Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) (CRYSTAL)

January 12, 2017 updated by: Merck KGaA, Darmstadt, Germany

Open, Randomized, Controlled, Multicenter Phase III Study Comparing 5FU/ FA Plus Irinotecan Plus Cetuximab Versus 5FU/FA Plus Irinotecan as First-line Treatment for Epidermal Growth Factor Receptor-expressing Metastatic Colorectal Cancer

Drugs used against cancer work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Giving combination chemotherapy together with cetuximab as first treatment after diagnosis of a metastatic colorectal cancer ('1st-line' treatment) may improve the treatment efficacy. However, it is not yet known whether giving combination chemotherapy together with cetuximab is more effective than combination chemotherapy alone. This open-label trial investigates the effectiveness of cetuximab in combination with a standard and effective chemotherapy (5-Fluorouracil (5FU)/Folinic acid (FA) plus irinotecan) for metastatic colorectal cancer in first-line setting, compared to the same chemotherapy alone on patient expressing the epidermal growth factor (EGF) receptor.

Patients expressing this EGF Receptor will be randomly assign in one of the 2 groups to either receive the combination chemotherapy alone or with cetuximab (open-label study) and will then be treated until progression of the disease or unacceptable toxicity occur. Regular efficacy assessments (every 8 weeks) based on imaging will be performed throughout the study together with regular safety assessments (e.g. safety labs). An independent Safety Board of experts will also monitor safety data.

After participant discontinuation from the trial, regular updates on further treatments and survival status will be requested from the investigator.

The entire study (from the first patient entering the study to the last collect of follow-up information) is 4-5 years long.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

