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Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases (CAIRO6)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02758951
Recruitment Status : Recruiting
First Posted : May 3, 2016
Last Update Posted : January 29, 2019
Sponsor:
Collaborators:
Dutch Cancer Society
Comprehensive Cancer Centre The Netherlands
Hoffmann-La Roche
Information provided by (Responsible Party):
Koen Rovers, Catharina Ziekenhuis Eindhoven

Brief Summary:
This is a multicentre, open-label, parallel-group, phase II-III, superiority study that randomises patients with isolated resectable colorectal peritoneal metastases in a 1:1 ratio to receive either perioperative systemic therapy and cytoreductive surgery with HIPEC (experimental arm) or upfront cytoreductive surgery with HIPEC alone (control arm).

Condition or disease Intervention/treatment Phase
Colorectal Neoplasm Colorectal Cancer Colorectal Neoplasms Malignant Colorectal Carcinoma Colorectal Adenocarcinoma Peritoneal Neoplasms Peritoneal Carcinomatosis Peritoneal Cancer Peritoneal Metastases Peritoneal Neoplasm Malignant Secondary Carcinomatosis Peritoneal Neoplasm Malignant Secondary Other: Perioperative systemic therapy Combination Product: Perioperative CAPOX-bevacizumab Combination Product: Perioperative FOLFOX-bevacizumab Combination Product: Perioperative FOLFIRI-bevacizumab Procedure: CRS-HIPEC, experimental arm Procedure: CRS-HIPEC, control arm Phase 2 Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 358 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Perioperative Systemic Therapy and Cytoreductive Surgery With HIPEC Versus Upfront Cytoreductive Surgery With HIPEC Alone for Isolated Resectable Colorectal Peritoneal Metastases: a Multicentre, Open-label, Parallel-group, Phase II-III, Randomised Superiority Study
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : August 1, 2024
Estimated Study Completion Date : August 1, 2026

Arm Intervention/treatment
Experimental: Perioperative systemic therapy and CRS-HIPEC

At the discretion of the treating physician, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by either four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles.

CRS-HIPEC is performed according to the Dutch protocol in all study centres.

Other: Perioperative systemic therapy
Neoadjuvant systemic therapy should start within four weeks after randomisation. Adjuvant systemic therapy should start within twelve weeks after CRS-HIPEC. In case of unacceptable toxicity or contraindications to oxaliplatin or irinotecan in the neoadjuvant setting, CAPOX or FOLFOX may be switched to FOLFIRI and vice versa. In case of unacceptable toxicity or contraindications to oxaliplatin in the adjuvant setting, CAPOX of FOLFOX may be switched to fluoropyrimidine monotherapy. Dose reduction, prohibited concomitant care, permitted concomitant care, and strategies to improve adherence are not specified a priori, but left to the discretion of the treating medical oncologist. Perioperative systemic therapy can be prematurely discontinued due to radiological or clinical disease progression, unacceptable toxicity, physicians decision, or at patients request.

Combination Product: Perioperative CAPOX-bevacizumab
Four three-weekly neoadjuvant and adjuvant cycles of CAPOX (130 mg/m2 body-surface area [BSA] of oxaliplatin, intravenously [IV] on day 1; 1000 mg/m2 BSA of capecitabine, orally twice daily on days 1-14), with bevacizumab (7.5 mg/kg body weight, IV on day 1) added to the first three neoadjuvant cycles.

Combination Product: Perioperative FOLFOX-bevacizumab
Six two-weekly neoadjuvant and adjuvant cycles of FOLFOX (85 mg/m2 body-surface area [BSA] of oxaliplatin, intravenously [IV] on day 1; 400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2), with bevacizumab (5 mg/kg body weight, IV on day 1) added to the first four neoadjuvant cycles.

Combination Product: Perioperative FOLFIRI-bevacizumab
Six two-weekly neoadjuvant cycles of FOLFIRI (180 mg/m2 body-surface area [BSA] of irinotecan, intravenously [IV] on day 1; 400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) and either four three-weekly (capecitabine (1000 mg/m2 BSA, orally twice daily on days 1-14) or six two-weekly (400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) adjuvant cycles of fluoropyrimidine monotherapy, with bevacizumab (5 mg/kg body weight, IV on day 1) added to the first four neoadjuvant cycles.

Procedure: CRS-HIPEC, experimental arm
CRS-HIPEC is performed according to the Dutch protocol in all study centres. The choice of HIPEC medication (oxaliplatin or mitomycin C) is left to the discretion of the treating physician, since neither one has a favourable safety or efficacy. CRS-HIPEC should be performed within six weeks after completion of neoadjuvant systemic therapy, and at least six weeks after the last administration of bevacizumab in order to minimise the risk of bevacizumab-related postoperative complications.

