Clinical trial NCT04811703: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Associated With Systemic Chemotherapy in Women With Advanced Ovarian Cancer
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Metastatic Ovarian Carcinoma
Peritoneal Carcinomatosis
Stage III Ovarian Cancer
Stage IV Ovarian Cancer
Stage III Fallopian Tube Cancer
Stage IV Fallopian Tube Cancer
Metastatic Malignant Neoplasm in the Peritoneum
Keywords: Dose escalation
Phase I study
Intravenous Chemotherapy
Intraperitoneal chemotherapy
PIPAC
RP2D
cytoreductive surgery
Ovarian epithelial cancer
peritoneal cancer
doxorubicin
cisplatin
CA-125 antigen
pharmacokinetic
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2021-03-23
Enrollment: 15
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Dose-limiting toxicities
timeFrame: First cycle of combined chemotherapy = day 1 up to day 28 of the first cycle
Secondary outcomes:
measure: Rate of complete surgical resection
timeFrame: 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
measure: Proportion of complete, partial or stabilized tumor response
timeFrame: After completing chemotherapy treatment, at 4 to 5 weeks after the third cycle of post PIPAC (each cycle is 28 days)
measure: Peritoneal cancer index (PCI) evolution
timeFrame: 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)]
measure: Area under the curve (AUC) for plasma concentration of DOXORUBICIN and CISPLATIN
timeFrame: 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.
measure: Change in CA-125 concentration
timeFrame: 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)
measure: Rates of adverse events and operative complications
timeFrame: Up to 8 months after inclusion
Other outcomes:
Locations:
city: Lille
country: France
facility: Hôpital Claude Huriez - Chirurgie générale et digestive
city: Lille
country: France
facility: Hôpital Claude Huriez - Oncologie médicale
city: Lyon
country: France
facility: Hôpital de la Croix-Rousse
city: Pierre-Bénite
country: France
facility: Hôpital Lyon Sud - Chirurgie Digestive et Oncologique
city: Pierre-Bénite
country: France
facility: Hôpital Lyon Sud - Chirurgie Gynécologique et oncologique-obstétrique
city: Pierre-Bénite
country: France
facility: Hôpital Lyon Sud - Oncologie Médicale
Study officials:
affiliation: Hospices Civils de Lyon
name: Justine ARQUILLIERE, MD
role: PRINCIPAL_INVESTIGATOR
References: