inclusion

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Associated With Systemic Chemotherapy in Women With Advanced Ovarian Cancer

Overview

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts