Clinical pharmacoloGy of platinUm-based hyperThermic Intraperitoneal Chemotherapy: Exploration of the Impact of Flushing on tumOur, Systemic and Personnel eXposure (GUTOX)
Conditions: Peritoneal Carcinomatosis
Sponsor: Radboud University Medical Center

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Clinical pharmacoloGy of platinUm-based 
hyperThermic intraperitoneal chemotherapy: 
the impact of flushing on tumOur, systemic and 
personnel eXposure  
(GUTOX) 
 
16-11-2017 
Version 2 
 
 
 

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Clinical pharmacology of platinum-based hyperthermic intraperitoneal chemotherapy: 
the impact of flushing on tumour, systemic and personnel exposure 
 
Protocol ID 
UMCN-AKF-17.09 
Short title 
GUTOX-STUDY 
EudraCT number  
not applicable 
Version 
2 
Date 
November 16, 2017 
Coordinating investigator/project 
leader 
 
Loek A.W. de Jong, PharmD 
Radboud University Medical Centre 
864 Department of Pharmacy 
Geert Grooteplein Zuid 10 
6525 GA Nijmegen, The Netherlands 
Loek.deJong@radboudumc.nl  
Telephone: (+31) 6 2543 5308 / (+31) 6 1383 0367 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
Nielka P. van Erp1, PharmD, PhD 
Rob ter Heine1, PharmD, PhD 
Prof.  Johannes HW de Wilt2, MD, PhD 
Radboud University Medical Centre 
1 Department of Pharmacy 
2 Department of Surgery 
Geert Grooteplein Zuid 10 
6525 GA Nijmegen, The Netherlands 
Nielka.vanErp@radboudumc.nl  
R.terHeine@radboudumc.nl   
Hans.deWilt@radboudumc.nl   
 
Co-investigators 
Andre JA Bremers1, MD, PhD 
Philip R de Reuver1, MD, PhD 
Sandra A Radema2, MD, PhD  
Fortuné Elekonawo 1, MD 
1 Department of Surgery 
2 Department of Oncology 
Radboud University Medical Centre 
Geert Grooteplein Zuid 10 

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6525 GA Nijmegen, The Netherlands 
The Netherlands 
Andre.Bremers@radboudumc.nl 
Philip.deReuver@radboudumc.nl  
Sandra.Radema@radboudumc.nl  
Fortune.Elekonawo@radboudumc.nl  
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboud University Medical Centre 
Geert Grooteplein 10 
6525 GA Nijmegen, The Netherlands 
 
Subsidising party 
not applicable 
Independent expert (s) 
J.J. Bonenkamp, MD, PhD 
 
Han.Bonenkamp@radboudumc.nl 
 
 
Laboratory sites 
1. The Cancer biology laboratory  
Institut Universitaire du Cancer de Toulouse 
(IUCT) Oncopole 
1 avenue Irène Joliot-Curie 
31059 Toulouse Cedex 9 
France 
2. The Bioanalytical Laboratory of the 
Netherlands Cancer Institute 
MC Slotervaart (2nd floor, B-wing) 
Louwesweg 6 
1066 EC Amsterdam 
The Netherlands 
 
Pharmacy 
Department of Pharmacy 
Radboud University Medical Centre 
Geert Grooteplein Zuid 10, 6525 GA, Nijmegen,  
The Netherlands 
Route / huispost 864 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of the Research Group of the 
Department of Pharmacy: 
Prof. David M. Burger, PharmD, PhD 
 
Principle Investigators: 
Nielka P. van Erp, PharmD, PhD 
 
Rob ter Heine, PharmD, PhD 
 
Prof. Johannes HW de Wilt, MD, PhD 
 
 
16/11/2017 
 
16/11/2017 
 
16/11/2017 
 
16/11/2017 
 
[Coordinating Investigator/Project 
leader]: 
 
Loek A.W. de Jong, PharmD 
  
 
 
 
 
16/11/2017 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................17 
4.1 
Population (base) ...................................................................................................17 
4.2 
Inclusion criteria .....................................................................................................17 
4.3 
Exclusion criteria ....................................................................................................17 
4.4 
Sample size calculation ..........................................................................................17 
5. 
TREATMENT OF SUBJECTS .......................................................................................18 
5.1 
Investigational product/treatment ............................................................................18 
5.2 
Use of co-intervention ............................................................................................18 
5.3 
Escape medication (if applicable) ...........................................................................18 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................19 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................20 
8. 
METHODS ....................................................................................................................21 
8.1 
Study parameters/endpoints ...................................................................................21 
8.1.1 
Main study parameter/endpoint .......................................................................21 
8.1.2 
Secondary study parameters/endpoints ..........................................................21 
8.1.3 
Other study parameters (if applicable) .............................................................21 
8.2 
Randomisation, blinding and treatment allocation ..................................................21 
8.3 
Study procedures ...................................................................................................21 
8.4 
Withdrawal of individual subjects ............................................................................22 
8.5 
Replacement of individual subjects after withdrawal ...............................................22 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................22 
8.7 
Premature termination of the study .........................................................................23 
9. 
SAFETY REPORTING ..................................................................................................24 
9.1 
Temporary halt for reasons of subject safety ..........................................................24 
9.2 
AEs, SAEs and SUSARs ........................................................................................24 
9.2.1 
Adverse events (AEs) ......................................................................................24 
9.2.2 
Serious adverse events (SAEs) .......................................................................24 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................25 
9.3 
Annual safety report ...............................................................................................25 
9.4 
Follow-up of adverse events ...................................................................................25 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................25 
10. 
DATA ANALYSIS .......................................................................................................26 
10.1 
Bioanalysis .............................................................................................................26 
10.2 
Statistical analysis ..................................................................................................26 
10.2.1 
Primary study parameter(s) .............................................................................26 
10.2.2 
Secondary study parameter(s) ........................................................................26 
10.2.3 
Other study parameters ...................................................................................27 
10.2.4 
Interim analysis ...............................................................................................27 

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11. 
ETHICAL CONSIDERATIONS ...................................................................................28 
11.1 
Regulation statement .............................................................................................28 
11.2 
Recruitment and consent........................................................................................28 
11.3 
Objection by minors or incapacitated subjects ........................................................28 
11.4 
Benefits and risks assessment, group relatedness .................................................28 
11.5 
Compensation for injury .........................................................................................28 
11.6 
Incentives ...............................................................................................................29 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................30 
12.1 
Handling and storage of data and documents ........................................................30 
12.2 
Monitoring and Quality Assurance ..........................................................................30 
12.3 
Amendments ..........................................................................................................30 
12.4 
Annual progress report ...........................................................................................30 
12.5 
Temporary halt and (prematurely) end of study report ............................................31 
12.6 
Public disclosure and publication policy ..................................................................31 
12.7 
Sample destruction after study completion .............................................................31 
13. 
STRUCTURED RISK ANALYSIS...............................................................................32 
14. 
REFERENCES ..........................................................................................................33 
15. 
Appendix ....................................................................................................................36 
APPENDIX 1: Radboudumc protocol primary HIPEC with oxaliplatin and 5-FU ................36 
APPENDIX 2: Karnofsky Performance Status Scale Definitions Rating Criteria ................44 
APPENDIX 3: Study procedures overview ........................................................................45 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
AAS 
Flameless atomic absorption spectrometry 
AE 
Adverse Event 
ALT 
Alanine tranaminase 
AR 
Adverse reaction 
AST 
Aspartate transaminase 
AUC 
Area Under the Curve 
Cmax 
Maximum observed plasma concentration after single dose administration 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
HIPEC 
hyperthermic intraperitoneal chemotherapy 
IEC 
Independent Ethics Committee 
ICP-OES 
inductively coupled plasma optical emission spectrometry 
IPCH 
intra-operative intra-peritoneal chemo-hyperthermia 
L 
Liter 
LDH 
Lactate Dehydrogenase 
MDRD 
Modified Diet in Renal Disease 
METC 
Medical research ethics committee (in Dutch: Medisch Ethische Toetsing Commissie) 
PC 
peritoneal carcinomatosis 
PI 
Principal Investigator: a person responsible for the conduct of a clinical study at a study 
site. Every study centre has a principal investigator. 
PK 
Pharmacokinetics 
Pt 
Platinum 
PUF 
plasma ultrafiltrate 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
Sponsor 
The sponsor is the party that commissions the organization or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organization or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidizing party 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Half life time 
Tmax 
Time to maximum observed plasma concentration after dose 
UAR 
Unexpected Adverse Reaction  
UMCN 
Radboud University Medical Center (in Dutch: Radboudumc) 
WHO 
World Health Organization 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-wetenschappelijk 
Onderzoek met Mensen) 
 
 
 
 

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SUMMARY 
 
Rationale 
Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is standard 
care in the treatment of patients with peritoneal carcinomatosis as a result of intra-abdominal cancers. 
Cytoreduction is a procedure that aims for the complete removal of all visible tumours affecting the 
protective lining of the abdomen. The cytoreductive procedure itself is complex and can last 
several hours. After the surgical procedure is completed, HIPEC is performed to attack non-visible 
tumour cells. The main goal of HIPEC is to obtain high local concentrations of the drug in the 
abdominal cavity with high penetration in tumour tissue, while avoiding systemic exposure. In many 
(inter)national centres oxaliplatin is used for the primary HIPEC treatment. The recommended dose of 
oxaliplatin is 460 mg/m2 perfused for 30 minutes at 43˚C in dextrose 5%, performed following the open 
‘coliseum’ technique. This includes lifting the edges of the surgical wound upwards and suspending 
them under traction by threads, thus optimizing exposure of intra-abdominal viscera. The abdomen is 
filled with dextrose 5% and with a rollerpump the perfusate is circulated in the abdominal cavity. 
Although the oxaliplatin dose of 460mg/m2 is widely accepted, the exact procedure of HIPEC differs 
between institutions and surgeons. Platinum concentration in the perfusate at the beginning of HIPEC 
depends on both body surface area and the volume of the abdominal cavity. Due to a great variety in 
the volume of the abdominal cavity, platinum concentration in the perfusate might differ between 
patients. Moreover, there is no consensus about the usefulness of flushing the HIPEC system with 
crystalloids at the end of oxaliplatin administration. Flushing is predominantly performed with the idea 
to minimize both systemic exposure of ultrafilterable platinum and personnel exposure to platinum-
contaminated exudate. On the other hand, HIPEC without flushing might increase effectiveness 
because intraperitoneal tumour cells are exposed to high concentrations of oxaliplatin for a longer time 
period. The option of flushing is based on an individual preference of the surgeon. Currently, there is a 
lack of knowledge on the effect of flushing on tumour platinum exposure, systemic platinum exposure 
and platinum concentration in drain exudate and thereby personal exposure. 
Therefore we want to perform a study to investigate the effect of flushing after HIPEC on tumour 
exposure, systemic exposure and on wound exudate concentration. The results of this study will 
provide answers about the effect of flushing  the abdominal cavity after HIPEC procedure. If flushing 
has no effect on peritoneal tissue exposure but does decrease systemic exposure and/or platinum 
concentration in exudate, flushing should be recommended to decrease personnel exposure and 
systemic toxicity. 
 
Objective 
Primary objective: 
1. To determine the effect of flushing after HIPEC on tissue platinum exposure 
Secondary objectives: 
1. To explore the effect of flushing after HIPEC on wound exudate platinum concentration 
2. To explore the effect of flushing after HIPEC on systemic exposure of total and unbound 
platinum  

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3. To explore the relation between the platinum concentration in instillate on tissue platinum 
exposure 
4. To explore the relation between the platinum concentration in instillate on systemic exposure 
of total and unbound platinum exposure  
5. To explore the effect of the degree of cytoreduction on systemic total and unbound platinum 
exposure  
 
Study design 
Single-centre, prospective, open, pharmacokinetic (PK) cohort study. 
 
Study population 
Twenty patients with peritoneal carcinomatosis as a result of intra-abdominal cancers who are already 
planned for HIPEC treatment with oxaliplatin as part of routine clinical care will be included in the 
study. 
 
Intervention 
The first 10 patients will undergo HIPEC procedure with flushing afterwards (the current practice by 
Radboudumc), followed by 10 patients who will be treated with HIPEC without flushing afterwards 
(new Radboudumc protocol that will be implemented in the beginning of 2018). Peritoneal fluid, 
peritoneal tissue, blood and wound exudate samples will be collected in all patients on prespecified 
time points during and after the HIPEC procedure. 
 
Main study parameters/endpoints:  
The main study parameter is the change in tissue platinum exposure before and after flushing. Tissue 
platinum exposure is expressed in concentration platinum per milligram tissue (ng/mg).  
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness 
Patients who participate in the study will receive the standard treatment. Therefore, the risk for 
participation in this study is regarded negligible. Collection of peritoneal fluid, blood, and wound 
exudate samples do not put patients at risk or interfere with standard treatment. Three 5ml peritoneal 
fluid samples will be taken 10, 20 and 30 minutes after intraperitoneal administration of oxaliplatin. 
Wound exudate samples of 5 ml will be taken from drain bottles at the moment that they are changed 
until day three post-surgery. During and after HIPEC a total of thirteen blood samples of 10ml will be 
taken from a central venous catheter that is placed as routine care prior to cytoreductive surgery with 
HIPEC. In the group of patients receiving HIPEC with flushing two 5-cm diameter non-tumour 
peritoneal tissue samples will be taken prior to and at the end of flushing. In the group of patients 
receiving HIPEC without flushing one 5-cm diameter non-tumour peritoneal tissue sample will be taken 
prior to abdominal closure. Compared to the complexity and amount of cytoreduction that is performed 
during surgery this can be considered as a negligible additional tissue collection procedure. 

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Benefits associated with participating in this study are that patients and their treating physician get 
insight into the effect of flushing after HIPEC on tumour platinum exposure and that the HIPEC 
procedure can be optimized for future patients. 

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1. INTRODUCTION AND RATIONALE 
 
Peritoneal carcinomatosis is generally considered to be an untreatable terminal disease with a median 
survival of 6 months with 5-FU-based chemotherapy(1) and 1 year with chemotherapy including 
oxaliplatin. Systemic chemotherapy provides limited benefit. The use of cytoreductive surgery followed 
by HIPEC for peritoneal carcinomatosis as a result of intra-abdominal cancers has shown great 
improvement of survival rates compared with standard palliative surgery and chemotherapy. Survival 
rates improved to a median of two years and 20% of patients live longer than five years after the 
treatment (2-6). Therefore cytoreductive surgery combined with HIPEC in the treatment of peritoneal 
carcinomatosis is progressing towards a new standard of care (7). Despite the success of the 
treatment, there is a lack of agreement on many issues concerning the cytotoxic drug, dose, duration, 
carrier solution and technique. 
 
Although no comparative studies between different cytotoxic drugs have been performed, the 
experience that has been obtained with oxaliplatin is most encouraging. Therefore primary HIPEC 
procedure consists of intraperitoneal administration of oxaliplatin. The main goal of HIPEC is to obtain 
high local oxaliplatin concentrations in the abdominal cavity with high penetration in tumour tissue, 
while avoiding systemic exposure. The advantage of intraperitoneal administration is confirmed in 
several PK studies (8, 9). Administration of 5-FU significantly increases the antitumor activity of 
intravenous administered oxaliplatin in the treatment of colorectal cancer (10-12). HIPEC with 
oxaliplatin is preceded by intravenous administration of 5-fluorouracil (400-450 mg/m2) and folic acid 
(20 mg/m2), to potentiate oxaliplatin efficacy in the tumour cells (9). 5-FU is distributed to peritoneal 
fluid and tumor nodules after intravenous administration during HIPEC (13). 
 
In order to balance cytotoxic activity and risk of toxicity, which is related to systemic exposure, it is 
important to study the PK of oxaliplatin during the HIPEC procedure. Based on previous PK work the 
most efficient dose for administration of oxaliplatin during HIPEC has been defined (8, 9, 14-27). The 
recommended dose of oxaliplatin is 460 mg/m2 perfused during 30 minutes at 43˚C in dextrose 5% 
following the open ‘coliseum’ technique. The open ‘coliseum’ technique is chosen because previous 
experimental data suggest higher tissue penetration and a more homogenous distribution compared to 
the closed technique (28). Some studies suggest the use of a standard volume of instillate of 2 L/m2, 
leading to a fixed concentration of oxaliplatin in the peritoneal cavity (9). In the Radboud University 
Medical Centre the abdominal cavity of the patient is completely filled with dextrose 5% before 
oxaliplatin is administered, to ensure contact with the whole peritoneum, for which a volume up to 6 
litres may be needed. Because the volume of the abdominal cavity differs largely between patients, 
there is a great variety of oxaliplatin concentration in the instillate and thereby in the abdominal cavity. 
Together with the duration of the procedure, oxaliplatin concentration in instillate is an important 
variable that might influence tumour penetration and systemic absorption (9, 16, 21). In addition to 
these variables tumour penetration can be influenced by several other pharmacokinetic and non-
pharmacokinetic variables, including carrier solution, pressure, tumor nodule size, nodule density, 
vascularity and interstitial fluid pressure. 
 

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Although a national standardized drug dose for oxaliplatin during HIPEC (460mg/m2) is accepted, the 
exact procedure of HIPEC can differ between institutions and surgeons. There is no consensus about 
the usefulness of flushing the HIPEC system with crystalloids at the end of oxaliplatin administration. 
Flushing is predominantly applied with the idea to minimize both systemic exposure and personnel 
exposure. On the other hand, HIPEC without flushing might increase effectiveness because 
intraperitoneal tumour cells might be exposed to oxaliplatin for a longer time period. The option of 
flushing is based on individual preferences of the surgeon. There is no standardized procedure for 
flushing after HIPEC. If a surgeon decides to flush after HIPEC the volume and time of flushing differs 
between patients and between surgeons. There is a lack of knowledge on the effect of flushing on 
tumour tissue exposure, systemic exposure and wound exudate platinum concentration. Therefore we 
want to perform a study to investigate the effect of flushing after HIPEC on tissue exposure, systemic 
exposure and wound exudate platinum concentration. The results of this study will help to further 
optimise and standardize the HIPEC procedure. 

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2. OBJECTIVES 
 
Primary objective: 
1. To determine the effect of flushing after HIPEC on tissue platinum exposure 
Secondary objectives: 
2. To explore the effect of flushing after HIPEC on wound exudate platinum concentration 
3. To explore the effect of flushing after HIPEC on systemic unbound platinum exposure 
4. To explore the relation between the platinum concentration in instillate on total tissue platinum 
exposure 
5. To explore the relation between the platinum concentration in instillate on systemic unbound 
platinum exposure  
6. To explore the effect of the degree of cytoreduction on systemic unbound platinum exposure  

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3. STUDY DESIGN 
 
Patients 
Eligible patients for study entry include patients with a diagnosis of peritoneal carcinomatosis as a 
result of intra-abdominal cancers who are already planned for HIPEC treatment with oxaliplatin as part 
of routine clinical care. To determine the effect of flushing after HIPEC on tissue exposure (primary 
objective)  a group of 10 patients are needed who undergo HIPEC with flushing afterwards. To explore 
the differences of flushing vs. non-flushing (secondary objectives) 10 more patients are needed who 
undergo HIPEC without flushing afterwards. Cytoreductive surgery and HIPEC will be performed  
according to the standard local procedure. 
 
Flushing 
Flushing after HIPEC will be performed in the first 10 patients. Flushing will be performed immediately 
after evacuation of the instillate. In this study the abdominal cavity will be flushed during 5 minutes with 
2L/m2 of sodium chloride 0.9%. 
 
PCI score 
To explore the effect of the degree of cytoreduction on systemic exposure of unbound platinum it is 
necessary to objectively classify the extensiveness of the peritoneal cancer and thereby the intensity 
of the surgical intervention. As part of routine work the peritoneal cancer index (PCI) is assessed prior 
to cytoreduction.  
 
CC-score 
To completeness of cytoreduction score (CC-Score), as described by Jacquet et al (29), is used to 
score the completeness of the surgery. A CC-0 score indicates that no macroscopic peritoneal tumour 
remains after cytoreduction, a CC-1 score indicates that persisting tumour nodules are < 2.5 mm, a 
CC-2 score indicates residual tumour nodules between 2.5 mm and 2.5 cm and a CC-3 score 
indicates tumour nodules > 2.5 cm or a confluence of unresected tumour. All patients who do not 
achieve a CC-0 score will be excluded. 
 
Peritoneal tissue samples 
Two 5-cm diameter non-tumour peritoneal tissue samples will be taken from all patients that 
underwent HIPEC with flushing afterwards. The first sample will be taken immediately after the 
instillate solution is evacuated from the abdominal cavity. The second sample will be taken 
immediately after flushing. In the group of patients receiving HIPEC without flushing one 5-cm 
diameter non-tumour peritoneal tissue sample will be taken immediately after the instillate solution is 
evacuated from the abdominal cavity. Immediately after resection, all tissue samples will be touched to 
filter paper in order to remove excess surface fluid. The processing of the tissue will be performed 
according to the method described by Elias et al. The concentration in non-tumour peritoneal bathed 
tissue is a good reflection of tumour bathed tissue (9). 

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Peritoneal fluid samples 
To determine the decrease in concentration of unbound platinum concentrations in the heated 
peritoneal instillate three different 5ml fluid samples will be collected at the following time points: 5 
minutes after the start of the HIPEC procedure, 15 minutes after the start of the procedure and at the 
end of the HIPEC procedure. Based on the measurements in these samples it is possible to follow the 
decrease of unbound platinum concentrations in the heated peritoneal instillate.  An additional 5ml 
fluid sample will be taken from the sodium chloride 0.9% flush solution at the end of flushing, to 
determine unbound platinum concentration in the flushing fluid. 
 
Blood samples 
A total of thirteen 10ml heparinised blood samples will be collected from each patient. Each sample 
will be centrifuged within 10 minutes after collection for 5 minutes (1,000 g, 4˚C) to separate plasma. 
Unbound platinum will be obtained by centrifuging the plasma fraction through a 30 kDa cut-off 
ultrafiltrate filter for 15 minutes (1,000 g, 20˚C). Unbound platinum from plasma is performed as soon 
as possible after blood collection, to prevent a decrease of Pt levels due to progressive ex vivo binding 
of Pt to plasma proteins and erythrocytes. The unbound platinum will be stored at -20˚C until analysis.  
The first three blood samples will be taken at 10, 20 and 30 minutes after the start of HIPEC. The 
other ten samples will be taken at ¼, ½, 1, 2, 4, 12, 24, 36, 48 and 72 hours after completion of the 
HIPEC procedure.  
Total unbound platinum concentrations will be measured. The individual AUCs are calculated with a 
trapezoidal approach. 
 
Wound exudate samples 
After the HIPEC procedure in the majority of patients one or more drains will be placed. The wound 
exudate is collected in drainage bottles. Each bottle is changed after 24 hours. This is the moment that 
personnel can be exposed to contaminated wound exudate. Each drain will produce around 100ml on 
the first day. The total volume of wound exudate per drain will be measured. A 5 ml sample of wound 
exudate will be collected from every drain bottle to determine total and unbound platinum 
concentration. Platinum concentrations will be measured with AAS in The Cancer biology laboratory, 
Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole.  
 
Duration and setting of the study 
The study takes place at Radboud University Medical Centre in Nijmegen, the Netherlands. The study 
is expected to start in November 2017 and is expected to be completed within 1 year after study 
initiation. 
 

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Figure 1. Schematic overview of the study design. 
* t0 is the moment that the instillate is evacuated from the abdominal cavity (the end of HIPEC) 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Eligible patients for study entry include patients with a diagnosis of peritoneal carcinomatosis as a 
result of intra-abdominal cancers who are already planned for HIPEC treatment with oxaliplatin as part 
of routine clinical care. In Radboud University Medical Centre an average number of one patient per 
week is being treated with cytoreduction and HIPEC with oxaliplatin. Therefore, it is expected that the 
planned number of patients (n=20) can be recruited from this group of patients. 
 
4.2 
Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
1) Subjects must provide written informed consent prior to performance of study-specific 
procedures or assessments and must be willing to comply with treatment and follow-up. 
Note:  Informed consent may be obtained prior to start of the specified screening window. 
Note:  Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes. 
2) Age ≥ 18 years  
3) Confirmed diagnosis of preoperatively identified primary or recurrent peritoneal carcinomatosis 
(PC) of colorectal origin who are planned for HIPEC treatment with oxaliplatin according to 
routine clinical care  
 
4.3 Exclusion criteria 
Patients who do not achieve a cytoreduction score of CC-0 will be excluded from the study. 
 
4.4 Sample size calculation 
The primary objective of the study is to determine the effect of flushing after HIPEC on tissue exposure 
of total platinum content. Therefore the difference in tumour exposure within the same subject before 
and after flushing will be studied. A difference of ≥25% is considered as clinical relevant.  For the 
sample size calculation we used an intra-patient variability in tumour exposure of 20%. A sample size 
of 10 patients is required to show a difference of ≥25% (90% confidence interval) with a power of 90% 
and a one-side significance level of 0.05. 
This study will serve as an exploratory study for all secondary objectives. Therefore no sample size 
calculation for these objectives has been performed. To make a good comparison possible between 
flushing and non-flushing we include 10 patients who will undergo HIPEC without flushing. 
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
Cytoreductive surgery combined with HIPEC is performed according to local standard treatment 
(APPENDIX 1). 
 
5.2 Use of co-intervention 
Not applicable. 
 
5.3 Escape medication (if applicable) 
Not applicable. 

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6. INVESTIGATIONAL PRODUCT  
Not applicable. Oxaliplatin is the standard primary HIPEC treatment. 

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7. NON-INVESTIGATIONAL PRODUCT 
Cytoreductive surgery combined with HIPEC is performed according to local standard treatment 
(APPENDIX 1). One and a half hour before the intraperitoneal administration of oxaliplatin, the patient 
is treated with an intravenous infusion of folic acid in a dose of 20mg/m2 administered over 30 
minutes. One hour prior to the beginning of IPCH the patient is treated with 5-FU in a dose of 
400mg/m2 administered in 60 minutes to augment the effects of hyperthermic intraperitoneal 
oxaliplatin. According to local protocol HIPEC is performed using an open abdominal cavity procedure 
with the skin pulled upwards (coliseum technique). The abdominal cavity is filled with 5% dextrose. 
2500IU of heparin are added to this solution. After 5-FU is administered and the instillate solution has 
reached a temperature of 41-42 ˚C, oxaliplatin is administered in a dose of 460 mg/m2. Oxaliplatin is 
delivered by the pharmacy in a 5% dextrose solution in the exact dose required for the patient in a 
concentration of 2mg/ml. Duration of IPCH is 30 minutes. 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
 
The main study endpoint is to show a difference in tissue platinum exposure of 
≥25% before and after flushing. Tissue platinum exposure is expressed in 
concentration platinum per milligram tissue (ng/mg). 
8.1.2 Secondary study parameters/endpoints 
 
To explore the difference in total platinum wound exudate concentration between 
patients with and without flushing after completion of HIPEC 
 
To explore, quantify and describe the effect of flushing after HIPEC on systemic 
unbound platinum exposure  
 
To explore, quantify and describe the effect of platinum concentration in instillate on 
tissue platinum exposure 
 
To explore, quantify and describe the effect of the degree of cytoreduction on 
systemic unbound platinum exposure  
 
To explore, quantify and describe the effect of platinum concentration in instillate on 
systemic unbound platinum exposure  
8.1.3 Other study parameters (if applicable) 
The following parameters are collected at baseline: date of birth, gender, ethnicity, medical 
history (including gastrointestinal resections if applicable), body height and weight and current 
medication. 
Furthermore patients will be asked about AEs.Laboratory tests for hematology and 
biochemistry will be performed as part of routine clinical care. 
 
 
8.2 Randomisation, blinding and treatment allocation 
As this is an open label study, blinding procedures are not applicable. A total of 20 patients will be 
included in the study. The first 10 included patients belong to the flushing group and the last 10 
included patients belong to the non-flushing group.  
 
8.3 Study procedures 
After the patient has given written informed consent, each patient will undergo an enrolment 
medical examination in the 14 days prior to the HIPEC procedure. In table 1 a summary is listed of 
the parameters that should be collected prior to the HIPEC procedure. 
 
 
 

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Table 1: summary of study procedures during the study 
Procedure 
Baseline 
Day 1 
Day 2 
Day 3 
              Time window 
-14d 
 
 
Informed consent form 
X 
 
 
Demographicsa 
X 
 
 
Medical history/progress notes 
X 
 
 
Concomitant medication and herbs 
X 
 
 
Treatment toxicity/ AEs (CTCAE 
v4.0) 
 
 
Routine laboratory testsb 
X 
X 
X 
X 
Pharmacokineticsc 
X 
X 
X 
Tissue sampling 
X 
 
Exudate sampling 
X 
X 
X 
Electrocardiogram 
X 
X 
 
 
 
a. 
Date of birth, gender, ethnicity, body weight, body height and current smoking status. 
b. 
Including Karnofsky performance status (see APPENDIX 2).  
c. 
Oxaliplatin administration at the hospital, blood samples at 10, 20 and 30 minutes after the start of HIPEC and at  ¼, 
½, 1, 2, 4, 12, 24, 36, 48 and 72 hours after completion of the HIPEC procedure. 
 
The study procedures overview is given in APPENDIX 3. The study procedures overview displays 
in detail the days and time-points for PK blood sampling, collection of peritoneal fluid samples, 
resection of peritoneal tissue and collection of wound exudate. Patients have to come to the 
hospital at screening and the day prior to the day of surgery. After surgery patients stay for 
approximately one to two days on the intensive care unit. After the study ended the effect of the 
cytoreduction and HIPEC procedure will be evaluated according to standard treatment care. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
8.5 Replacement of individual subjects after withdrawal 
Patients who do not achieve a cytoreduction score of CC-0 will be excluded from the study and 
replaced by another patient. Patients will be replaced if only <50% of the required pharmacokinetic 
samples can be collected for any reason. A maximum number of 10 patients will be replaced. 
 
8.6 Follow-up of subjects withdrawn from treatment 
Patients will be followed up conform standard routine care. Besides standard clinical care, no 
additional follow-up for study purpose is required.  
 

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8.7 Premature termination of the study 
Not applicable. Patients are treated according to routine and consolidated clinical car 
 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there 
is sufficient ground that continuation of the study will jeopardise subject health or safety.  The 
sponsor will notify the accredited METC without undue delay of a temporary halt including the 
reason for such an action. The study will be suspended pending a further positive decision by the 
accredited METC. The investigator will take care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to [the investigational product / trial procedure/ the 
experimental intervention]. All adverse events as consequence of the additional sample 
collection in this study that are reported spontaneously by the subject or observed by the 
investigator or his staff will be recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs as consequence of the additional sample collection in this 
study to the sponsor without undue delay after obtaining knowledge of the events. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in death 
or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
 

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9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Patients who participate in the study will receive standard treatment conform local procedure. 
All SUSARs will therefore be handled following standard work procedure. The SUSAR will be 
reported directly to Lareb (the Netherlands Pharmacovigilance Centre) and Lareb will take 
care of the data input in EudraVigilance.  
 
9.3 Annual safety report 
 
The sponsor will submit, once a year throughout the clinical trial, a safety report to the accredited 
METC.   
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs will be reported till end of study within the Netherlands, as defined in the protocol. 
 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
Regarding the nature of this study no data safety monitoring board will be appointed. 

