Clinical trial NCT03304210
Conditions: 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
Keywords: PIPAC Peritoneal carcinomatosis Ovarian cancer Pharmacokinetics Pharmacodynamics Safety and efficacy Abraxane Breast cancer Pancreas cancer Stomach cancer
Sponsor: University Hospital, Ghent
Start date: 2017-09-16; Completion date: 2020-05-06
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: PIPAC with Abraxane (35 mg/m²) will be administered every 4 weeks for 3 cycles. arm 2: PIPAC with Abraxane (70 mg/m²) will be administered every 4 weeks for 3 cycles. arm 3: PIPAC with Abraxane (90 mg/m²) will be administered every 4 weeks for 3 cycles. arm 4: PIPAC with Abraxane (112.5 mg/m²) will be administered every 4 weeks for 3 cycles. arm 5: PIPAC with Abraxane (140 mg/m²) will be administered every 4 weeks for 3 cycles.
Interventions: intervention 1: PIPAC with Abraxane
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol 1, version 4, dd 03/07/2018 
1 
INTRAPERITONEAL AEROSOLISATION OF ALBUMIN-STABILIZED PACLITAXEL NANOPARTICLES FOR 
PERITONEAL CARCINOMATOSIS – PHASE I/II STUDY PROTOCOL 
 
1 Trial number 
 
Protocol nr: AGO/2017/003 
EudraCT: 2017-001688-20  
 
2 Objective of the study 
2.1 Primary objective 
To study the safety and efficacy of IV paclitaxel combined with repeated pressurized 
intraperitoneal aerosol therapy (PIPAC) using albumin bound nanoparticle paclitaxel (nab-pac, 
Abraxane) in a multicentre, multinational phase I/II trial. 
2.2 Primary endpoint 
Phase I: Maximally tolerated dose of Abraxane, administered every four weeks using 
intraperitoneal laparoscopy-assisted aerosolisation (PIPAC) 
Phase II: Progression free survival, measured from the day of randomization 
2.3 Secondary endpoints 
Phase I:  
- 
Surgical morbidity and mortality of laparoscopy 
- 
Technical failure rate 
- 
Pathological response rate 
- 
Pharmacokinetic/Pharmacodynamic analysis 
- 
Quality of life at 2 and 6 months after third PIPAC 
Phase II:  
- 
Surgical morbidity and mortality of laparoscopy 
- 
Technical failure rate 
- 
Pathological response rate 
- 
Overall survival 
- 
Disease free survival 
 
3 General information 
3.1 Investigators 
 
Trial coordinator: 
 
Prof. dr. Wim Ceelen 
Ghent University Hospital – Department of gastro-intestinal surgery 
Corneel Heymanslaan 10, 9000 Ghent, Belgium 


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2 
Tel +32 9332 6251 
Fax +32 9332 1503 
Wim.Ceelen@UGent.be 
 
Co-investigators: 
 
dr. Wouter Willaert 
Ghent University Hospital – Department of gastro-intestinal surgery 
Corneel Heymanslaan 10, 9000 Ghent, Belgium 
Tel +32 9332 8950 
Wouter.Willaert@UGent.be 
 
Leen Van de Sande 
Ghent University – Department of surgery 
Corneel Heymanslaan 10, 9000 Ghent, Belgium 
Tel +32 9332 1564 
Leen.VandeSande@UGent.be 
 
Prof. dr. Hannelore Denys 
Ghent University Hospital – Department of medical oncology 
Corneel Heymanslaan 10, 9000 Ghent, Belgium 
Tel +32 9332 3862 
Hannelore.Denys@UGent.be 
 
Dr Philippe Tummers 
Ghent University Hospital – Department of Gynecological Oncology 
Corneel Heymanslaan 10, 9000 Ghent, Belgium 
Tel +32 9332 0338 
Philippe.tummers@uzgent.be 
 
dr. Pieter Colin 
Ghent University – Department of bioanalysis 
Ottergemsesteenweg 460, 9000 Ghent, Belgium 
Tel +32 9264 8114 
Pieter.Colin@UGent.be 
 
Prof. dr. Els Goetghebeur 
Ghent University – Department of Applied Mathematics, Computer Science and Statistics  
Krijgslaan 281 (S9), 9000 Ghent, Belgium 
Tel +32 9264 4811 
Els.Goetghebeur@UGent.be 
 
Dries Reynders 
Ghent University  - Department of Applied Mathematics, Computer Science and Statistics 
Krijgslaan 281, S9 - 9000 Gent, België 
tel +32 9264 9686  
Dries.Reynders@UGent.be 


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3 
 
Prof. dr. Katrien Remaut 
Ghent University – Laboratory for general biochemistry and physical pharmacy 
Harelbekestraat 72, 9000 Ghent, Belgium 
Tel +32 9264 8046 
Katrien.Remaut@UGent.be 
 
Prof. Marc Pocard 
Lariboisière hospital – Digestive and cancer surgical unit 
Rue Ambroise-Paré 2, 75475 Paris Cedex 10, France 
Tel +33 149 95 82 58 
Marc.Pocard@Gmail.com 
 
Prof. Marc Reymond 
Director, PIPAC Program 
Dept. of Surgery and Transplantation 
University Hospital 
Hoppe-Seyler-Strasse 3 
D - 72076 Tübingen (Germany) 
marc.reymond@med.uni-tuebingen.de 
Tel: +49 (0)7071 29-86722 
 
Dr. Marco Vaira 
Candiolo cancer institute – IRCCS 
Strada Provinciale 142, 10060 Candiolo (Torino), Italy 
Tel +39 1199 33111 
Marco.Vaira@ircc.it 
 
Dr. Martin Hubner 
Centre hospitalier universitaire Vaudois – FMH chirurgie viscérale 
Rue du Bugnon 21, 1011 Lausanne (Vaud), Suisse 
Tel +41 2131 42400 
Martin.Hubner@chuv.ch 
 
Dr Martin Graversen 
Staff Specialist 
Odense PIPAC Center 
Upper GI & HPB Section, Department of Surgery, 
Odense University Hospital, 
Sdr.Boulevard, DK-5000 Odense C, Denmark 
Phone: +45 2617 2081 
Martin.Graversen@rsyd.dk 
 
3.2 Sponsor 
 
Ghent University Hospital, B-9000 Ghent, Belgium  


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3.3 Departments/laboratories involved in the study 
 
1. Ghent University / Ghent University Hospital 
 Department of gastro-intestinal surgery; 
 Department of medical oncology; 
 Department of bioanalyses; 
 Department of Applied Mathematics, Computer Science and Statistics  
 Laboratory for general biochemistry and physical pharmacy. 
 
