Women with a history of tumor response insufficient to allow complete cytoreductive surgery after three cycles of prior neoadjuvant systemic carboplatin-paclitaxel chemotherapy will be prospectively enrolled in this phase I study. After providing written informed consent and confirmation of unresectable disease by multidisciplinary assessment, patients will undergo three cycles of combined chemotherapy consisting of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with doxorubicin and cisplatin at escalating dose levels, combined with systemic intravenous chemotherapy using carboplatin and paclitaxel at standard doses. Treatment cycles will last 28 days, with PIPAC administered on Day 1 and systemic chemotherapy on Day 8, for a maximum of three cycles in the absence of unacceptable toxicity. Dose escalation of PIPAC chemotherapy will follow a Continual Reassessment Method (CRM) algorithm. The first patient will be treated at the lowest dose level, and subsequent patients will receive the recommended dose according to the CRM, conditional on the occurrence of dose-limiting toxicity (DLT) observed during Cycle 1. From dose level 7 onward, corresponding to cisplatin and doxorubicin doses associated with an increased risk of renal toxicity, sodium thiosulfate will be systematically administered prior to each PIPAC procedure for its nephroprotective effect, in accordance with the cisplatin dose level and current clinical practice. The primary objective of the study is to determine the maximum tolerated dose (MTD) of doxorubicin-cisplatin administered by PIPAC and to define the recommended dose for a subsequent phase II trial. DLTs will be actively collected and reviewed as soon as they are identified during the first treatment cycle. Secondary objectives include evaluation of pathological response, radiological tumor response, and changes in the extent of peritoneal disease following combined chemotherapy, as well as characterization of the pharmacokinetics of PIPAC-administered drugs. Additional exploratory objectives include assessment of the KELIM parameter as a predictive marker of sensitivity to combined chemotherapy and evaluation of the overall safety profile of the treatment strategy. On Day 1 of the first treatment cycle, blood samples will be collected for pharmacokinetic analysis of doxorubicin and cisplatin. Serum CA-125 levels will be measured before each intraperitoneal or intravenous chemotherapy administration throughout the study. At the end of combined chemotherapy, radiological tumor assessment by CT scan or MRI and a final CA-125 measurement will be performed. Patients achieving complete response, partial response, or stable disease according to RECIST v1.1 criteria will undergo re-evaluation for surgical resectability. If complete cytoreductive surgery is deemed feasible, surgery will be scheduled with a post-operative follow-up visit planned one month later. Patients with progressive or persistently unresectable disease will discontinue study participation.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Addition of cisplatin-doxorubicin (with or without sodium thiosulfate according to the cisplatin dose level) PIPAC sessions to carboplatin-paclitaxel systemic Chemotherapy
Hôpital Claude Huriez - Chirurgie générale et digestive
Lille, France
RECRUITINGHôpital Claude Huriez - Oncologie médicale
Lille, France
RECRUITINGHôpital de la Croix-Rousse
Lyon, France
RECRUITINGHôpital Lyon Sud - Chirurgie Digestive et Oncologique
Pierre-Bénite, France
RECRUITINGHôpital Lyon Sud - Chirurgie Gynécologique et oncologique-obstétrique
Pierre-Bénite, France
RECRUITINGHôpital Lyon Sud - Oncologie Médicale
Pierre-Bénite, France
RECRUITINGDose-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
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
Evaluation of sodium thiosulfate-associated nephroprotection during PIPAC procedures : Change in serum creatinine levels
Serum creatinine levels will be measured before each treatment (PIPAC or intravenous chemotherapy) and after each PIPAC procedure.
Time frame: From baseline to after each PIPAC procedure, assessed at the end of each treatment cycle (each cycle defined as 28 days), for up to 3 cycles
Evaluation of sodium thiosulfate-associated nephroprotection during PIPAC procedures : Change in estimated glomerular filtration rate (eGFR)
Estimated glomerular filtration rate (eGFR) will be measured before each treatment (PIPAC or intravenous chemotherapy) and after each PIPAC procedure.
Time frame: From baseline to after each PIPAC procedure, assessed at the end of each treatment cycle (each cycle defined as 28 days), for up to 3 cycles
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