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10. DATA ANALYSIS 
10.1 Bioanalysis 
Platinum concentrations in blood, instillate, exudate and tissue samples will be analyzed at the Cancer 
biology laboratory in Toulouse or in the Bioanalytical Laboratory of the Netherlands Cancer Institute in 
Amsterdam. The Cancer biology laboratory uses validated  flameless atomic absorption 
spectrophotometry to measure platinum concentrations (30). The Bioanalytical Laboratory of the 
Netherlands Cancer Institute uses a validated method based on quantification of Pt by inductively 
coupled plasma mass spectrometry (31-33).  
 
10.2 Statistical analysis 
10.2.1 Primary study parameter(s) 
The main study endpoint is to show a difference in tumour platinum exposure of ≥25% before and 
after flushing. The tissue platinum exposure before and after flushing will be compared by 
performing a paired sample t-test.  
 
10.2.2 Secondary study parameter(s)  
 
To explore the difference in platinum wound exudate concentration between patients 
with and without flushing after completion of HIPEC:  mean wound exudate 
concentrations will be calculated for both groups (flushing vs. non-flushing). An 
independent t-test will be performed to explore differences. 
 
To explore, quantify and describe the effect of flushing after HIPEC on systemic 
exposure of oxaliplatin: The mean AUCs of unbound platinum will be calculated. 
AUCs of flushing vs. no flushing will be compared by performing an independent t-
test 
 
To explore, quantify and describe the effect of platinum concentration in instillate on 
tissue platinum exposure: Regression analysis will be performed to model the 
relationship 
 
To explore, quantify and describe the effect of the degree of cytoreduction on 
systemic unbound platinum exposure: Regression analysis will be performed to 
model the relationship 
 
To explore, quantify and describe the effect of platinum concentration in instillate on 
systemic unbound platinum exposure: Regression analysis will be performed to 
model the relationship 
 
PK parameters for unbound platinum (AUC0-72h, Cmax and  tmax) will be calculated by non-
compartmental analysis. After finalizing the study the data will additionally be analyzed by Nonlinear 
mixed effect modeling to estimate the PK parameters  for the population and the individual patients. 
 

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Based on the individual concentration-time data, the following PK parameters will be determined (non-
compartmental analysis). 
AUC0-72h : the area under the unbound platinum concentration-time curve calculated (linear 
trapezoidal method) until the last measurable platinum concentration. 
Cmax 
: the maximum unbound platinum drug concentration 
tmax 
: the time to reach maximum unbound platinum drug concentration. 
 
Individual and mean unbound platinum concentrations will be presented. Overlay presentations will be 
given to illustrate intersubject variability. Descriptive statistics will used to calculated the unbound 
platinum concentration at each sampling time. 
10.2.3 Other study parameters 
Descriptive statistics will be performed for demographics collected at baseline.  
 
10.2.4 Interim analysis 
Not applicable.  

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The investigator will ensure that this study is conducted in full compliance with the principles of the 
“Declaration of Helsinki” (as amended in Seoul, Tokyo, Venice, Hong Kong, South Africa and 
Edinburgh), ICH guidelines, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study subject. 
 
11.2 Recruitment and consent 
Eligible patients will be asked for participation by their treating physician or a committed research 
nurse. A patient information folder with extensive information will be handed out to possible 
subjects. It is the responsibility of the investigator to obtain written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and prior to undertaking any study-related procedures. The 
investigator must utilize an IEC-approved consent form for documenting written informed consent. 
Each informed consent will be appropriately signed and dated by the subject and the persons 
obtaining consent. 
An oral summary of the most important topics (e.g. the burden and the right to withdraw without 
consequences) will be given before screening, including time for additional questions. If necessary, 
additional time to (re)consider participation will be provided. 
 
11.3 Objection by minors or incapacitated subjects 
Not applicable. 
 
11.4 Benefits and risks assessment, group relatedness 
Benefits associated with participating in this study are that patients and their treating physician get 
insight into the effect of flushing after HIPEC on tumour exposure. 
Patients who participate in the study will receive standard treatment conform local protocol. 
Therefore the risk for participation in this study is regarded negligible. Collection of peritoneal fluid, 
blood, and wound exudate samples do not put patients at risk or interfere with standard treatment. 
In the group of patients receiving HIPEC with flushing two 5-cm diameter non-tumour peritoneal 
tissue samples will be taken prior to and at the end of flushing. In the group of patients receiving 
HIPEC without flushing one 5-cm diameter non-tumour peritoneal tissue sample will be taken prior 
to  abdominal closure. Compared to the complexity and amount of cytoreduction that is performed 
during surgery this can be considered as a minor procedure. 
 
11.5 Compensation for injury 
 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the WMO. 

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The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 
 
11.6 Incentives 
 
Subjects will receive no compensation for participating in the study. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Blood samples for PK analysis will be identified 
by study name, patient number, date and time of sampling and sample code. The medical record 
and other source documents are only accessible by the medical staff of the clinical research centre, 
the investigator and monitor. CRFs do not contain identifiable information and will be coded with 
randomization numbers only. Information and study files that are  necessary for the evaluation of 
the research are stored anonymously and the identification key will not be accessible by 
unauthorized parties. 
 
12.2 Monitoring and Quality Assurance  
The monitor will be a staff member at the Pharmacy at the Radboud University Nijmegen Medical 
Centre. The monitor will work independently and has no involvement in the set up of the study, the 
conduct of the study and interpretation of the results.  
 
