PIPAC Nab-pac for Stomach, Pancreas, Breast and Ovarian Cancer

Study Overview
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Brief Summary
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The PIPAC nab-pac study is designed to examine the maximal tolerated dose of albumin bound nanoparticle paclitaxel (nab-pac, Abraxane) administered with repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC), in a multicentre, multinational phase I trial.

Detailed Description
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Over 85% of women with ovarian cancer (OC) will develop a peritoneal recurrence after initial therapy. The prognosis of patients with recurrent disease is poor, with a median survival ranging from 12 to 24 months. Most of these patients ultimately develop platinum resistant disease (PROC). Current systemic therapy results in a very modest improvement of progression free and overall survival. The addition of locoregional, intraperitoneal (IP) therapy may improve disease control in recurrent OC. Recently, pressurized intraperitoneal aerosol therapy (PIPAC) was added to the therapeutic arsenal. This novel technique allows repeated laparoscopy aided aerosol delivery of anticancer drugs to the peritoneal cavity. Abraxane (nab-pac, Celgene) is a novel 130 nm, albumin-bound (nab) nanoparticle formulation of paclitaxel which has noteworthy single-agent activity and a favourable toxicity profile when used systemically in PROC. A recent phase I study showed a significant pharmacokinetic advantage after IP instillation of nab-pac in patients with peritoneal carcinomatosis from ovarian or gastro-intestinal (GI) origin. In phase I of this study, dose escalation will be combined with pharmacokinetic/pharmacodynamic modelling which incorporates, in addition to plasma, tumour tissue, and peritoneal drug concentrations, biomarkers of toxicity and efficacy.

Official Title
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Intraperitoneal Aerosolization of Albumin-stabilized Paclitaxel Nanoparticles for Stomach, Pancreas, Breast and Ovarian Cancer

Conditions
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Peritoneal Carcinomatosis, Ovarian Cancer Stage IIIB, Ovarian Cancer Stage IIIC, Ovarian Cancer Stage IV, Breast Cancer Stage IIIB, Breast Cancer Stage IIIc, Breast Cancer Stage IV, Stomach Cancer Stage III, Stomach Cancer Stage IV With Metastases, Pancreas Cancer, Stage III, Pancreas Cancer, Stage IV

Intervention / Treatment
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* Drug: PIPAC with Abraxane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I study: patients with advanced carcinomatosis from ovarian, breast, gastric, or pancreatic origin. No alternative systemic treatment options are available. Age over 18 years Adequate performance status (Karnofsky index > 60%) Absence of intestinal or urinary obstruction Limited size of the majority of peritoneal tumor implants (< 5 mm) Absent or limited ascites Ability to understand the proposed treatment protocol and provide informed consent Expected life expectancy more than 6 months Laboratory data Serum creatinine ≤ 1.5 mg/dl or a calculated GFR (CKD-EPI) ≥ 60 mL/min/1.73 m² Serum total bilirubin ≤ 1.5 mg/dl, except for known Gilbert's disease Platelet count > 100.000/µl Hemoglobin > 9g/dl Neutrophil granulocytes > 1.500/ml No major blood coagulation disorders. Parameters within normal range. Absence of alcohol and/or drug abuse No other concurrent malignant disease Written informed consent Exclusion Criteria: Pregnancy or breast feeding. Women who can become pregnant must ensure effective contraception. Active bacterial, viral or fungal infection Active gastro-duodenal ulcer Parenchymal liver disease (any stage cirrhosis) Uncontrolled diabetes mellitus Psychiatric pathology affecting comprehension and judgement faculty General or local (abdominal) contra-indications for laparoscopic surgery Documented intolerance or allergy to paclitaxel Patients who receive other taxane therapy until three weeks before the first experimental treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abraxane 35 mg/m²<br>PIPAC with Abraxane (35 mg/m²) will be administered every 4 weeks for 3 cycles. | Drug: PIPAC with Abraxane<br>* Albumin bound nanoparticle paclitaxel (Abraxane) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 35 to 140 mg/m². PIPAC will be performed every 4 weeks for 3 cycles.<br>|
| Experimental: Abraxane 70 mg/m²<br>PIPAC with Abraxane (70 mg/m²) will be administered every 4 weeks for 3 cycles. | Drug: PIPAC with Abraxane<br>* Albumin bound nanoparticle paclitaxel (Abraxane) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 35 to 140 mg/m². PIPAC will be performed every 4 weeks for 3 cycles.<br>|
| Experimental: Abraxane 90 mg/m²<br>PIPAC with Abraxane (90 mg/m²) will be administered every 4 weeks for 3 cycles. | Drug: PIPAC with Abraxane<br>* Albumin bound nanoparticle paclitaxel (Abraxane) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 35 to 140 mg/m². PIPAC will be performed every 4 weeks for 3 cycles.<br>|
| Experimental: Abraxane 112.5 mg/m²<br>PIPAC with Abraxane (112.5 mg/m²) will be administered every 4 weeks for 3 cycles. | Drug: PIPAC with Abraxane<br>* Albumin bound nanoparticle paclitaxel (Abraxane) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 35 to 140 mg/m². PIPAC will be performed every 4 weeks for 3 cycles.<br>|
| Experimental: Abraxane 140 mg/m²<br>PIPAC with Abraxane (140 mg/m²) will be administered every 4 weeks for 3 cycles. | Drug: PIPAC with Abraxane<br>* Albumin bound nanoparticle paclitaxel (Abraxane) will be administered intraperitoneally using the PIPAC technique. The administered dose will escalate ranging from 35 to 140 mg/m². PIPAC will be performed every 4 weeks for 3 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally Tolerated Dose (MTD) of Abraxane | The MTD was defined as the highest dose of aerosolized Abraxane, administered 3 times using PIPAC, that does not cause unacceptable side effects. Dose limiting toxicity was recorded in a 14 week-window starting from the first PIPAC and defined a priori as any of the following: 1. any Grade 3 or 4 non-hematologic toxicity excluding fatigue and controllable nausea, vomiting, abdominal pain, and diarrhoea; 2. grade 4 thrombocytopenia; 3. grade 4 neutropenia lasting more than 7 days or associated with fever; 4. failure to perform more than one PIPAC due to toxicity; 5. surgical complication Dindo-Clavien grade IIIB or higher. In order to optimize the balance between safety and efficacy, we used a time-to-event continual reassessment model (TITE-CRM), where an initial design was followed until the first DLT occurred. Conservative a priori estimates of DLT were used to calculate the original dose escalation scheme. | Within 14 weeks of the start of the treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical Morbidity | Surgical complications were scored using the Clavien Dindo classification. Grade I: Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics, analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are opened at the bedside Grade II: Complications requiring drug treatments other than those allowed for Grade I complications; this includes blood transfusion and total parenteral nutrition (TPN) Grade III: Complications requiring surgical, endoscopic or radiological intervention Grade IV: Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient ischaemic attacks (TIAs) Grade V: Death of the patient | 6 months after third PIPAC | 
| Maximum Plasma Concentration of Abraxane | Abraxane will be measured in plasma, using UPLC-MS/MS. | T = 0 minutes, T = 15 minutes, T = 30 minutes, T = 60 minutes, T = 1.5 hour, T = 2 hours, T = 4 hours, T = 8 hours, T = 12 hours, T = 24 hours | 
| Area Under The Curve (AUC) of Abraxane | Abraxane will be measured in plasma, using LC-MS/MS. | T = 0 minutes, T = 15 minutes, T = 30 minutes, T = 60 minutes, T = 1.5 hour, T = 2 hours, T = 4 hours, T = 8 hours, T = 12 hours, T = 24 hours | 
| Histological Response Via Peritoneal Regression Grading Scoring (PRGS) | Punch biopsies are taken at the same location, which are marked with a stainless-steel surgical clip during each PIPAC procedure. Samples are fixed in 4% paraformaldehyde in PBS for 72 hours and embedded in paraffin. Tissues are serially sectioned and stained with haematoxylin & eosin; immunohistochemical staining is performed for epithelial cellular adhesion molecule (EpCAM). The peritoneal regression grading score (PRGS) is determined by a GI pathologist. The mean score of all samples is calculated per treatment, and percentage changes in mean PRGS between successive PIPAC treatments is calculated. The unit of measure represented is the amount of participants in which tumor regression was observed. | T = 0 minutes, before nebulization | 
| Neutropenia - Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Blood samples will be collected to analyse the absolute neutrophil count | Pre-operatively, and 12 hours, 24 hours and 1 week after each PIPAC | 
| Decreased Platelets - Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Blood samples will be collected to analyse the amount of platelets. | Pre-operatively, and 12 hours, 24 hours and 1 week after each PIPAC | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PIPAC, Peritoneal carcinomatosis, Ovarian cancer, Pharmacokinetics, Pharmacodynamics, Safety and efficacy, Abraxane, Breast cancer, Pancreas cancer, Stomach cancer