2. Digestive and cancer surgical unit, Lariboisière Hospital, Paris, France 
 
3. Dept. of Surgery and Transplantation, Tübingen University Hospital, Tübingen, 
Germany 
 
4. Department of Surgery, Candiolo cancer institute – IRCCS, Torino, Italy 
 
5. FMH chirurgie viscérale, Centre hospitalier universitaire Vaudois, Geneva, 
Switzerland 
 
6. Department of Surgery, Odense University Hospital, Denmark 
 


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4 Introduction 
In the European Union, approximately 44000 women are diagnosed with ovarian cancer (OC) 
every year (eco.iarc.fr/eucan/CancerOne.aspx?Cancer=27&Gender=2). The cancer specific 
mortality in these patients is over 67%. Ovarian cancer represents the second most common 
gynecological malignancy (1). Almost 70% of affected women is diagnosed with stage IIIC 
disease, and only a modest improvement in survival has been achieved over the last two 
decades. Even after achieving a complete remission induced by a combination of platinum 
based chemotherapy and surgery, over 85% of patients will develop a peritoneal recurrence 
originating from peritoneal minimal residual disease. The prognosis of patients with recurrent 
disease is poor, with a median survival ranging from 12 to 24 months. Platinum resistance 
eventually occurs in virtually all patients with recurrent OC. It includes patients with a very 
heterogeneous group of tumors; those who do not respond to first-line therapy (platinum 
refractory), relapse within 6 months of treatment, or relapse within 6 months of several lines 
of treatment for recurrent disease. In selected patients with recurrent disease, cytoreductive 
surgery with or without intraperitoneal (IP) chemotherapy may result in a survival benefit 
(2,3). However, the morbidity of repeated surgery is considerable, and a complicated 
postoperative course may render further systemic treatment impossible. 
 
Recently, the technique of laparoscopic pressurized IP aerosol chemotherapy (PIPAC) was 
introduced in clinical practice (4). During laparoscopy, chemotherapy is delivered as an 
aerosol, generated by a dedicated micropump connected to a high-pressure injector. 
Advantages of PIPAC include minimal patient discomfort, possibility of repeated delivery, 
potential to combine with systemic treatment, and possibility to assess pathological response 
of peritoneal disease by serial biopsies. A recent prospective cohort study in women with 
peritoneal carcinomatosis (of which 84% OC) showed that repeated PIPAC resulted in an 
objective response (histological regression after first procedure) in 76%, a significant decrease 
in peritoneal cancer index, and a significantly decreased ascites volume (5). 
 
In theory, any cancer drug may be delivered IP as an aerosol. The taxanes are ideal candidates 
for IP administration because of their activity profile and molecular size. The potential of 
Taxol™ for IP administration is, however, limited by the local toxicity and potential of 
hypersensitivity reactions associated with the Cremophor EL™ component. Abraxane® 
(Celgene) is a novel 130 nm albumin-bound (nab™) nanoparticle formulation of paclitaxel 
which has demonstrated activity in metastatic breast, pancreatic, and non-small cell lung 
cancer (6). In platinum resistant OC, a phase II study showed that nab-paclitaxel by 
intravenous administration has noteworthy single-agent activity and a favorable toxicity 
profile (7). Preclinical studies have demonstrated that IP administration of nano- and 
microsized formulations of paclitaxel results in superior antitumor activity against mouse OC 
xenografts compared to intravenous administration (8). 
In clinical studies, paclitaxel has been shown to be highly bound to protein, with Cremophor 
EL™ further decreasing the unbound fraction of the drug (1,2). The advantage of Abraxane is 
its water solubility, achieved without the use of Cremophor EL™ and ethanol. Gardner et al. 
(3) reported that the formulation of Abraxane allowed a much higher fraction of unbound 
paclitaxel than that of Taxol™, and that the maximal concentration of unbound paclitaxel was 
~10-fold higher for Abraxane in their pharmacologic study.  
A comparative in vivo study was set up by Kinoshita et al. (4) to evaluate the antitumor activity 
after intraperitoneal (IP) administration of Abraxane and paclitaxel. Female athymic nude 


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mice bearing peritoneal carcinomatosis were divided into three groups: a control group (n = 
5), an Abraxane (IP) treatment group (n = 5) and a paclitaxel (IP) treatment group (n = 5). 
Antitumor activity was compared among these three groups at equitoxic doses, as determined 
by Desai et al (5). After tumor inoculation on day 0, drug treatment was initiated on day 7, and 
drug was administered once daily for 7 consecutive days. The Abraxane treatment group 
showed significantly (p < 0,05) greater antitumor activity than the paclitaxel treatment group 
(figure 1). All five mice in the control group developed ascites and died within 19 – 32 days 
after tumor cell inoculation; the median survival time was 25 days. At equitoxic doses, the 
median survival time was 96 days for the paclitaxel treatment group and 126 days for the 
Abraxane treatment group (figure 2). As such, in vivo studies performed in mice have shown 
the noteworthy antitumor activity of IP administration of Abraxane compared to IP 
administration of paclitaxel. 
 
 
Figure 1: Antitumor activity at equitoxic doses of paclitaxel (Sb-PTX) and Abraxane (Nab-PTX) 
(4). 
 
 
 
 
Intraperitoneal catheter based delivery of Abraxane® was recently studied in a phase I clinical 
trial in advanced carcinomatosis patients. The maximum tolerated dose of IP nab-paclitaxel 
was 140 mg/m²; dose limiting toxicities included grade 3 neutropenia, grade 3 abdominal pain 
and grade 4 neutropenia. Over the four dose levels, there was a 150-fold pharmacokinetic 
advantage (intraperitoneal versus plasma) with low intra-patient variability (9). 


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5 Patients and methods 
5.1 Study design 
During the phase I part of this study, dose escalation will be combined with 
pharmacokinetic/pharmacodynamic modelling which incorporates, in addition to plasma, 
tumor tissue, and peritoneal drug concentrations, biomarkers of toxicity and efficacy including 
caspase-cleaved cytokeratin 18, CA 125 and human epididymal secretory protein (HE4). 
During the phase II part of the study, ovarian cancer patients will be randomized to either 
weekly paclitaxel IV (days 1, 8, 15 every 4 weeks for 6 cycles) or the same schedule combined 
with three PIPAC treatments (every 4 weeks). 
5.2 Intraperitoneal Drug Delivery 
5.2.1 Abraxane 
5.2.1.1 Composition and dosing 
Abraxane® (nanoparticle albumin-bound paclitaxel, nab-pac, ABI-007) is approved in the US 
and EU for the treatment of metastatic breast cancer, locally advanced or metastatic non-
small cell lung cancer (NSCLC), and metastatic adenocarcinoma of the pancreas as first-line 
treatment, in combination with gemcitabine. The date of issue of marketing authorisation 
from the European Medicines Agency was 11/01/2008 (Agency product number 
EMEA/H/C/000778). 
 
