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NCT Number: NCT04811703

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

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.

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Key information

Conditions

Metastatic Ovarian Carcinoma Abdominal Neoplasms Adnexal Diseases Carcinoma Carcinoma, Ovarian Epithelial Digestive System Diseases Digestive System Neoplasms Endocrine Gland Neoplasms Endocrine System Diseases Fallopian Tube Diseases Fallopian Tube Neoplasms Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Genital Neoplasms, Female Gonadal Disorders Metastatic Malignant Neoplasm in the Peritoneum Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Ovarian Diseases Ovarian Neoplasms Peritoneal Carcinomatosis Peritoneal Diseases Peritoneal Neoplasms Stage III Fallopian Tube Cancer Stage III Ovarian Cancer Stage IV Fallopian Tube Cancer Stage IV Ovarian Cancer Urogenital Diseases Urogenital Neoplasms

Age range

18 year–75 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 1

Primary location

Hôpital Claude Huriez - Chirurgie générale et digestive, Lille, France

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for 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.

Treatment and study plan

Combined PIPAC / IV chemotherapy treatment

Drug

Addition of cisplatin-doxorubicin (with or without sodium thiosulfate according to the cisplatin dose level) PIPAC sessions to carboplatin-paclitaxel systemic Chemotherapy

Primary outcomes

  1. Dose-limiting toxicities

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

    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 outcomes

  1. Rate of complete surgical resection

    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

    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.

  2. Proportion of complete, partial or stabilized tumor response

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

    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).

  3. Peritoneal cancer index (PCI) evolution

    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)]

    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.

  4. Area under the curve (AUC) for plasma concentration of DOXORUBICIN and CISPLATIN

    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.

    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.

  5. Change in CA-125 concentration

    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)

    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.

  6. Rates of adverse events and operative complications

    Time frame: Up to 8 months after inclusion

    Adverse events according to the NCI CTCAE v5.0 classification (including toxicities) and per- and post-operative complications according to the Clavien-Dindo classification.

  7. Evaluation of sodium thiosulfate-associated nephroprotection during PIPAC procedures : Change in serum creatinine levels

    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

    Serum creatinine levels will be measured before each treatment (PIPAC or intravenous chemotherapy) and after each PIPAC procedure.

  8. Evaluation of sodium thiosulfate-associated nephroprotection during PIPAC procedures : Change in estimated glomerular filtration rate (eGFR)

    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

    Estimated glomerular filtration rate (eGFR) will be measured before each treatment (PIPAC or intravenous chemotherapy) and after each PIPAC procedure.

Study contacts

Contact information is provided by the study sponsor or research team.

Justine ARQUILLIERE, MD

CONTACT

[email protected]

04 78 86 23 71 ext. +33

Naoual BAKRIN, MD

CONTACT

[email protected]

04 78 86 23 71 ext. +33

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Official study 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

Acronym: PIPACOVA

Important dates

Study start
2021
Primary completion
2028
Study completion
2029
First posted
Mar 23, 2021
Registry last updated
May 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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