Active Comparator: Upfront CRS-HIPEC alone
CRS-HIPEC is performed according to the Dutch protocol in all study centres.
Procedure: CRS-HIPEC, control arm
CRS-HIPEC is performed according to the Dutch protocol in all study centres. The choice of HIPEC medication (oxaliplatin or mitomycin C) is left to the discretion of the treating physician, since neither one has a favourable safety or efficacy. CRS-HIPEC should be performed within six weeks after randomisation.




Primary Outcome Measures :
  1. Phase II (n=80): feasibility of perioperative systemic therapy (1) [ Time Frame: Approximately one month after randomisation ]
    Number of patients that start neoadjuvant systemic therapy

  2. Phase II (n=80): feasibility of perioperative systemic therapy (2) [ Time Frame: Approximately four months after randomisation ]
    Number of patients that complete neoadjuvant systemic therapy

  3. Phase II (n=80): feasibility of perioperative systemic therapy (3) [ Time Frame: Approximately four months after randomisation ]
    Number of patients with a dose reduction during neoadjuvant systemic therapy

  4. Phase II (n=80): feasibility of perioperative systemic therapy (4) [ Time Frame: Approximately five months after randomisation ]
    Number of patients that are scheduled for CRS-HIPEC

  5. Phase II (n=80): feasibility of perioperative systemic therapy (5) [ Time Frame: Approximately five months after randomisation ]
    Number of patients that undergo complete CRS-HIPEC

  6. Phase II (n=80): feasibility of perioperative systemic therapy (6) [ Time Frame: Approximately eight months after randomisation ]
    Number of patients that start adjuvant systemic therapy

  7. Phase II (n=80): feasibility of perioperative systemic therapy (7) [ Time Frame: Approximately eleven months after randomisation ]
    Number of patients that complete adjuvant systemic therapy

  8. Phase II (n=80): feasibility of perioperative systemic therapy (8) [ Time Frame: Approximately eleven months after randomisation ]
    Number of patients with a dose reduction during adjuvant systemic therapy

  9. Phase II (n=80): safety of perioperative systemic therapy (1) [ Time Frame: Up to one month after the last administration of systemic therapy (approximately one year after randomisation) ]
    Number of patients with systemic related toxicity, defined as grade 2 or higher according to CTCAE v4.0

  10. Phase II (n=80): safety of perioperative systemic therapy (2) [ Time Frame: Up to three months after CRS-HIPEC (approximately eight months after randomisation) ]
    Number of patients with postoperative morbidity, defined as grade 2 or higher according to Clavien-Dindo

  11. Phase II (n=80): tolerance of perioperative systemic therapy (1) [ Time Frame: Up to six months after CRS-HIPEC (approximately eleven months after randomisation) ]
    EuroQol Five-Dimension Five-Level Questionnaire (EQ-5D-5L) during the initial treatment

  12. Phase II (n=80): tolerance of perioperative systemic therapy (2) [ Time Frame: Up to six months after CRS-HIPEC (approximately eleven months after randomisation) ]
    European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire C30 during the initial treatment

  13. Phase II (n=80): tolerance of perioperative systemic therapy (3) [ Time Frame: Up to six months after CRS-HIPEC (approximately eleven months after randomisation) ]
    European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire CR29 during the initial treatment

  14. Phase II (n=80): radiological response of colorectal PM to neoadjuvant systemic therapy [ Time Frame: Approximately three months after randomisation ]
    Number of patients with an objective radiological response. Central review of thoracoabdominal CT during neoadjuvant systemic therapy. Classification not defined a priori.

  15. Phase II (n=80): histological response of colorectal PM to neoadjuvant systemic therapy [ Time Frame: Approximately five months after randomisation ]
    Number of patients with an objective histological response. Central review of specimens resected during CRS-HIPEC. Classification not defined a priori.

  16. Phase III (n=358): overall survival [ Time Frame: Up to five years after randomisation ]
    Time between randomisation and death

  17. Phase III (n=358): progression-free survival [ Time Frame: Up to five years after randomisation ]
    Time between randomisation and disease progression before CRS-HIPEC, CRS-HIPEC in case of unresectable disease, radiological proof of recurrence, or death

  18. Phase III (n=358): disease-free survival [ Time Frame: Up to five years after randomisation ]
    Time between CRS-HIPEC and radiological proof of recurrence or death in operated patients

  19. Phase III (n=358): health-related quality of life (1) [ Time Frame: Up to five years after randomisation ]
    EuroQol Five-Dimension Five-Level Questionnaire (EQ-5D-5L)

  20. Phase III (n=358): health-related quality of life (2) [ Time Frame: Up to five years after randomisation ]
    European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire C30

  21. Phase III (n=358): health-related quality of life (3) [ Time Frame: Up to five years after randomisation ]
    European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire CR29