The recommended intravenous dose is 100-260 mg/m2. A recent clinical trial in carcinomatosis 
patients using repeated intraperitoneal instillation of Abraxane suggested a maximum 
tolerated dose (MTD) of 140 mg/m². Therefore, in the phase I part of the present study, the 
dose levels for PIPAC will be 35, 70, 90, 112.5, and 140 mg/m2. 
 
After creation of a CO2 pneumoperitoneum, the Abraxane® aerosol is generated by a 
micropump with a 200 µm nozzle (Capnomed GmbH, Villingendorf, Germany) which delivers 
a polydisperse aerosol with a flowrate of 30 ml/min. The aerosol is left in the peritoneal cavity 
during 30 minutes and evacuated afterwards. 
5.2.1.2 Producer 
Celgene Europe Limited, 1 Longwalk Road, Stockley Park, Uxbridge UB11 1DB, United Kingdom 
5.2.1.3 Distributor 
The drug will be purchased by the participating centers from Celgene. 
 
5.2.1.4 Packaging 
Abraxane® is a white to yellow powder for the production of an infusion suspension. Abraxane® 
is available in glass vials containing 100 mg or 250 mg paclitaxel as albumin-bound 
nanoparticle formulation. 


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5.2.1.5 Route of Administration 
Abraxane® will be administered into the peritoneal cavity (IP) using the PIPAC-technique. 
5.2.1.6 Labelling 
This is a commercialized product and the commercially available labelling will be used. 
The following particulars will be added to the original packaging, but will not obscure the 
original labelling: 
 
i)    Sponsor: Ghent University Hospital 
ii)   Study reference code: AGO/2017/003 
iii)  Subject number  
iv)  Address & phone number of the sponsor or investigator 
v)   Direction for use 
vi)  For clinical trial use only 
5.2.1.7 Storage conditions 
Abraxane® as a powder: 
Unopened vials with Abraxane® are stable up to the date indicated on the package, when the 
vial is stored in the outer carton to protect the contents from light. The stability of the drug is 
not affected by either freezing or storage in the refrigerator. No special storage conditions are 
required for this medicinal product. 
 
Abraxane® in a reconstituted suspension in the vial: 
After the first reconstitution, the suspension should be immediately filled into an infusion bag. 
The chemical and physical stability will be preserved at 2 - 8 °C in the original box and 
protected against bright light for 8 hours. 
 
Abraxane® in a reconstituted suspension in the infusion bag: 
After reconstitution, the reconstituted suspension in the infusion bag should be used 
immediately. The chemical and physical stability until application was established at a 
maximum temperature of 25°C for 8 hours. 
5.2.1.8 Known side effects of the medication 
Abraxane® is currently approved for intravenous (IV) use only. The known side effects after IV 
administration are listed below. In the present study, Abraxane® is administered 
intraperitoneally. It is expected that the side effects will be less severe as compared to 
intravenous administration due to the presence of the peritoneum-blood barrier. To date, 
only one study has examined IP administration of Abraxane (Cristea et al. Pharmacologic 
advantage (PA) of intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies 
primarily confined to the peritoneal cavity. J Clin Oncol 33, 2015 (suppl; abstr 2553)). Patients 
received IP nab-paclitaxel on D1, 8, 15 of a 28-day cycle with a 3+3 dose-escalation design, 
with the dose ranging from 35mg/m2 - 170mg/m2. The MTD was established at 140 mg/m2, 
with dose limiting toxicities including grade 3 neutropenia resulting in treatment delay >15 
days, grade 3 abdominal pain, and grade 4 neutropenia > 7 days. Pharmacokinetic analysis 
showed a clear advantage of IP administration, with plasma AUC’s resulting from IP nab-


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paclitaxel at the MTD of 140 mg/m2 similar to plasma AUC’s associated with IV nab-paclitaxel 
at 100 mg/m2. 
 
Very common side effects (may affect more than 1 out of 10 patients): 
- 
hair loss (the majority of cases of hair loss occurred within less than one month after 
the start of treatment with Abraxane®. In addition to this, hair loss is pronounced (more 
than 50 %) in the majority of cases); 
- 
rash; 
- 
decrease in the number of white blood cells (neutrophilic granulocytes, lymphocytes 
or leukocytes); 
- 
lack of red blood cells; 
- 
decrease of blood platelets; 
- 
impact on peripheral nerves (pain, numbness, tingling or loss of tactile sensation); 
- 
pain in one or more joints; 
- 
pain in the muscles; 
- 
nausea, diarrhea, constipation, inflammation of the oral mucosa, loss of appetite; 
- 
sickness; 
- 
weakness and fatigue, fever; 
- 
internal dehydration, taste disorders, weight loss; 
- 
decreased potassium levels in the blood; 
- 
depression, sleeping disorders; 
- 
headache; 
- 
shivering; 
- 
difficulty in breathing; 
- 
dizziness; 
- 
swelling of mucous membranes; 
- 
increased liver values; 
- 
pain in the limbs; 
- 
coughing; 
- 
stomach pain; 
- 
nose bleedings. 
 
Frequent side effects (may affect up to 1 out of 10 patients): 
- 
itching, dry skin, nail disorders; 
- 
infection, fever with a decrease of white blood cells (neutrophilic granulocytes), 
reddening with heat sensation, oror; 
- 
decrease in the number of all blood cells; 
- 
chest pain or throat pain; 
- 
digestive disorders, stomach discomfort; 
- 
stuffy nose; 
- 
back pain, bone pain; 
- 
reduced or difficult muscle coordination; 
- 
difficulty reading, increased or decreased tear flow, loss of eyelashes; 
- 
changes of heart rate or heart rhythm, heart failure; 
- 
decreased or increased blood pressure; 
- 
redness or swelling at the entrance of the needle into the skin; 
- 
anxiety; 


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- 
infections of the lungs; 
- 
urinary tract infection; 
- 
intestinal narrowing, colon inflammation, bile duct inflammation; 
- 
acute renal failure; 
- 
increased bilirubin concentration in blood; 
- 
hemoptysis; 
- 
dry mouth, swallowing complaints; 
- 
muscle weakness; 
- 
blurred vision. 
 
Occasional side effects (may affect up to 1 out of 100 patients): 
- 
weight gain, increase of lactate dehydrogenase in blood, impaired renal function, 
increased glucose level in blood, increased phosphate level in blood; 
- 
reduced or absent reflexes, involuntary movements, pain along a nerve, fainting, 
dizziness while standing, trembling, paralysis of the facial nerve; 
- 
irritated, painful, red or itchy eyes, reduced eyesight, blurred vision due to nasal 
congestion (cystoid macular edema); 
- 
earache, tinnitus; 
- 
productive cough, shortness of breath when walking or climbing stairs, runny nose or 
dry nose, reduced breathing, water in the lungs, loss of voice, blood clot in the lungs, 
dry throat; 
- 
bloating, stomach cramps, aching or sore gums, rectal bleeding; 
- 
painful urination, frequent urination, blood in the urine, inability to hold the urine; 
- 
fingernail pain, fingernail discomfort, fingernail loss, hives, red skin by sunlight, skin 
discoloration, sweating, night sweats, white areas on the skin, sore spots, swollen face; 
- 
reduced phosphorus levels in the blood, accumulation of water, low albumin levels in 
the blood, increased thirst, decreased calcium levels in the blood, decreased sodium 
levels in the blood; 
- 
pain and swelling in the nose, skin infections, infections due to the catheter; 
- 
bruises; 
- 
pain at the tumor site; 
- 
hypotension when standing up, cold hands and feet; 
- 
difficulty walking, swelling; 
- 
allergic reaction; 
- 
decreased liver function, enlarged liver; 
- 
pain in the chest; 
- 
restlessness; 
- 
small hemorrhages caused by blood clots; 
- 
a condition that results in red blood cell destruction and acute kidney failure. 
 
 
 
Rare side effects (may affect up to 1 out of 1000 patients): 
- 
skin reaction to another substance or inflammation of the lungs after irradiation; 
- 
blood clot; 
- 
strongly slow pulse, heart attack; 
- 
leakage of drugs out of the veins; 


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- 
a disturbance of the cardiac electrical conduction system (atrioventricular block). 
 
Very rare side effects (may affect up to 1 out of 10 000 patients): 
- 
Severe inflammation/rash of the skin and mucous membranes (Stevens-Johnson 
syndrome, toxic epidermal necrolysis). 
5.2.2 Paclitaxel (intravenous use only in the Phase II randomized part) 
5.2.2.1 Composition and dosing 
Paclitaxel vials contain 30 mg, 100 mg, 150 mg or 300 mg paclitaxel as 6 mg/ml solution. 
The following dose will be administered to patients in the phase II trial: 60 mg/m2 body surface 
area, repeated 9x over 12 weeks. The total dose will be 540 mg/m2. 
5.2.2.2 Producer 
Paclitaxel is available as a generic molecule from numerous manufacturers.  
5.2.2.3 Distributor 
Local pharmacy of the participating centers 
5.2.2.4 Packaging 
Concentrate for solution for infusion. 
Paclitaxel concentrate for solution for infusion is a clear, colourless or slightly yellow, 
viscous solution. 
5.2.2.5 Route of Administration 
Intravenous 
5.2.2.6 Labelling 
This is a commercialised product and the commercially available labelling will be used. 
The following particulars will be added to the original packaging, but will not obscure the 
original labelling: 
 
i)   Sponsor: Ghent University Hospital 
ii)  Study reference code: AGO/2017/003 
iii) Subject number  
iv) Address & phone number of the sponsor or investigator 
v)  Direction for use 
vi) For clinical trial use only 
5.2.2.7 Storage conditions 
Before and after opening: Do not store above 25°C. Store in original package in order to 
protect from light. 
Diluted solutions: Do not refrigerate or freeze diluted solutions. 
5.2.2.8 Known side effects of the medication 
Cardiovascular 


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Very common (10% or more): Hypotension 
Common (1% to 10%): Bradycardia 
Uncommon (0.1% to 1%): Cardiomyopathy, asymptomatic ventricular tachycardia, 
tachycardia with bigeminy, atrioventricular block and syncope, myocardial infarction, 
hypertension, thrombosis, thrombophlebitis  
Rare (0.01% to 0.1%): Cardiac failure 
Very rare (less than 0.01%): Atrial fibrillation, supraventricular tachycardia, shock 
Frequency not reported: Phlebitis 
 
Dermatologic 
Very common (10% or more): Alopecia (90%), rash 
Common (1% to 10%): Transient and mild nail and skin changes, discoloration of the nail bed  
Rare (0.01% to 0.1%): Pruritus, rash, erythema  
Very rare (less than 0.01%): Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), 
erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy 
should wear sun protection on hands and feet), scleroderma-like reaction 
 
Gastrointestinal 
Very common (10% or more): Nausea (52%), mucositis (31%), vomiting, diarrhea mucosal 
inflammation 
Rare (less than 0.1%): Peritonitis, bowel obstruction, bowel perforation, ischemic colitis, 
pancreatitis 
Very rare (less than 0.01%): Pseudomembranous colitis, mesenteric thrombosis, neutropenic 
colitis, esophagitis, constipation, ascites 
 
Hematologic 
Very common (10% or more): Myelosuppression, neutropenia (90%), anemia, 
thrombocytopenia, leucopenia, bleeding  
Rare (less than 0.1%): Febrile neutropenia 
 
Hepatic 
Very common (10% or more): Elevated alkaline phosphatase (22%), elevated AST (SGOT) (19%) 
Common (1% to 10%): Elevated bilirubin 
Very rare (less than 0.01%): Hepatic necrosis, hepatic encephalopathy (both with reported 
cases of fatal outcome 
 
Hypersensitivity 
Very common (10% or more): Minor hypersensitivity reactions (mainly flushing and rash)  
Uncommon (0.1% to 1%): Significant hypersensitivity reactions requiring therapy (e.g., 
hypotension, angioneurotic edema, respiratory distress, generalized urticaria, chills, back 
pain, chest pain, tachycardia, abdominal pain, pain in extremity, diaphoresis, hypertension) 
Rare (less than 0.1%): Anaphylactic reactions 
Very rare (less than 0.01%): Anaphylactic shock 
 
Immunologic 
Very common (10% or more): Infections (mainly urinary tract and upper respiratory tract 
infections), with reported cases of fatal outcome 


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Uncommon (0.1% to 1%): Septic shock 
Rare (less than 0.1%): Sepsis, pseudomembranous colitis 
 
Local 
Common (1% to 10%): Injection site reactions (including localized edema, pain, erythema, 
induration, on occasion extravasation can result in cellulitis, skin fibrosis and skin necrosis)  
Rare (less than 0.1%): Phlebitis 
 
Musculoskeletal 
Very common (10% or more): Arthralgia/myalgia (44%) 
Frequency not reported: Systemic lupus erythematosus, scleroderma 
 
Metabolic 
Common (1% to 10%): Severe elevation in aspartate aminotransferase (AST) (serum glutamic 
oxaloacetic transaminase (SGOT)), severe elevation in alkaline phosphatase  
Uncommon (0.1% to 1%): Severe elevation in bilirubin 
Rare (0.01% to 0.1%): Dehydration, increased blood creatinine  
Very rare (less than 0.01%): Anorexia 
Frequency not reported: Tumor lysis syndrome 
 
Nervous system 
Very common (10% or more): Neurotoxicity (mainly peripheral neuropathy)  
Rare (0.01% to 0.1%): Motor neuropathy (with resultant minor distal weakness) 
Very rare (less than 0.01%): Autonomic neuropathy (resulting in paralytic ileus and orthostatic 
hypotension), optic nerve disturbance, grand mal seizures, convulsions, encephalopathy, 
dizziness, headache, ataxia 
 
Ocular 
Very rare (less than 0.01%): Optic nerve and/or visual disturbances (scintillating scotomata), 
particularly in patients who have received higher doses than recommended 
Frequency not reported: Macular edema, photopsia, vitreous floaters 
 
Oncologic 
Very rare (less than 0.01%): Acute myeloid leukemia, myelodysplastic syndrome 
 
Other 
Rare (0.01% to 0.1%): Asthenia, pyrexia, edema, malaise 
Very rare (less than 0.01%): Ototoxicity, hearing loss, tinnitus, vertigo 
 
Psychiatric 
Very rare (less than 0.01%): Confusional state 
Respiratory 
Rare (0.01% to 0.1%): Pneumonia, dyspnea, pleural effusion, interstitial pneumonia, lung 
fibrosis, pulmonary embolism, respiratory failure  
Frequency not reported: Bronchospasm 


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5.2.3 Number of subjects 
Phase I:  
- 
Total study sample size: 20 
- 
Target inclusion in Belgium: maximally 20 (depending on participation of other 
centers) 
Phase II: 
- 
Total sample size: 50 
- 
Target inclusion in Belgium: 10 
 
5.2.4 Inclusion- and exclusion criteria 
5.2.4.1 Inclusion criteria 
- 
Phase I study: patients with advanced carcinomatosis from ovarian, gastric, breast, or 
pancreatic origin.  
- 
No concurrent taxane based systemic chemotherapy 
- 
Phase II study: platinum resistant or refractory recurrent ovarian cancer or primary 
peritoneal carcinoma, FIGO stage IIIB or C. 
- 
Selected stage IV patients with very limited metastatic disease are eligible for inclusion 
- 
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 
o Serum creatinine ≤ 1.5 mg/dl or calculated GFR (CKD-EPI) ≥ 60 mL/min/1.73 m² 
o Serum total bilirubin ≤ 1.5 mg/dl, except for known Gilbert’s disease 
o Platelet count > 100.000/µl 
o Hemoglobin > 9g/dl 
o Neutrophil granulocytes > 1.500/ml 
o Blood coagulation parameters within normal range 
- 
Absence of alcohol and/or drug abuse 
- 
No other concurrent malignant disease 
- 
Written informed consent 
5.2.4.2 Exclusion criteria 
- 
Concurrent systemic taxane therapy until three weeks before the first experimental 
treatment 
- 
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 


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- 
General or local (abdominal) contra-indications for laparoscopic surgery 
- 
Documented intolerance or allergy to paclitaxel  
5.2.5 Replacement of subjects 
Patients who drop out from the study will be replaced until the target accrual is reached. 
 
 
6 Experimental procedures 
6.1 Phase I part 
 
 
1. Baseline assessment 
 
- 
Staging 
 
 CT, 18F-FGD-PET-CT, and/or total body diffusion weighed MRI, according to local 
practice 
 Serum tumor markers: CA125, CEA, CA19.9, CA15.3 
 
- 
Quality of life assessment: patients will be asked to fill in the QLQ-C30, QLQ-OV28, 
and/or the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires 
preoperatively (outpatient visit or hospital admission), at week 2 after each of the 
three PIPAC procedures, and at month 2 and 6 after the third PIPAC procedure. 
 
2. Experimental treatment 
 
Patients will undergo laparoscopy and PIPAC as per local procedural protocol. After creation 
of a CO2 pneumoperitoneum, the Abraxane® aerosol is generated by a micropump with a 200 
µm nozzle (Capnomed GmbH, Villingendorf, Germany) which delivers a polydisperse aerosol 
with a flow rate of 30 ml/min. The aerosol is left in the peritoneal cavity during 30 minutes 
and will be evacuated afterwards. The dose of Abraxane will be escalated (35, 70, 90, 112.5, 
and 140 mg/m2) until the MTD is observed. 
 
3. Plasma and tissue samples for PK/PD modelling 
 
 Tumor tissue samples will be collected (5x5x5 mm) before and at the end of the aerosol 
delivery after each PIPAC procedure. 
 Plasma samples (5 ml) will be collected preoperatively and at  
 15, 30, 60 min, 1.5, 2, 4, 8, 12 and 24 h, and after day 7, 28, 35, 56, 63, 84 and 91 after 
the first PIPAC procedure. 
 
 4. Plasma samples for systemic toxicity assessment 
 
Blood samples (5 ml) will be collected preoperatively and 12 h, 24 h and 7 days after 
each PIPAC procedure. 


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6.2 Phase II part 
 
Patients with recurrent OC will be randomized (1:1) to receive either weekly paclitaxel alone 
or weekly paclitaxel combined with PIPAC using nab-paclitaxel, using the dose identified from 
the phase I part. 
Randomization will be central (computer generated) and stratified according to treatment 
center. 
 
Quality of life assessment: patients will be asked to fill in the QLQ-C30, QLQ-OV28, and/or the 
Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires preoperatively 
(outpatient visit or hospital admission), at week 6 and 12, and after 3 months, 6 months, 1 
year, and 2 years. 
 
7 Statistical analysis 
 
Phase I 
In the phase I study we determine the maximum tolerated dose (MTD) (and associated dose-
limiting toxicity (DLT)) that will next be tested in a randomized phase II study. The target 
probability of DLT is set on 50%.  In order to optimize the balance between safety and efficacy 
at this stage, we will design the study following a two-stage TITE-CRM (ref: Cheung, Ying 
Kuen. Dose finding by the continual reassessment method. CRC Press, 2011).  In a two-stage 
TITE-CRM, an initial design is followed until the first DLT occurs. From that moment, TITE-CRM 
updates an initial prior estimate of the probabilities of DLT based on all available information. 
Patients are assigned the dose whose estimated probability of DLT at that time is closest to 
the target probability. This method allows for continuous, staggered accrual of patients. 
 
Dose limiting toxicity (DLT) will be defined as any of the following: 
 
1. Any Grade 3 or 4 non-hematologic toxicity excluding fatigue and controllable nausea, 
vomiting, abdominal pain, and diarrhea 
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 
 


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Only DLT’s that take place within 14 weeks of the start of the treatment, are taken into account 
for selecting the MTD. 
 
In the phase I study we examine 5 therapeutic dose levels: 35, 70, 90, 112.5, and 140 mg/m2 
with a priori estimated chance of DLT at each of the doses under study is 10%, 20%, 25%, 35% 
and 40%, respectively. For safety reasons, however, the prior estimate used by TITE-CRM is 
80%, 85%, 90%, 95%, 98%. This allows for the use of an initial design with a moderate pace of 
escalation (35 - 35 - 70 - 70 - 90 - 90 - 90 - 112.5 - 112.5 - 112.5 - 140 - 140 - 140 - 140 - 140 - 
140 - 140 - 140 - 140 - 140 mg/m2), while preserving the logical escalation rules of escalating 
only one dose at a time and not escalating when the previous patient had a DLT. Results of 
this design have been simulated under a number of possible true values for the chance of DLT 
at each of the dose levels examined. These simulations show that in case of relatively low 
probabilities of DLT, this design is only moderately efficient in identifying the optimal dose. 
When true probabilities of DLT are high, however, this design results in reasonably low 
chances of selecting a dose with a probability of DLT higher than the target. In the second 
example below for instance, where doses 112.5 and 140 mg/m2 have real probability of DLT 
of respectively 60% and 70%, these doses where selected as optimal respectively 6% and 0% 
out of the 1000 simulations. 
 
For each simulation, a sample size of 20 patients was assumed and 1000 runs were performed. 
As an example of low probabilities of DLT: with true probabilities of DLT equal to 15%, 20%, 
25%, 30% and 45% over the 5 increasing dose levels under study, the ordered doses 35, 70, 
90, 112.5, and 140 mg/m2 were identified as optimal dose respectively 0.4%, 4.6%, 34.2%, 
48.5% and 12.3% of the time. With high true probabilities of DLT 30%, 40%, 50% 60%, 70%, 
the ordered doses were identified as optimal dose respectively 17%, 39.3%, 37.7%, 6%, 0% of 
the time.  
 
Phase II 
Once the final dose has thus been selected, the randomized phase II will start.  No patients of 
phase I will be incorporated. To screen for effectiveness of the treatment under study, the 
phase IIB will be designed to have 80% power to detect an improvement in progression free 
survival time (PFS) from a median 3.5 to 6 months, when performing a one-sided log rank test 
at the 20% significance level. Based on a PH-assumption (HR=0.60), 44 events are needed.  
Based on a log rank test and with a loss to follow up of 5%, a sample size of 48 is needed with 
an accrual of 30 months and a follow up of 6 months. With a foreseen accrual of 20 patients 
per year, this seems feasible.  
 
8 Randomisation/blinding 
During the Phase II part of the trial, eligible patients will be randomized 1:1 to one of both 
treatment arms using sealed envelopes. The randomization will be stratified on treating 
center. For each center, a variable length block design will be prepared with block sizes 2 and 
4. Within each block, the patients are randomly assigned to one of both arms, where the 
balance is maintained within each block. Given the specifics of the trial, blinding of either the 
investigators or the participants is not possible. 
 


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9 Prior and concomitant therapy 
Patients should not receive other taxanes therapy until three weeks before the first 
experimental treatment. 
10 Adverse event reporting 
 
General considerations 
 
Data Safety Monitoring Committee (DMC) 
 
Composition 
 
1. Prof. Dr. Sylvie Rottey 
 
Medical Oncologist, Clinical Pharmacologist 
Head of the Drug Research Unit Ghent 
 
Ghent University Hospital    
Corneel Heymanslaan 10 - 9000 Gent 
 
Tel +32 9332 2692 
Sylvie.Rottey@ugent.be  
 
2. Prof. Dr. Piet Ost 
 
Radiation Oncologist 
 
Ghent University Hospital    
Corneel Heymanslaan 10 - 9000 Gent 
Tel +32 9332 2411 
Piet.Ost@ugent.be 
 
3. Prof. dr. Tom Loeys 
 
Statistician 
 
Department of Data-analysis 
Faculty of Psychology and Educational Sciences 
Ghent University 
Henri Dunantlaan 1 - 9000 Gent 
Tel +32 9264 6388  
Tom.Loeys@UGent.be 
 
Role 
 


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The DMC will, based on independent assessment of trial data as they become available, 
safeguard patient safety and trial integrity. The DMC will take decisions on trial continuation, 
protocol adaptation, or discontinuation based on efficacy or futility.  
 
 
The experimental treatment involves the instillation of chemotherapy during a standard of 
care surgical procedure. Therefore, attribution of toxicity and morbidity to either the 
chemotherapy (intervention) or the surgery (standard of care) will not always be possible. 
 
In the phase II part of the study, patients will undergo weekly low dose paclitaxel IV treatment 
until one week before each PIPAC treatment. The toxicity from low dose weekly paclitaxel is 
relatively mild. In a phase II trial by Markman et al., serious adverse events were relatively 
uncommon (neuropathy-grade 2: 21%; grade 3: 4%; and grade 3 fatigue: 8%).[1] Since 
paclitaxel does not exhibit cumulative toxicity and the plasma half-life after a systemic dose 
of 80 mg/m2 was estimated at approximately 12 hours, it is anticipated that the toxicity or 
morbidity of PIPAC will not be affected by the antecedent IV treatment.[2] Conversely, 
pharmacokinetic studies with IV nab-paclitaxel showed that at the clinical dose range of 80 to 
300 mg/m2, the mean terminal half-life ranges from 13 to 27 hours. Therefore, the proposed 
interval between the PIPAC procedure and resumption of IV paclitaxel seems feasible. 
 
Surgical complications will be scored according to the Dindo-Clavien classification. 
Possibly drug related toxicity will be scored using the Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.0. 
 
 
Reporting of Adverse Events 
 
List of abbreviations 
AE 
 
Adverse Event 
CA 
 
Competent Authority 
EC 
 
Ethics Committee 
SAE 
 
Serious Adverse Event 
SSAR  
Suspected Serious Adverse Reaction 
SUSAR Suspected Unexpected Serious Adverse Reaction 
 
Adverse events (AE) 
The following information will be recorded: 
 
nature of adverse event 
 
date and time of occurrence and disappearance 
 
intensity: mild, moderate or severe 
 
frequency: once, continuous or intermittent 
 
decision regarding study: continuation or withdrawal 
 
relation to the study medication (see below) 
 
AE’s will be recorded from the first drug administration until 30 days after the last PIPAC 
procedure. 


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20 
Special attention will be given to those subjects who have discontinued the trial for an AE, or 
who experienced a severe or a serious AE. 
 
Definitions of Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
 
Serious Adverse Avent (SAE) 
Any untoward medical occurrence that at any dose: 
- results in death 
- is life-threatening 
- requires inpatient hospitalization or prolongation of existing hospitalization, 
- results in persistent or significant disability/incapacity, 
or 
- is a congenital anomaly/birth defect. 
 
Note: Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the outcomes listed in the definition 
above. 
 
Unexpected adverse event 
An adverse event, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator's Brochure for an unapproved investigational product or 
package insert/summary of product characteristics for an approved product). 
 
Life-threatening 
Any event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe. 
 
Associated with the use of the drug 
An adverse event is considered associated with the use of the drug if the attribution is 
possible, probable or definitive. 
 
Attribution definitions 
Not related 
An adverse event which is not related to the use of the drug. 
 
Unlikely 


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An adverse event for which an alternative explanation is more likely - e.g. concomitant drug(s), 
concomitant disease(s), and/or the relationship in time suggests that a causal relationship is 
unlikely. 
 
Possible 
An adverse event which might be due to the use of the drug. An alternative explanation - e.g. 
concomitant drug(s), concomitant disease(s), - is inconclusive. The relationship in time is 
reasonable; therefore the causal relationship cannot be excluded. 
 
Probable 
An adverse event which might be due to the use of the drug. The relationship in time is 
suggestive (e.g. confirmed by dechallenge). An alternative explanation is less likely - e.g. 
concomitant drug(s), concomitant disease(s). 
 
Definitely 
An adverse event which is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation - e.g. concomitant drug(s), concomitant disease(s). 
The relationship in time is very suggestive (e.g. it is confirmed by dechallenge and 
rechallenge). 
 
Reporting of adverse events 
 
Adverse events will be reported between the first PIPAC and 30 after the last PIPAC procedure. 
All AEs and SAE’s will be recorded in the patient’s file and in the CRF. All SAE’s will be reported 
as described below.   
 
Medical events that occur between signing of the Informed Consent and the first intake of 
trial medication will be documented on the medical and surgical history section and 
concomitant diseases page of the CRF. 
SAE’s occurring within a period of 30 days following the last intake of trial medication will also 
be handled as such if spontaneously reported to the investigator. 
 
All serious adverse events (SAE) and pregnancies occurring during clinical trials must be 
reported by the local Principal Investigator and local Ethical Committee within 2 working days 
after becoming aware of the SAE. This reporting is done by using the appropriate SAE form.  It 
is the responsibility of the local Principal Investigator to report the local SAE’s to the local EC. 
 
In case the investigator decides the SAE is a SUSAR (Suspected Unexpected Serious Adverse 
Reaction), Bimetra Clinics will report the SUSAR to the Central EC and the CA within the 
timelines as defined in national legislation. The National Coordinating Investigator reports the 
SUSAR to all National Coordinating Investigators. 
 
In case of a life-threatening SUSAR the entire reporting process must be completed within 7 
calendar days.  In case of a non-life-threatening SUSAR the reporting process must completed 
within 15 calendar days. The first report of a serious adverse event may be made by telephone, 
e-mail or facsimile (FAX).  
 


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The investigator must provide the minimal information: i.e. trial number, subject's initials and 
date of birth, medication code number, period of intake, nature of the adverse event and 
investigator's attribution. 
This report of a serious adverse event by telephone must always be confirmed by a written, 
more detailed report. For this purpose the appropriate SAE form will be used. Pregnancies 
occurring during clinical trials are considered immediately reportable events. They must be 
reported as soon as possible using the same SAE form. The outcome of the pregnancy must 
also be reported. 
 
If the subjects are not under 24-hour supervision of the investigator or his/her staff (out-
patients, volunteers), they (or their designee, if appropriate) must be provided with a "trial 
card" indicating the name of the investigational product, the trial number, the investigator's 
name and a 24-hour emergency contact number. 
 
Annual Safety Reporting 
 
Bimetra Clinics will ask the National Coordinating Investigator for an annual report containing 
an overview of all SSARs (Suspected Serious Adverse Reaction) and a summary regarding the 
safety of the trial subjects. Bimetra Clinics will send this report to the Central EC and the CA 
within the timelines as defined in national legislation. The National Coordinating Investigator 
will pass this annual report to all National Coordinating Investigators.    
 
11 Quality control and quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit of the site records, and the regulatory agencies may conduct 
a regulatory inspection at any time during or after completion of the study. In the event of an 
audit or inspection, the investigator (and institution) must agree to grant the auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the time of 
their staff to discuss any findings/relevant issues. 
A study monitor is responsible for visiting the institution at regular intervals throughout the 
study to verify adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH GCP and local regulations on the conduct of clinical research. The 
nature and extent of the monitoring will be captured in a monitoring plan. The monitor should 
have access to subject medical records and other study-related records needed to verify the 
entries on the workbooks. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are addressed and 
documented. 
Quality control of the data in the CRF will be done by comparing the data in source documents 
with the data in the CRF by a person who was not involved in completing the CRF. There will 
be no medical data recorded in the CRF which are not mentioned in the medical file of the 
patients.    
 
 


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12 Indemnity insurance 
Ghent University Hospital will undersign a no fault insurance within Belgium. 
 
13 Publication policy 
The decision whether, when, and where to publish the results of the trial will be the 
responsibility of the principal investigator. The PI will, however, involve the co-investigators 
prior to making any decision. Co-authorship of any scientific output will be offered to 
participating co-investigators, with the exact author order to be based on number of included 
patients and in consensus. 
 
