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

ConditionsMetastatic Ovarian CarcinomaPeritoneal CarcinomatosisStage III Ovarian CancerStage III Fallopian Tube CancerMetastatic Malignant Neoplasm in the PeritoneumStage IIb Ovarian CancerStage IVa Ovarian CancerStage IVa Fallopian Tube CancerStage IIB Fallopian Tube Cancer
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexFemale
Age18-75
SponsorHospices Civils de Lyon

About this trial

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).

Since the 7th amendment of the study, sodium thiosulfate as nephrtoxicity prevention has been administered concurrently with each PIPAC chemotherapy

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).

Following the addition of sodium thiosulfate to the treatment regimen, an exploratory objective was added to assess its nephroprotective effects 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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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;

Absolute neutrophil count > 1,500/mm³ (or 1.5 × 10⁹/L);

Disqualifiers

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;

Known hypersensitivity to cisplatin or other platinum compounds;

Trial design

Design model

Single group

Treatments tested in this trial

  • Combined PIPAC / IV chemotherapy treatment

    Drug

    Addition of cisplatin-doxorubicin PIPAC sessions to carboplatin-paclitaxel systemic Chemotherapy Auxiliary treatment : Since amendment n°7,, sodium thiosufate thiosulfate as nephrtoxicity prevention during each PIPAC sessions

Treatment groups

15 Participants
are divided into 1 treatment group
Group A: Combined PIPAC / IV chemotherapy treatmentExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

1

Dose-limiting toxicities

Dose-limiting toxicities (DLTs) will be defined as any event occurring during the first treatment cycle and considered by the investigator as possibly related to treatment, according to NCI CTCAE v5.0. DLTs include: Grade 4 neutropenia (absolute neutrophil count \<500/mm³ \[0.5 × 10⁹/L\]) lasting ≥7 consecutive days; Grade ≥3 neutropenia (absolute neutrophil count \<1000/mm³ \[1 × 10⁹/L\]) associated with a temperature ≥38.5°C; Grade 4 thrombocytopenia (\<25,000/mm³ platelets \[25 × 10⁹/L\]) or Grade 3 thrombocytopenia (\<50,000/mm³ \[50 × 10⁹/L\]) associated with bleeding; Grade ≥3 non-hematological toxicity despite adequate medical intervention, excluding non-life-threatening toxicities such as alopecia or asymptomatic hypophosphatemia; and Grade ≥2 acute kidney injury according to the 2024 KDIGO classification, defined as at least a twofold increase in serum creatinine compared with baseline.

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

Secondary outcomes

1

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
2

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)
3

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)]
4

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.

Other outcomes

Sponsors and contacts

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Hospices Civils de Lyon

Lead sponsor

Source ClinicalTrials.gov
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