1221

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
      • Buenos Aires, Argentina
        • Research Site
  • Australia
      • Bedford Park, Australia
        • Research Site
      • Darlinghurst, Australia
        • Research Site
      • Heidelberg, Australia
        • Research Site
      • Nedlands, Australia
        • Research Site
      • West Perth, Australia
        • Research Site
      • Woodville, Australia
        • Research Site
  • Austria
      • Innsbruck, Austria
        • Research Site
      • Klagenfurt, Austria
        • Research Site
      • Kufstein, Austria
        • Research Site
      • Salzburg, Austria
        • Research Site
      • St. Pölten, Austria
        • Research Site
      • St. Veit an der Glan, Austria
        • Research Site
      • Wels, Austria
        • Research Site
      • Wien, Austria
        • Research Site
  • Belgium
      • Antwerpen, Belgium
        • Research Site
      • Bonheiden, Belgium
        • Research Site
      • Bruxelles, Belgium
        • Research Site
      • Edegem, Belgium
        • Research Site
      • Gent, Belgium
        • Research Site
      • Leuven, Belgium
        • Research Site
      • Liège, Belgium
        • Research Site
  • Brazil
      • Goiania, Brazil
        • Research Site
      • Porto Alegre, Brazil
        • Research Site
      • Santo André, Brazil
        • Research Site
      • Sao Paulo, Brazil
        • Research Site
  • Bulgaria
      • Pleven, Bulgaria
        • Research Site
      • Plovidiv, Bulgaria
        • Research Site
      • Sofia, Bulgaria
        • Research Site
      • Varna, Bulgaria
        • Research Site
  • Chile
      • Santiago-Las Condes, Chile
        • Research Site
      • Santiago-Providencia, Chile
        • Research Site
  • Czech Republic
      • Chomutov, Czech Republic
        • Research Site
      • Prague, Czech Republic
        • Research Site
  • Finland
      • Turku, Finland
        • Research Site
  • France
      • Bordeaux, France
        • Research Site
      • Boulogne-Billancourt, France
        • Research Site
      • Colmar, France
        • Research Site
      • Grenoble, France
        • Research Site
      • La Roche sur Yon, France
        • Research Site
      • Lorient, France
        • Research Site
      • Marseille, France
        • Research Site
      • Nantes, France
        • Research Sites
      • Perigueux, France
        • Research Site
      • Rennes Cedex, France
        • Research Site
      • Saint Gregoire, France
        • Research Site
      • Strasbourg, France
        • Research Site
      • Toulon, France
        • Research Site
      • Villejuif Cedex, France
        • Research Site
  • Germany
      • Dortmund, Germany
        • Research Site
      • Dresden, Germany
        • Research Site
      • Düsseldorf, Germany
        • Research Site
      • Essen, Germany
        • Research Site
      • Frankfurt am Main, Germany
        • Research Site
      • Freiburg, Germany
        • Research Site
      • Göttingen, Germany
        • Research Site
      • Halle, Germany
        • Research Site
      • Hamburg, Germany
        • Research Site
      • Heidelberg, Germany
        • Research Site
      • Homburg/Saar, Germany
        • Research Site
      • Jena, Germany
        • Research Site
      • Mainz, Germany
        • Research Site
      • Mannheim, Germany
        • Research Site
      • München, Germany
        • Research Site
      • Oldenburg, Germany
        • Research Site
      • Ulm, Germany
        • Research Site
  • Greece
      • Alexandroupolis, Greece
        • Research Site
      • Athens, Greece
        • Research Site
      • Heraklion, Greece
        • Research Site
  • Hong Kong
      • Pokfulam, Hong Kong
        • Research Site
      • Shatin, Hong Kong
        • Research Site
  • Hungary
      • Budapest, Hungary
        • Research Site
      • Debrecen, Hungary
        • Research Site
      • Györ, Hungary
        • Research Site
      • Kecskemét, Hungary
        • Research Site
      • Pécs, Hungary
        • Research Site
  • Italy
      • Ancona, Italy
        • Research Site
      • Aviano, Italy
        • Research Site
      • Bari, Italy
        • Research Site
      • Benevento, Italy
        • Research Site
      • Firenze, Italy
        • Research Site
      • Mantova, Italy
        • Research Site
      • Milano, Italy
        • Research Site
      • Modena, Italy
        • Research Site
      • Napoli, Italy
        • Research Site
      • Reggio Emilia, Italy
        • Research Site
      • Roma, Italy
        • Research Site
      • Rozzano, Italy
        • Research Site
  • Korea, Republic of
      • Seoul, Korea, Republic of
        • Research Site
  • Mexico
      • Mexico, Mexico
        • Research Site
  • Netherlands
      • Amsterdam, Netherlands
        • Research Site
      • Apeldoom, Netherlands
        • Research Site
      • Blaricum, Netherlands
        • Research Site
      • Den Haag, Netherlands
        • Research Site
      • Roosendaal, Netherlands
        • Research Site
      • Zwolle, Netherlands
        • Research Site
  • Poland
      • Bialystok, Poland
        • Research Site
      • Gliwice, Poland
        • Research Site
      • Krakow, Poland
        • Research Site
      • Opole, Poland
        • Research Site
      • Poznan, Poland
        • Research Site
      • Warsaw, Poland
        • Research Site
      • Wroclaw, Poland
        • Research Site
  • Romania
      • Cluj Napoca, Romania
        • Research Site
      • Iasi, Romania
        • Research Site
      • Suceava, Romania
        • Research Site
  • Russian Federation
      • Moscow, Russian Federation
        • Research Site
      • Saint Petersburg, Russian Federation
        • Research Site
      • Yaroslavl, Russian Federation
        • Research Site
  • Singapore
      • Singapore, Singapore
        • Research Site
  • Slovakia
      • Banska Bystrica, Slovakia
        • Research Site
      • Bratislava, Slovakia
        • Research Site
      • Kosice, Slovakia
        • Research Site
      • Trnava, Slovakia
        • Research Site
      • Zilina, Slovakia
        • Research Site
  • South Africa
      • Cape Town, South Africa
        • Research Site
      • Durban, South Africa
        • Research Site
      • Johannesburg, South Africa
        • Research Site
      • Port Elizabeth, South Africa
        • Research Site
      • Pretoria, South Africa
        • Research Site
  • Spain
      • A Coruna, Spain
        • Research Site
      • Barcelona, Spain
        • Research Site
      • Cadiz, Spain
        • Research Site
      • Madrid, Spain
        • Research Site
      • Palma de Mallorca, Spain
        • Research Site
      • Valencia, Spain
        • Research Site
  • Sweden
      • Göteborg, Sweden
        • Research Site
      • Stockholm, Sweden
        • Research Site
  • Taiwan
      • Changhua, Taiwan
        • Research Site
      • Chiayi, Taiwan
        • Research Site
      • Taipei, Taiwan
        • Research Site
      • Taoyuan, Taiwan
        • Research Site
  • Turkey
      • Ankara, Turkey
        • Research Site
      • Istanbul, Turkey
        • Research Site
      • Izmir, Turkey
        • Research Site
  • Ukraine
      • Charkassy, Ukraine
        • Research Site
      • Donetsk, Ukraine
        • Research Site
      • Ivano-Frankivsk, Ukraine
        • Research Site
      • Kiev, Ukraine
        • Research Site
      • Krivoy Rog, Ukraine
        • Research Site
      • Lugansk, Ukraine
        • Research Site
      • Lviv, Ukraine
        • Research Site
      • Uzhgorod, Ukraine
        • Research Site
      • Zhaporozhye, Ukraine
        • Research Site
  • United Kingdom
      • Brighton, United Kingdom
        • Research Site
      • Cambridge, United Kingdom
        • Research Site
      • Glasgow, United Kingdom
        • Research Site
      • Guildford, United Kingdom
        • Research Site
      • Kent, United Kingdom
        • Research Site
      • Leicester, United Kingdom
        • Research Site
      • London, United Kingdom
        • Research Site
      • Peterborough, United Kingdom
        • Research Site
      • Rhyl, United Kingdom
        • Research Site
      • Sutton, United Kingdom
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum
  • Inoperable metastatic disease
  • Immunohistochemical evidence of epidermal growth factor receptor expression in tumor tissue
  • Presence of at least 1 bi-dimensionally measurable index lesion