14 Independent Ethics Committee (IEC) / Institutional Review Bord 
(IRB) 
This trial can only be undertaken after full approval of the protocol and addenda has been 
obtained from the IEC/IRB. This document must be dated and clearly identify the protocol, 
amendments (if any), the informed consent form and any applicable recruiting materials and 
subject compensation programs approved. 
During the trial, the following documents will be sent to the IEC/IRB for their review: 
 reports of adverse events that are serious, unexpected and associated with the 
investigational drug 
 all protocol amendments and revised informed consent form (if any). 
Amendments should not be implemented without prior review and documented approval / 
favorable opinion form the IEC/IRB except when necessary to eliminate an immediate hazard 
to trial subjects or when the change involves only logistical or administrative aspects of the 
trial. 
Reports on, and reviews of the trial and its progress will be submitted to the IEC/IRB by the 
investigator at intervals stipulated in their guidelines. 
At the end of the trial, the investigator will notify the IEC/IRB about the trial completion. 
 
15 ICH/GCP guidelines 
 
This trial will be conducted in accordance with the protocol, current ICH-GCP guidelines and 
applicable law(s). 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting trials that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety and 
well-being of trial subjects are protected, consistent with the principles that have their origin 
in the Declaration of Helsinki, and that the clinical trial data are credible. 
 
16 Subject information and informed consent 
 


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Prior to entry in the trial, the investigator must explain to potential subjects or their legal 
representatives the trial and the implication of participation. Subjects will be informed that 
their participation is voluntary and that they may withdraw consent to participate at any time. 
Participating subjects will be told that their records may be accessed by competent authorities 
and by authorized persons without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) and/or regulations. By signing the Informed Consent Form 
(ICF), the subjects or legally acceptable representatives are authorizing such access. 
After this explanation and before entry to the trial, written, dated and signed informed 
consent should be obtained from the subject or legally acceptable representative. The ICF 
should be provided in a language sufficiently understood by the subject. Subjects must be 
given the opportunity to ask questions. 
The subject or legally acceptable representative will be given sufficient time to read the ICF 
and to ask additional questions. After this explanation and before entry to the trial, consent 
should be appropriately recorded by means of either the subject's or his/her legal 
representative's dated signature or the signature of an independent witness who certifies the 
subject's consent in writing. After having obtained the consent, a copy of the ICF must be given 
to the subject. 
In case the subject or legally acceptable representative is unable to read, an impartial witness 
must attest the informed consent. 
Subjects who are unable to comprehend the information provided or pediatric subjects can 
only be enrolled after consent of a legally acceptable representative. 
 
17 Case Report Forms 
The source documents are to be completed at the time of the subject’s visit. The CRFs are to 
be completed within reasonable time after the subject’s visit. 
The investigator must verify that all data entries in the CRFs are accurate and correct. If certain 
information is Not Done, Not Available or Not Applicable, the investigator must enter "N.D." 
or "N.AV." or "N.AP", respectively in the appropriate space. 
 
18 Direct access to source data / documents 
The investigator will permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s), providing direct access to source data/documents. 
 
19 Data handling and record keeping 
The investigator and sponsor specific essential documents will be retained for at least 20 years. 
At that moment, it will be judged whether it is necessary to retain them for a longer period, 
according to applicable regulatory or other requirement(s). 
 
 
 
 


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20 Signature page 
 
 
Investigator: 
 
 
 
Name:  
________________________________________________ 
 
 
 
 
Title:  
________________________________________________ 
 
 
 
 
Signature: 
________________________________________________ 
 
 
 
 
Date:  
________________________________________________ 
 
 
 
Investigator: 
 
 
 
Name:  
________________________________________________ 
 
 
 
 
Title:  
________________________________________________ 
 
 
 
 
Signature: 
________________________________________________ 
 
 
 
 
Date:  
________________________________________________ 
 


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References 
 
1.  
Belgian Cancer Registry — Kankerregistratie [Internet]. [geciteerd 6 oktober 2016]. 
Beschikbaar op: http://www.kankerregister.org/kankerregistratie 
2.  
Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, e.a. Surgical 
cytoreduction for recurrent epithelial ovarian cancer. In: The Cochrane Collaboration, 
redacteur. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John 
Wiley & Sons, Ltd; 2013 [geciteerd 30 november 2016]. Beschikbaar op: 
http://doi.wiley.com/10.1002/14651858.CD008765.pub3 
3.  
Oseledchyk A, Zivanovic O. Intraoperative Hyperthermic intraperitoneal Chemotherapy 
in Patients With Advanced Ovarian Cancer. Oncol-N Y. september 2015;29(9):695–701.  
4.  
Solass W, Kerb R, Mürdter T, Giger-Pabst U, Strumberg D, Tempfer C, e.a. Intraperitoneal 
Chemotherapy of Peritoneal Carcinomatosis Using Pressurized Aerosol as an Alternative 
to Liquid Solution: First Evidence for Efficacy. Ann Surg Oncol. februari 2014;21(2):553–
9.  
5.  
Tempfer CB, Rezniczek GA, Ende P, Solass W, Reymond M-A. Pressurized Intraperitoneal 
Aerosol Chemotherapy with Cisplatin and Doxorubicin in Women with Peritoneal 
Carcinomatosis: A Cohort Study. Anticancer Res. december 2015;35(12):6723–9.  
6.  
Scheithauer W, Kornek G, Prager G, Stranzl N, Laengle F, Schindl M, e.a. Phase II trial of 
capecitabine plus nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma. 
J Gastrointest Oncol. april 2016;7(2):234–8.  
7.  
Coleman RL, Brady WE, McMeekin DS, Rose PG, Soper JT, Lentz SS, e.a. A phase II 
evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent 
or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: A 
Gynecologic Oncology Group Study. Gynecol Oncol. juli 2011;122(1):111–5.  
8.  
Tsai M, Lu Z, Wang J, Yeh T-K, Wientjes MG, Au JL-S. Effects of carrier on disposition and 
antitumor activity of intraperitoneal paclitaxel. Pharm Res. september 2007;24(9):1691–
701.  
9.  
Cristea MC, Synold TW, Frankel PH, Rivkin SE, Lim D, Chung VM, e.a. Pharmacologic 
advantage (PA) of intraperitoneal (IP) nab-paclitaxel in patients with advanced 
malignancies primarily confined to the peritoneal cavity. J Clin Oncol. 20 mei 
2015;33(15).  
10.  Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset 
toxicities. Biometrics. december 2000;56(4):1177–82.  
 


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Appendix A – Performance status criteria  
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
1. 
Gynecologic Oncology, G., et al., Phase II trial of weekly paclitaxel (80 mg/m2) in 
platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a 
Gynecologic Oncology Group study. Gynecologic Oncology, 2006. 101(3): p. 436-40. 
2. 
Nokihara, H., et al., Pharmacokinetics of Weekly Paclitaxel and Feasibility of 
Dexamethasone Taper in Japanese Patients with Advanced Non-small Cell Lung 
Cancer. Clinical Therapeutics, 2016. 38(2): p. 338-47.