  22. Phase III (n=358): costs (1) [ Time Frame: Up to five years after randomisation ]
    Institute for Medical Technology Assessment Productivity Cost Questionnaire

  23. Phase III (n=358): costs (2) [ Time Frame: Up to five years after randomisation ]
    Institute for Medical Technology Assessment Medical Consumption Questionnaire

  24. Phase III (n=358): major postoperative morbidity [ Time Frame: Up to three months after CRS-HIPEC (approximately eight months after randomisation) ]
    Number of patients with postoperative morbidity, defined as grade 2 or higher according to Clavien-Dindo

  25. Phase III (n=358): major systemic therapy related toxicity [ Time Frame: Up to one month after the last administration of systemic therapy (approximately one year after randomisation) ]
    Number of patients with systemic related toxicity, defined as grade 2 or higher according to CTCAE v4.0

  26. Phase III (n=358): radiological response of colorectal PM to neoadjuvant systemic therapy [ Time Frame: Approximately three months after randomisation ]
    Number of patients with an objective radiological response. Central review of thoracoabdominal CT during neoadjuvant systemic therapy. Classification determined after exploration of the radiological response in the phase II study

  27. Phase III (n=358): histological response of colorectal PM to neoadjuvant systemic therapy [ Time Frame: Approximately five months after randomisation ]
    Number of patients with an objective histological response. Central review of specimens resected during CRS-HIPEC. Classification determined after exploration of the histological response in the phase II study.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Eligible patients are adults who have:

  • a World Health Organisation (WHO) performance status of ≤1;
  • histological or cytological proof of PM 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 CRS-HIPEC;
  • no previous CRS-HIPEC;
  • no concurrent malignancies that interfere with the planned study treatment or the prognosis of resected colorectal PM.

Importantly, enrolment is allowed for patients with radiologically non-measurable disease. The diagnostic laparoscopy/laparotomy may be performed in a referring centre, provided that the peritoneal cancer index (PCI) is appropriately scored and documented before enrolment.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02758951


Contacts
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Contact: Koen P Rovers, MD +31402396351 koen.rovers@catharinaziekenhuis.nl
Contact: Checca Bakkers, MD +31402396351 checca.bakkers@catharinaziekenhuis.nl