Exclusion Criteria:

  • Previous irinotecan-based chemotherapy
  • Previous chemotherapy for colorectal cancer except adjuvant treatment if terminated more than 6 months before the start of study treatment
  • Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before the start of study treatment
  • Brain metastasis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Cetuximab Plus FOLFIRI
Drug: Cetuximab
Cetuximab intravenous infusion of 400mg/m^2 for the first infusion then weekly intravenous infusion of 250mg/m^2. Number of Cycles: until progression or unacceptable toxicity develops
Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)
Bi-weekly Irinotecan infusion of 180mg/m^2, Folinic Acid infusion of 400mg/m^2 (racemic) or 200mg/m^2 (L-form), 5-Fluorouracil bolus of 400mg/m^2 followed by a 46-hour continuous infusion of 2400mg/m^2 Number of Cycles: until progression or unacceptable toxicity develops
ACTIVE_COMPARATOR: FOLFIRI Alone
Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)
Bi-weekly Irinotecan infusion of 180mg/m^2, Folinic Acid infusion of 400mg/m^2 (racemic) or 200mg/m^2 (L-form), 5-Fluorouracil bolus of 400mg/m^2 followed by a 46-hour continuous infusion of 2400mg/m^2 Number of Cycles: until progression or unacceptable toxicity develops

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival (PFS) Time - Independent Review Committee (IRC) Assessments
Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006

Duration from randomization until radiological progression (based on modified World Health Organisation (WHO) criteria) or death due to any cause.

Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Progression-free Survival Time (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) - Independent Review Committee (IRC) Assessments
Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006

Duration from randomization until radiological progression (based on modified WHO criteria) or death due to any cause.

Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Progression-free Survival Time (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments
Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006

Duration from randomization until radiological progression (based on modified WHO criteria) or death due to any cause.

Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival Time (OS)
Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is later.
Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009
Overall Survival Time (KRAS Wild-Type Population)
Time Frame: Time from randomisation to death or last day known to be alive reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is later.
Time from randomisation to death or last day known to be alive reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009
Overall Survival Time (KRAS Mutant Population)
Time Frame: Time from randomisation to death or last day known to be alive reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is later.
Time from randomisation to death or last day known to be alive reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 31 May 2009
Best Overall Response Rate - Independent Review Committee (IRC) Assessments
Time Frame: evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).
evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Best Overall Response Rate (KRAS Wild-Type Population) - Independent Review Committee (IRC) Assessments
Time Frame: evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).
evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Best Overall Response Rate (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments
Time Frame: evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).
evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Disease Control Rate - Independent Review Committee (IRC) Assessments
Time Frame: Evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
The disease control rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments (based on modified WHO criteria).
Evaluations were performed every 6 weeks until progression reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Duration of Response - Independent Review Committee (IRC) Assessments
Time Frame: Time from first assessment of complete response or partial response to disease progression, death or last tumor assessment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006

Time from first assessment of Complete Response or Partial Response to disease progression or death (within 60 days of last tumor assessment).

Patients without event are censored on the date of last tumor assessment. Tumor assessments based on modified WHO criteria.
Time from first assessment of complete response or partial response to disease progression, death or last tumor assessment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Participants With No Residual Tumor After Metastatic Surgery
Time Frame: time from first dose up to 30 days after last dose of study treatment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 30 Nov 2007
Participants with no residual tumor after on-study surgery for metastases
time from first dose up to 30 days after last dose of study treatment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 30 Nov 2007
Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status
Time Frame: at baseline, at week 8, at week 16, at week 24, at week 32, and at week 40, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL.
at baseline, at week 8, at week 16, at week 24, at week 32, and at week 40, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Quality of Life Assessment (EORTC QLQ-C30) Social Functioning
Time Frame: at baseline, at week 8, at week 16, at week 24, at week 32, and at week 40, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of functioning.
at baseline, at week 8, at week 16, at week 24, at week 32, and at week 40, reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 27 July 2006
Safety - Number of Patients Experiencing Any Adverse Event
Time Frame: time from first dose up to 30 days after last dose of study treatment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 30 Nov 2007
Please refer to Adverse Events section for further details
time from first dose up to 30 days after last dose of study treatment reported between day of first patient randomised, 10 Aug 2004, until cut-off date, 30 Nov 2007

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Merck KGaA, Darmstadt, Germany

Investigators

  • Principal Investigator: Eric van Cutsem, Professor, University Hospital Gasthuisberg, Department Internal Medicine, Leuven, Belgium

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2004

Primary Completion (ACTUAL)

December 1, 2006

Study Completion (ACTUAL)

March 1, 2011

Study Registration Dates

First Submitted

September 8, 2005

First Submitted That Met QC Criteria

September 8, 2005

First Posted (ESTIMATE)

September 12, 2005

Study Record Updates

Last Update Posted (ESTIMATE)

January 30, 2017

Last Update Submitted That Met QC Criteria

January 12, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EMR 62202-013

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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