Monitoring consists of:  
 
check essential documents at the site 
 
check eligibility of subjects prior to study start 
 
monitoring for completeness and correctness of the source documents 
 
monitoring of the data in the workbook, and transfer of data from source documents to the 
CRF  
 
write monitoring reports  
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse events/ 
serious adverse reactions as consequence of the additional sample collection, other problems, 
and amendments.  
 

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12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period of 
8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the accredited 
METC.  
 
12.6 Public disclosure and publication policy 
 
The study will be registered to a publicly accessible registry and results database 
(ClinicalTrials.gov). The investigator will submit any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 7 days prior to submission of the 
publication or presentation to all co-investigators.  
12.7 Sample destruction after study completion 
 
Any samples left over after analysis will be destroyed when the study is completed. Samples will be 
discarded in compliance with local biologic waste disposal requirements. 

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13. STRUCTURED RISK ANALYSIS  
 
Half of the patients who participate in the study will receive standard treatment conform current 
practice in Radboudumc, HIPEC with flushing afterwards. The other half of the patients will receive 
standard treatment conform  future protocol that will be implemented in the beginning of 2018, HIPEC 
without flushing afterwards. Because both procedures are currently used in the Netherlands, the 
additional risk for participation in this study is regarded negligible. 
 
 
 

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32. 
Brouwers EE, Tibben MM, Pluim D, Rosing H, Boot H, Cats A, et al. 
Inductively coupled plasma mass spectrometric analysis of the total amount of platinum in 
DNA extracts from peripheral blood mononuclear cells and tissue from patients treated with 
cisplatin. Anal Bioanal Chem. 2008;391(2):577-85. 
33. 
Brouwers EE, Tibben MM, Rosing H, Hillebrand MJ, Joerger M, Schellens 
JH, et al. Sensitive inductively coupled plasma mass spectrometry assay for the 
determination of platinum originating from cisplatin, carboplatin, and oxaliplatin in human 
plasma ultrafiltrate. J Mass Spectrom. 2006;41(9):1186-94. 
 

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15. Appendix 
APPENDIX 1: Radboudumc protocol primary HIPEC with oxaliplatin and 5-FU  
 

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APPENDIX 2: Karnofsky Performance Status Scale Definitions Rating Criteria 
 
WHO/ECOG Performance Status 
Karnofsky Performance status scale 
0 
Able to carry out all normal activity 
without restriction 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
1 
Restricted in physically strenuous 
activity but ambulatory and able to carry 
out light 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 
Ambulatory and capable of all selfcare 
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 personal needs. 
50 
Requires considerable assistance and frequent 
medical care. 
3 
Capable of only limited selfcare, 
confined to bed or chair more than 50% 
of waking hours 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
4 
Completely disabled. Cannot carry on 
any selfcare. Totally confined to bed or 
chair 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
5 
Dead 
0 
Dead 
 
 
 
 

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APPENDIX 3: Study procedures overview 
 
Procedure  
Flushing group  
Screening 
Time relative to the day of surgery 
Day -14 
until day 0 
Day 0 
Day 1 
Day 2 
Day 3 
Written informed 
consent 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Anamnesis/ 
medical history 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Concomitant 
Medications 
X 
 
 
 
 
Laboratory clinical 
chemistry  
X 
 
 
 
 
Cytoreduction and 
HIPEC with flushing 
afterwards 1 
 
X 
 
 
 
Blood PK sampling2 
 
X 
X 
X 
X 
Peritoneal PK 
sampling3 
 
X 
 
 
 
Tissue collection4 
 
X 
 
 
 
Wound exudates 
sampling5 
 
X 
X 
X 
X 
1 flushing is performed with 2L/m2 of sodium chloride 0.9% during 5 minutes 
2 blood samples (timepoints relative to the start of HIPEC): 10min, 20min, 30min, 45min, 1h, 1½ h, 2h, 4h, 12h, 24h, 36h, 48h, 
72h.  
3 peritoneal samples (timepoints relative to the start of HIPEC): oxaliplatin solution: 5min, 15min, 30min; flushing solution: 45min. 
4 tissue samples of peritoneum: pre- and post-flushing 
5 wound exudate samples will be taken each time a drain bottle is changes. Sampling continues until the drain is removed or 
until day 3 post-HIPEC has been reached. 
 
 

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Procedure  
Non-flushing group  
Screening 
Time relative to the day of surgery 
Day -14 
until day 0 
Day 0 
Day 1 
Day 2 
Day 3 
Written informed 
consent 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Anamnesis/ 
medical history 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Concomitant 
Medications 
X 
 
 
 
 
Laboratory clinical 
chemistry  
X 
 
 
 
 
Cytoreduction and 
HIPEC without 
flushing afterwards1 
 
X 
 
 
 
Blood PK 
sampling2 
 
X 
X 
X 
X 
Peritoneal PK 
sampling3 
 
X 
 
 
 
Tissue collection4 
 
X 
 
 
 
Wound exudates 
sampling5 
 
X 
X 
X 
X 
1 no additional flushing is performed 
2 blood samples (timepoints relative to the start of HIPEC): 10min, 20min, 30min, 45min, 1h, 1½ h, 2h, 4h, 12h, 24h, 36h, 48h, 
72h.  
3 peritoneal samples (timepoints relative to the start of HIPEC): oxaliplatin solution: 5min, 15min, 30min 
4 tissue sample of peritoneum after evacuation of oxaliplatin-solution 
5 wound exudate samples will be taken each time a drain bottle is changes. Sampling continues until the drain is removed or 
until day 3 post-HIPEC has been reached.