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

Phase 1

Completed

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

Interventions: Drug: PIPAC with Abraxane

Registration Number: NCT03304210

Lead Sponsor: University Hospital, Ghent

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Abraxane 35 mg/m²	PIPAC with Abraxane	PIPAC with Abraxane (35 mg/m²) will be administered every 4 weeks for 3 cycles.
Abraxane 70 mg/m²	PIPAC with Abraxane	PIPAC with Abraxane (70 mg/m²) will be administered every 4 weeks for 3 cycles.
Abraxane 90 mg/m²	PIPAC with Abraxane	PIPAC with Abraxane (90 mg/m²) will be administered every 4 weeks for 3 cycles.
Abraxane 112.5 mg/m²	PIPAC with Abraxane	PIPAC with Abraxane (112.5 mg/m²) will be administered every 4 weeks for 3 cycles.
Abraxane 140 mg/m²	PIPAC with Abraxane	PIPAC with Abraxane (140 mg/m²) will be administered every 4 weeks for 3 cycles.

Primary Outcome Measures

Name	Time	Method
Maximally Tolerated Dose (MTD) of Abraxane	Within 14 weeks of the start of the treatment	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.

Secondary Outcome Measures

Name	Time	Method
Surgical Morbidity	6 months after third PIPAC	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
Decreased Platelets - Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	Pre-operatively, and 12 hours, 24 hours and 1 week after each PIPAC	Blood samples will be collected to analyse the amount of platelets.
Maximum Plasma Concentration of Abraxane	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	Abraxane will be measured in plasma, using UPLC-MS/MS.
Area Under The Curve (AUC) of Abraxane	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	Abraxane will be measured in plasma, using LC-MS/MS.
Histological Response Via Peritoneal Regression Grading Scoring (PRGS)	T = 0 minutes, before nebulization	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.
Neutropenia - Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	Pre-operatively, and 12 hours, 24 hours and 1 week after each PIPAC	Blood samples will be collected to analyse the absolute neutrophil count