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    Summary
    EudraCT Number:2016-001865-99
    Sponsor's Protocol Code Number:NL57644.100.16
    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:2016-09-14
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-001865-99
    A.3Full title of the trial
    Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone: a multicentre, open-label, parallel-group, phase II-III, randomised superiority study (CAIRO6).
    Perioperatieve systemische therapie en cytoreductieve chirurgie met HIPEC versus alleen upfront cytoreductieve chirurgie met HIPEC: een multicenter, open-label, parallel-groep, fase II-III, gerandomiseerde superioriteitsstudie (CAIRO6).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemo-immunotherapy before and after surgery for peritoneal metastases of large bowel cancer
    Chemo-immunotherapie rondom de HIPEC-operatie voor buikvliesuitzaaiingen uit dikkedarmkanker.
    A.3.2Name or abbreviated title of the trial where available
    CAIRO-6
    CAIRO-6
    A.4.1Sponsor's protocol code numberNL57644.100.16
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN15977568
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02758951
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1182-2871
    A.5.4Other Identifiers
    Name:NTRNumber:NTR6301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCatharina Ziekenhuis
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHoffman-La Roche
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportCatharina Research Fund
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportDutch Cancer Society (KWF Kankerbestrijding)
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCatharina Ziekenhuis
    B.5.2Functional name of contact pointKoen Rovers
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 1350
    B.5.3.2Town/ cityEindhoven
    B.5.3.3Post code5602 ZA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31402396351
    B.5.5Fax number31402397219
    B.5.6E-mailkoen.rovers@catharinaziekenhuis.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Bevacizumab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Oxaliplatin
    D.2.1.1.2Name of the Marketing Authorisation holderPharmachemie B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 5-fluorouracil
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intravenous bolus use (Noncurrent)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Leucovorin
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Capecitabine
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Irinotecan
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Isolated resectable colorectal peritoneal metastases.
    Geïsoleerde resectabele colorectale peritoneale metastasen.
    E.1.1.1Medical condition in easily understood language
    Operable peritoneal metastases of large bowel cancer.
    Operabele buikvliesuitzaaiingen uit dikkedarmkanker.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Objectives of the phase II study (80 patients) are to explore the feasibility of accrual, the feasibility, safety, and tolerance of perioperative systemic therapy, and the radiological and histological response of colorectal peritoneal metastases to neoadjuvant systemic therapy. The primary objective of the phase III study (an additional 278 patients) is to compare survival outcomes between both arms.
    Doel van de fase II studie (80 patiënten) is het exploreren van de haalbaarheid van inclusie, de haalbaarheid, veiligheid, en tolerantie van perioperatieve systemische therapie, en de radiologische/histologische response van colorectale peritoneale metastasen op neoadjuvante systemische therapie. Het primaire doel van de fase III studie (278 patiënten meer) is het vergelijken van overlevingsuitkomsten tussen beide armen.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to compare surgical characteristics, major postoperative morbidity, health-related quality of life, and costs between both arms. Other objectives are to assess major systemic therapy related toxicity and the objective radiological and histological response of colorectal peritoneal metastases to neoadjuvant systemic therapy.
    Secundaire doelen zijn het vergelijken van chirurgische karakteristieken, ernstige postoperatieve morbiditeit, kwaliteit van leven, en kosten tussen beide armen. Andere doelen zijn het bepalen van de ernstige systemische therapie gerelateerde toxiciteit en de radiologische/histologische respons van colorectale peritoneale metastasen op neoadjuvante systemische therapie.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible patients are adults who have:
     a World Health Organisation (WHO) performance status of ≤1;
     histological or cytological proof of peritioneal metastases of a non-appendiceal colorectal adenocarcinoma with ≤50% of the tumour cells being signet ring cells;
     resectable disease determined by abdominal computed tomography (CT) and a diagnostic laparoscopy/laparotomy;
     no evidence of systemic colorectal metastases within three months prior to enrolment;
     no systemic therapy for colorectal cancer within six months prior to enrolment;
     no contraindications for cytorductive surgery with HIPEC;
     no previous cytoreductive surgery with HIPEC;
     no concurrent malignancies that interfere with the planned study treatment or the prognosis of resected colorectal peritoneal metastases.
    Geschikte patiënten zijn volwassenen met de volgende criteria:
     een World Health Organisation (WHO) performance score van ≤1;
     histologisch of cytologisch bewijs van peritoneale metastasen van een niet-appendiceaal colorectaal carcinoom waarbij ≤50% van de tumorcellen zegelringcellen zijn;
     resectabele ziekte, bepaald door een CT-abdomen en een diagnostische laparoscopie/laparotomie;
     geen bewijs van systemische metastasen in de 3 maanden voorafgaand aan inclusie;
     geen systemische therapie in de 6 maanden voorafgaand aan inclusie;
     geen contraindicaties voor cytoreductieve chirurgie met HIPEC;
     geen eerdere cytoreductieve chirurgie met HIPEC;
     geen andere maligniteiten die interfereren met de geplande studiebehandeling of de prognose van gereseceerde colorectale peritoneale metastasen.
    E.4Principal exclusion criteria
    Patients are excluded in case of any comorbidity or condition that prevents safe administration of the planned perioperative systemic therapy, determined by the treating medical oncologist, e.g.:
     Inadequate bone marrow, renal, or liver functions (e.g. haemoglobin <6.0 mmol/L, neutrophils <1.5 x 109/L, platelets <100 x 109/L, serum creatinine >1.5 x ULN, creatinine clearance <30 ml/min, bilirubin >2 x ULN, serum liver transaminases >5 x ULN);
     Previous intolerance of fluoropyrimidines or both oxaliplatin and irinotecan;
     Dehydropyrimidine dehydrogenase deficiency;
     Serious active infections;
     Severe diarrhoea;
     Stomatitis or ulceration in the mouth or gastrointestinal tract;
     Recent major cardiovascular events;
     Unstable or uncompensated respiratory or cardiac disease;
     Bleeding diathesis or coagulopathy;
     Pregnancy or lactation.
    Patiënten worden geëxcludeerd als zij een comorbiditeit/conditie hebben die veilige administratie van de geplande systemische therapie voorkomt, zoals bepaald door de behandelend medisch oncoloog, bijvoorbeeld:
     inadequate beenmerg-, nier-, or leverfuncties (bijv. hemoglobine <6.0 mmol/L, neutrofielen <1.5 x 109/L, plaatjes <100 x 109/L, serum kreatinine >1.5 x ULN, kreatinine klaring <30 ml/min, bilirubine >2 x ULN, serum levertransaminases >5 x ULN);
     eerdere intolerantie voor fluoropyrimidines of zowel oxaliplatin als irinotecan;
     dehydropyrimidine dehydrogenase deficiëntie;
     actieve infecties;
     ernstige diarree;
     stomatitis of ulceratie van de mond of gastrointestinale tractus;
     recente grote cardiovasculaire events;
     instabiele of gedecompenseerde respiratiore of cardiale aandoening(en);
     bloedingsdiathese of coagulopathie;
     zwangerschap of lactatie.
    E.5 End points
    E.5.1Primary end point(s)
    Outcomes of the phase II study are to explore:
     the feasibility of accrual, based on the total accrual rate, the accrual rate in each study cen-tre, and screening failures;
     the feasibility of perioperative systemic therapy, based on the number of patients that (1) start and complete neoadjuvant systemic therapy, with or without dose reductions, (2) are scheduled for CRS-HIPEC, (3) undergo complete CRS-HIPEC, and (4) start and complete ad-juvant systemic therapy, with or without dose reductions;
     the safety of perioperative systemic therapy, based on the number of patients with (1) systemic therapy related toxicity, defined as grade ≥2 according to the Common Terminol-ogy Criteria for Adverse Events (CTCAE) v4.0 [87], up to one month after the last admin-istration of systemic therapy, and (2) postoperative morbidity, defined as grade ≥2 accord-ing to Clavien-Dindo [88], up to three months after CRS-HIPEC;
     the tolerance of perioperative systemic therapy, based on health-related quality of life ex-tracted from EQ-5D-5L, QLQ-C30, and QLQ-CR29 during study treatment;
     the radiological and histological response of colorectal peritoneal metastases to neoadjuvant systemic thera-py, based on central review of thoracoabdominal CT and resected specimens during CRS-HIPEC, respectively. Classifications are not defined a priori.

    The primary outcome of the phase III study is 3-year overall survival, defined as the number of patients who are alive three years after randomisation.
    Uitkomsten van de fase II studie zijn het exploreren van:
     de haalbaarheid van inclusie, gebaseerd op de totale inclusie, de inclusie per centrum, en screening failures;
     de haalbaarheid van perioperatieve systemische therapie, gebaseerd op het aantal patiënten dat (1) neoadjuvante systemische therapie start/completeert met/zonder dosisreducties, (2) wordt gepland voor CRS-HPEC, (3) complete CRS-HIPEC ondergaan, en (4) adjuvante systemische therapie start/completeert met/zonder dosisreducties;
     de veiligheid van perioperatieve systemische therapie, gebaseerd op het aantal patiënten met (1) systemische therapie gerelateerde toxiciteit, gedefinieerd als graad ≥2 volgens CTCAE v4.0, tot 1 maand na de laatste gift systemische therapie, en (2) postoperatieve morbiditeit, gedefinieerd als graad ≥2 volgens Clavien-Dindo, tot 3 maanden na CRS-HIPEC;
     de tolerantie van perioperatieve systemische therapie, gebaseerd op kwaliteit van leven geextraheerd uit EQ-5D-5L, QLQ-C30, and QLQ-CR29 gedurende de studiebehandeling;
     de radiologische en histologische respons van colorectale peritoneale metastasen op neoadjuvante systemische therapie, gebaseerd op centrale review van CT's en gereseceerde weefsels tijdens CRS-HIPEC, respectievelijk. Classificaties zijn niet van tevoren gespecificeerd.

    De primaire uitkomst van de fase III studie is 3-jaars algehele overleving, gedefinieerd als het aantal patiënten die in leven zijn 3 jaar na randomisatie.
    E.5.1.1Timepoint(s) of evaluation of this end point
    See E.5.1
    Zie E.5.1
    E.5.2Secondary end point(s)
    Secondary outcomes in both arms are:

     progression-free survival, defined as the time between randomisation and disease pro-gression before CRS-HIPEC, CRS-HIPEC in case of unresectable disease, radiological proof of recurrence, or death;
     disease-free survival, defined as the time between CRS-HIPEC and radiological proof of re-currence or death;
     health-related quality of life, extracted from questionnaires (EQ-5D-5L, QLQ-C30, QLQ-CR29) at different points in time;
     costs, extracted from questionnaires (iMTA PCQ, iMTA MCQ) at different points in time;
     surgical characteristics of CRS-HIPEC (e.g. PCI, intraoperative complications, operating time, visceral and peritoneal resections, completeness of cytoreduction, hospital stay);
     the number of patients with major postoperative morbidity, defined as grade ≥3 according to Clavien-Dindo, up to three months after CRS-HIPEC

    Secondary outcomes in the experimental arm are:

     The number of patients with major systemic therapy related toxicity, defined as grade ≥3 according to the CTCAE, up to one month after the last administration of systemic therapy;
     The number of patients with an objective radiological and histological response of colorectal PM to neoadjuvant systemic therapy, determined by central review of thoracoabdominal CT and resected specimens during CRS-HIPEC, respectively. Classifications are determined after exploration of the radiological and histological response in the phase II study.
    Secundaire uitkomsten in beide armen zijn:

     progressievrije overleving, gedefinieerd als de tijd tussen randomisatie en ziekteprogressie voor CRS-HIPEC, CRS-HIPEC bij irresectabele ziekte, radiologisch bewijs van recidief, of overlijden;
     ziektevrije overleving, gedefinieerd als de tijd tussen CRS-HIPEC en radiologisch bewijs van recidief of overlijden;
     kwaliteit van leven, geextraheerd uit vragenlijsten (EQ-5D-5L, QLQ-C30, QLQ-CR29) op verschillende tijdsmomenten;
     kosten, geextraheerd uit vragenlijsten (iMTA PCQ, iMTA MCQ) op verschillende tijdsmomenten;
     chirurgische karakteristieken van CRS-HIPEC (bijv. intraoperatieve complicaties, operatieduur, resecties, CC-score, ziekenhuisopname);
     het aantal patiënten met ernstige postoperatieve morbiditeit, gedefinieerd als graad ≥3 volgens Clavien-Dindo, tot 3 maanden na CRS-HIPEC

    Secundaire uitkomsten in de experimentele arm zijn:

     het aantal patiënten met ernstige systemische therapie gerelateerde toxiciteit, gedefinieerd als graad ≥3 volgens CTCAE v4.0, tot 1 maand na de laatste gift systemische therapie;
     het aantal patiënten met een objectieve radiologische/histologische response, bepaald door centrale review van CT-scans en gereseceerde weefsels tijdens CRS-HIPEC, respectievelijk. Classificaties worden bepaald na exploratie van de radiologische/histologische respons in de fase II studie.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See E.5.2
    Zie E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Geen perioperatieve systemische therapie
    No perioperative systemic therapy
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    This study ends when all patients are 5 years after randomisation.

    The study is prematurely terminated after the first interim analysis (80 patients) if less than 50% of the patients in the experimental arm undergo complete CRS-HIPEC or if the percentage of patients with major postoperative morbidity (Clavien-Dindo grade ≥3) is ≥20% higher in the experimental arm compared to the control arm
    Deze studie eindigt wanneer alle patiënten 5 jaar na randomisatie zijn.

    De studie wordt vroegtijdig beëindigd na de eerste interim-analyse (80 patiënten) als minder dan 50% van de patiënten in de experimentele arm complete CRS-HIPEC ondergaan of als het percentage patiënten met ernstige postoperatieve morbiditeit (Clavien-Dindo graad ≥3 ≥20% hoger is in de experimentele arm dan in de controle-arm.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 179
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 179
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state358
    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)
    Standard oncological care according to local treatment guidelines.
    Standaard oncologische zorg aan de hand van lokale behandelprotocollen.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Dutch Peritoneal Oncology Group
    G.4.3.4Network Country Netherlands
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Dutch Colorectal Cancer Group
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-13
    P. End of Trial
    P.End of Trial StatusOngoing
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