Clinical Trials Register

Summary
EudraCT Number:	2019-002290-63
Sponsor's Protocol Code Number:	NL70298.100.19
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2019-002290-63

A.3

Full title of the trial

Bidirectional treatment consisting of repetitive laparoscopic electrostatic pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) and systemic intravenous chemotherapy for isolated unresectable colorectal peritoneal metastases: feasibility, safety, tolerability, and preliminary efficacy.

Bidirectionele behandeling bestaande uit repetitieve laparoscopische electrostatische pressurized intraperitoneal aerosol chemotherapy met oxaliplatine (ePIPAC-OX) en systemische intraveneuze chemotherapie voor geïsoleerde irresectabele colorectale peritoneale metastasen: haalbaarheid, veiligheid, tolerantie, en voorlopige effectiviteit.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Repetitive cycles of combination treatment consisting of three cycles of regular chemotherapy followed by a PIPAC-surgery for the treatment of irresectable peritoneal metastases from colorectal cancer: feasibility, safety, tolerability, efficacy.

Repetitieve rondes van combinatie-therapie bestaand uit drie kuren standaard chemotherapie gevolgd door een PIPAC-operatie voor de behandeling van niet te opereren buikvliesuitzaaiingen van dikke darm kanker: haalbaarheid, veiligheid, tolerantie, effectiviteit.

A.3.2

Name or abbreviated title of the trial where available

CRC-PIPAC-II

A.4.1

Sponsor's protocol code number

NL70298.100.19

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Catharina Ziekenhuis
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Capnomed GmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	St. Antonius Hospital
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Catharina Hospital
B.5.2	Functional name of contact point	Robin Lurvink
B.5.3	Address:
B.5.3.1	Street Address	Michelangelolaan 2
B.5.3.2	Town/ city	Eindhoven
B.5.3.3	Post code	5623EJ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031402391750
B.5.6	E-mail	robin.lurvink@catharinaziekenhuis.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Oxaliplatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare Limited
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxaliplatin
D.3.2	Product code	L01XA03
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Isolated peritoneal metastases (PM) from colorectal cancer (CRC)

Geïsoleerde peritoneale metastasen (PM) van colorectaal carcinoom (CRC)

E.1.1.1

Medical condition in easily understood language

Colorectal cancer with metastases in the peritoneum without other metastases

Dikkedarmkanker met uitzaaiingen in het buikvlies zonder andere uitzaaiingen

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the safety of repetitive cycles of bidirectional treatment consisting of systemic chemotherapy followed by ePIPAC with oxaliplatin (92 mg/m2) in patients with isolated PM from CRC

Het bepalen van de veiligheid van herhaaldelijke rondes bidirectionele therapie, welke bestaat uit systemische chemotherapie gevolgd door ePIPAC met oxaliplatin (92 mg/m2) in patiënten met geïsoleerde PM uit CRC

E.2.2

Secondary objectives of the trial

Given the limited space, this is a continuation of E2.2.2. above:
- The number of patients with a readmission during treatment with repetitive bidirectional therapy.
- Renal, hepatic, and haematological function and tumour markers at inclusion, before start of each cycle of systemic chemotherapy and before each PIPAC.
- The histopathological tumour response of tumour tissue biopsied during each second or third PIPAC procedure.
- Quality of life at inclusion, 1 week before each PIPAC and 4 weeks after each PIPAC.
- The date of macroscopic intraperitoneal tumour progression
- The date of radiologically confirmed systemic tumour progression
- The date of death due to any cause, and the reason of death

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- 18 years or older
- Histologically confirmed PM from a colorectal (including appendiceal) carcinoma that are not amenable for complete cytoreductive surgery, as determined by laparotomy, laparoscopy or radiology.
- WHO performance score of 0-1
- Written informed consent

- 18 jaar of ouder
- Histologisch bevestigde PM van colorectaal (inclusief appendiceaal) carcinoom die niet in aanmerking komt voor cytoreductieve chirurgie, zoals bepaald middels laparotomie, laparoscopie, of radiologie
- WHO 0-1
- Ondertekend informed consent

E.4

Principal exclusion criteria

- Radiological evidence of systemic metastatic disease (e.g. liver, lung);
- Symptomatic presentation (e.g. non-deviated obstructive symptoms);
- Histologically confirmed PM from a low grade appendiceal carcinoma (Disseminated Peritoneal Adeno-Mucinosis / Low-grade Appendiceal Mucinous Neoplasm);
- Inadequate organ functions, defined as an Hb of <5.0 mmol/L, an absolute neutrophil count of <1.5 x 10^9/L, platelet count of <100 x 10^9/L, serum creatinine of >1.5 x ULN, creatinine clearance (Cockroft formula) of <30 ml/min, and liver transaminases of >5 x ULN;
- Any contraindication for the planned chemotherapy (e.g. severe allergy, pregnancy, uncompensated cardiac disease, coagulopathy, serious active infections), as determined by the medical oncologist;
- Any contraindication for a laparoscopy, as determined by the surgeon and/or anesthesiologist;
- Previous PIPAC-procedures;
- Previous treatment with palliative systemic chemotherapy (Note: this criterium does not include patients that received systemic chemotherapy in a (neo-)adjuvant setting).

- Radiologische aanwijzingen voor systemische metastasen
- Symptomatische presentatie (zoals obstructieve symptomen)
- Histologische bevestigde PM uitgaand van een laaggradig appendiceaal carcinoom (DPAM/LAMN)
- inadequate orgaanfunctie, gedefinieerd als een Hb <5.0 mmol/L, een absoluut neutrofielen aantal van <1.5 x 10^9/L, trombocyten van <100 x 10^9/L, serum kreatinine van >1.5x ULN, kreatinine klaring (Cockroft formule) van <30 ml/min, lever transaminasen van >5x ULN.
- Elke contra-indicatie voor de geplande chemotherapie, vastgesteld door de medisch oncoloog (bijv. allergie, zwangerschap, decompensatio cordis, stollingsstoornissen, ernstige actieve infectie)
- Elke contraindicatie voor een laparoscopie, zoals bepaald door de chirurg en/of anesthesist
- Eerdere behandelingen met PIPAC
- Eerdere eerste lijns palliatieve systemische chemotherapie

E.5 End points

E.5.1

Primary end point(s)

The number of patients with CTCAE severe toxicity, measured up to 4 weeks after the last PIPAC procedure

Het aantal patienten met ernstige toxiciteit, bepaald tot 4 weken na de laatste PIPAC procedure

E.5.1.1

Timepoint(s) of evaluation of this end point

From trial inclusion up to 4 weeks after the last PIPAC procedure

Vanaf inclusie in de studie tot en met 4 weken na de laatste PIPAC procedure

E.5.2

Secondary end point(s)

- The number of patients with moderate or mild toxicity, measured up to 4 weeks after the last PIPAC procedure.
- The technical difficulties with PIPAC technology during each PIPAC procedure
- The number of PIPAC procedures in each patient
- The number of cycles of bidirectional therapy (each cycle consisting of two/three cycles of systemic chemotherapy followed by a PIPAC procedure) in each patient and reasons for discontinuation.
- The number of cycles of systemic chemotherapy completed, the number of dose reductions, and reasons for discontinuation or dose reduction.
- The possibility of laparoscopic access during each PIPAC procedure
- The volume of ascites during each PIPAC procedure
- The PCI during each PIPAC procedure
- The operating time of each PIPAC procedure
- The blood loss during each PIPAC procedure
- The occurrence of intraoperative complications during each PIPAC procedure
- The hospital stay after each PIPAC procedure
- The number of patients with a readmission during treatment with repetitive bidirectional therapy.
- Renal, hepatic, and haematological function and tumour markers at inclusion, before start of each cycle of systemic chemotherapy and before each PIPAC.
- The histopathological tumour response of tumour tissue biopsied during each second or third PIPAC procedure.
- Quality of life at inclusion, 1 week before each PIPAC and 4 weeks after each PIPAC.
- The date of macroscopic intraperitoneal tumour progression
- The date of radiologically confirmed systemic tumour progression
- The date of death due to any cause, and the reason of death

- Het aantal patiënten met matige tot milde toxiciteit, gemeten tot 4 weken na de laatste PIPAC procedure.
- Technische moeizaamheden met PIPAC technologie tijdens elke PIPAC procedure
- Het aantal PIPAC procedures in elke patient
- Het aantal cycli van bidirectionele therapie (elke cycli bestaat uit 2-3 kuren systemische chemotherapie gevolgd door een PIPAC procedure) in elke patient en redenen voor discontinuatie.
- Het aantal cycli van systemische chemotherapie dat is afgerond, het aantal dosis reducties, en redenen voor stoppen met chemotherapie of dosis reductie.
- De laparoscopische toegang tijdens elke PIPAC operatie
- De PCI tijdens elke PIPAC operatie
- De operatieduur tijdens elke PIPAC operatie
- Het bloedverlies tijdens elke PIPAC operatie
- Het aantal intraoperatieve complicaties tijdens elke PIPAC operatie
- De opnameduur na elke PIPAC operatie
- Het aantal patienten dat wordt heropgenomen tijdens behandeling met repetitieve bidirectionele therapie
- Renale, hepatische en hematologische functie en tumor markers bij inclusie, voor start van elke chemokuur, en voor elke PIPAC.
- Histopathologische tumor respons van tumor weefsel dat gebiopteerd wordt bij de tweede of derde PIPAC
- Kwaliteit van leven bij inclusie, 1 week voor elke PIPAC, en 4 weken na elke PIPAC
- De datum van macroscopische intraperitoneale tumor progressie
- De datum van radiologisch bevestigde systemische ziekteprogressie
- De datum van overlijden door elke reden, en de reden van overlijden

E.5.2.1

Timepoint(s) of evaluation of this end point

Continuation of E 5.2.1. above:
- Blood loss during each PIPAC procedure
- Occurrence of intraoperative complications during each PIPAC procedure
- Hospital stay after each PIPAC procedure
- Number of patients with a readmission during trial participation
- Renal, hepatic, and haematological function and tumour markers at inclusion, before start of each cycle of systemic chemotherapy and before each PIPAC.
- Histopathological tumour response of tumour tissue biopsied during each second or third PIPAC procedure.
- Quality of life at inclusion, 1 week before each PIPAC and 4 weeks after each PIPAC.
- Date of macroscopic intraperitoneal tumour progression
- Date of radiologically confirmed systemic tumour progression
- Date of death due to any cause, and the reason of death

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

After the 20th patient completed his/her 1 year follow-up

Nadat de 20e patiënt zijn 1-jaarsfollowup afspraak eheft gehad

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Regular oncological follow-up according to standardised local protocol

Reguliere oncologische follow-up volgens gestandaardiseerd lokaal protocol

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-08

P. End of Trial
P.	End of Trial Status	Ongoing

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