Locations
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Netherlands
Amsterdam University Medical Centre, Location VUMC Recruiting
Amsterdam, Netherlands
Contact: Jurriaan B Tuynman, MD, PhD    +31204444444    j.tuynman@vumc.nl   
Contact: Henk M Verheul, MD, PhD    +31204444444    h.verheul@vumc.nl   
Principal Investigator: Jurriaan B Tuynman, MD, PhD         
Sub-Investigator: Henk M Verheul, MD, PhD         
Netherlands Cancer Institute Recruiting
Amsterdam, Netherlands
Contact: Arend G Aalbers, MD    +31205129111    a.aalbers@nki.nl   
Contact: Myriam Chalabi, MD    +31205129111    m.chalabi@nki.nl   
Principal Investigator: Arend G Aalbers, MD         
Sub-Investigator: Myriam Chalabi, MD         
Catharina Hospital Recruiting
Eindhoven, Netherlands
Contact: Ignace H de Hingh, MD, PhD    +31402397150    ignace.d.hingh@catharinaziekenhuis.nl   
Contact: Geert-Jan M Creemers, MD, PhD    +31402396622    geert-jan.creemers@catharinaziekenhuis.nl   
Principal Investigator: Ignace H de Hingh, MD, PhD         
Sub-Investigator: Geert-Jan M Creemers, MD, PhD         
Medisch Spectrum Twente Recruiting
Enschede, Netherlands
Contact: Eino B van Duyn, MD, PhD    +31534873440    e.vanduyn@mst.nl   
Contact: Leonie M Mekenkamp, MD, PhD    +31534872440    j.mekenkamp@mst.nl   
Principal Investigator: Eino B van Duyn, MD, PhD         
Sub-Investigator: Leonie M Mekenkamp, MD, PhD         
University Medical Centre Groningen Recruiting
Groningen, Netherlands
Contact: Patrick H Hemmer, MD    +31503616161    p.h.j.hemmer@umcg.nl   
Contact: Derk Jan A de Groot, MD, PhD    +31503616161    d.j.a.de.groot@umcg.nl   
Principal Investigator: Patrick H Hemmer, MD         
Sub-Investigator: Derk Jan A de Groot, MD, PhD         
St. Antonius Hospital Recruiting
Nieuwegein, Netherlands
Contact: Marinus J Wiezer, MD, PhD    +31883201900    r.wiezer@antoniusziekenhuis.nl   
Contact: Maartje Los, MD, PhD    +31883205700    m.los@antoniusziekenhuis.nl   
Principal Investigator: Marinus J Wiezer, MD, PhD         
Sub-Investigator: Maartje Los, MD, PhD         
Radboud University Medical Centre Recruiting
Nijmegen, Netherlands
Contact: Sandra A Radema, MD, PhD    +31243618800    sandra.radema@radboudumc.nl   
Contact: Johannes H de Wilt, MD, PhD    +31243613808    hans.dewilt@radboudumc.nl   
Principal Investigator: Sandra A Radema, MD, PhD         
Sub-Investigator: Johannes H de Wilt, MD, PhD         
Erasmus University Medical Centre Recruiting
Rotterdam, Netherlands
Contact: Alexandra R Brandt-Kerkhof, MD    +31107041506    a.brandt-kerkhof@erasmusmc.nl   
Contact: Esther van Meerten, MD, PhD    +31107040704    e.vanmeerten@erasmusmc.nl   
Principal Investigator: Alexandra R Brandt-Kerkhof, MD         
Sub-Investigator: Esther van Meerten, MD, PhD         
University Medical Centre Utrecht Recruiting
Utrecht, Netherlands
Contact: Wilhelmina M van Grevenstein, MD, PhD    +31887556901    w.m.u.vangrevenstein@umcutrecht.nl   
Contact: Miriam Koopman, MD, PhD    +31887556308    m.koopman-6@umcutrecht.nl   
Principal Investigator: Wilhelmina M van Grevenstein, MD, PhD         
Sub-Investigator: Miriam Koopman, MD, PhD         
Sponsors and Collaborators
Koen Rovers
Dutch Cancer Society
Comprehensive Cancer Centre The Netherlands
Hoffmann-La Roche
Investigators
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Study Chair: Ignace H de Hingh, MD, PhD Catharina Hospital, Eindhoven, Netherlands
Study Director: Pieter J Tanis, MD, PhD Department of Surgery, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands
Study Director: Cornelis J Punt, MD, PhD Department of Medical Oncology, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands
Principal Investigator: Alexandra R Brandt-Kerkhof, MD Department of Surgery, Erasmuc University Medical Centre, Rotterdam, Netherlands
Principal Investigator: Jurriaan B Tuynman, MD, PhD Department of Surgery, Amsterdam University Medical Centre, Location VUMC, Amsterdam, Netherlands
Principal Investigator: Arend G Aalbers, MD Department of Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands
Principal Investigator: Marinus J Wiezer, MD, PhD Department of Surgery, St. Antonius Hospital, Nieuwegein, Netherlands
Principal Investigator: Patrick H Hemmer, MD Department of Surgery, University Medical Centre Groningen, Groningen, Netherlands
Principal Investigator: Sandra A Radema, MD, PhD Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands
Principal Investigator: Wilhemina M van Grevenstein, MD, PhD Department of Surgery, University Medical Centre Utrecht, Utrecht, Netherlands
Principal Investigator: Eino B van Duyn, MD, PhD Department of Surgery, Medisch Spectrum Twente, Enschede, Netherlands
Principal Investigator: Ignace H de Hingh, MD, PhD Department of Surgery, Catharina Hospital, Eindhoven, Netherlands

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Koen Rovers, Coordinating Investigator, Catharina Ziekenhuis Eindhoven
ClinicalTrials.gov Identifier: NCT02758951     History of Changes
Other Study ID Numbers: NL57644.100.16
2016-001865-99 ( EudraCT Number )
ISRCTN15977568 ( Registry Identifier: ISRCTN )
NTR6301 ( Registry Identifier: NTR )
First Posted: May 3, 2016    Key Record Dates
Last Update Posted: January 29, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The full protocol and Dutch informed consent forms are publicly accessible (https://dccg.nl/trial/cairo-6). Participant-level datasets and statistical codes will become available upon reasonable request after the results of the study have been published.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Analytic Code
Time Frame: The full protocol and Dutch informed consent forms are publicly accessible (https://dccg.nl/trial/cairo-6). Participant-level datasets and statistical codes will become available upon reasonable request after the results of the study have been published.
Access Criteria: Reasonable request.
URL: https://dccg.nl/trial/cairo-6

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Koen Rovers, Catharina Ziekenhuis Eindhoven:
Colorectal Neoplasms
Peritoneal Neoplasms
Cytoreduction Surgical Procedures
Hyperthermia, Induced
Neoadjuvant Therapy
Adjuvant Chemotherapy
Bevacizumab
Randomized Controlled Trial
Mortality
Progression-Free Survival

Additional relevant MeSH terms:
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Neoplasms
Colorectal Neoplasms
Adenocarcinoma
Neoplasm Metastasis
Carcinoma
Peritoneal Neoplasms
Colonic Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Abdominal Neoplasms
Peritoneal Diseases
Bevacizumab
Capecitabine
Oxaliplatin
Irinotecan
Fluorouracil
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors