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.

Inclusion Criteria:

• Age ≥ 18 years and ≤ 75 years;

• ECOG Performance Status 0-2;

• Histologically confirmed epithelial carcinoma of the ovary, fallopian tubes, or peritoneum, FIGO stage IIb to IVa, with a tumor response after three cycles of carboplatin-paclitaxel that does not correspond to disease progression but is insufficient to allow complete cytoreductive surgery, as assessed by the investigators after multidisciplinary tumor board discussion and validation;

• Adequate hematological function:

  • Absolute neutrophil count > 1,500/mm³ (or 1.5 × 10⁹/L);
  • Hemoglobin ≥ 9.0 g/dL;
  • Platelet count > 100 × 10⁹/L;

• Adequate renal and hepatic function:

  • Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or estimated glomerular filtration rate ≥ 60 mL/min/1.73 m² (CKD-EPI equation);
  • Total bilirubin ≤ 1.5 × ULN;
  • AST and ALT ≤ 1.5 × ULN (≤ 5 × ULN in patients with liver metastases);

• No unstable medical conditions, including myocardial infarction within 6 months prior to study entry, congestive heart failure, unstable angina, active cardiomyopathy, unstable arrhythmia, uncontrolled hypertension, uncontrolled psychiatric disorders, severe infection, peptic ulcer disease, or any condition that could be worsened by the study treatment or impair compliance, as judged by the investigator;

• Written informed consent obtained prior to any study-specific procedures;

• Patient affiliated with a national health insurance system.

Exclusion Criteria:

• Extra-peritoneal metastases whose location or extent precludes a potentially curative surgical procedure;

• Signs of bowel obstruction, bowel lesions with a high risk of intestinal perforation based on their location, or evidence of inflammatory bowel disease;

• Contraindication to intravenous carboplatin-paclitaxel chemotherapy, including known severe hypersensitivity to paclitaxel;

• Contraindication to PIPAC procedures, including:

  • Known hypersensitivity to cisplatin or other platinum compounds;
  • Known hypersensitivity to doxorubicin or other anthracyclines or anthracenediones;
  • Cardiac disease with myocardial insufficiency;
  • Uncontrolled coronary artery disease;

• Known hypersensitivity to sodium thiosulfate, sulfites, or any of its excipients;

• Administration of a live attenuated vaccine within 3 months prior to study treatment initiation or planned during the study;

• Pregnant or breastfeeding women;

• Individuals deprived of liberty, under guardianship, or subject to legal protection measures;

• Participation in another interventional research study with an ongoing exclusion period at inclusion, or in a study that could interfere with the results of the present study, as judged by the investigator;

• Inability to comply with study follow-up for geographical, social, or psychological reasons, as judged by the investigator.