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

• ClinicalTrials.gov Identifier: NCT00154102
• Recruitment Status: Completed
• First Posted: September 12, 2005
• Results First Posted: February 23, 2011
• Last Update Posted: January 30, 2017
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by: Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: September 8, 2005
• First Posted Date: September 12, 2005
• Results First Submitted Date: November 30, 2010
• Results First Posted Date: February 23, 2011
• Last Update Posted Date: January 30, 2017
• Study Start Date: May 2004
• Actual Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2011)

• 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.
• 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.
• 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.

• Original Primary Outcome Measures (submitted: September 8, 2005): Progression-free survival time under 5-FU/FA plus irinotecan with or without cetuximab

Current Secondary Outcome Measures (submitted: May 27, 2011)

• 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.
• 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.
• 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.
• 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).
• 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).
• 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).
• 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).
• 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.
• 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
• 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.
• 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.
• 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

Original Secondary Outcome Measures (submitted: September 8, 2005)

• Overall Survival time
• Response Rate and Disease Control rate
• Duration or Response
• Quality of Life
• Safety

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL)
• Official Title: 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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Epidermal Growth Factor Receptor (EGFR) Expressing Metastatic Colorectal Cancer

Intervention

• 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

Study Arms

• Experimental: Cetuximab Plus FOLFIRI
  Interventions:

  • Drug: Cetuximab
  • Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)
• Active Comparator: FOLFIRI Alone
  Intervention: Drug: FOLFIRI (5-Fluorouracil, Folinic acid, Irinotecan)

Publications *

• Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.
• Van Cutsem E, Lang I, Folprecht G, Nowacki M, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Celik I, Kohne C Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): The influence of KRAS and BRAF biomarkers on outcome: Updated data from the CRYSTAL trial. ASCO 2010 Gastrointestinal Cancers Symposium, Orlando, USA January 2010 Abstract No: 281
• Lang I, Kohne CH, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Zubel A, Van Cutsem E Cetuximab plus FOLFIRI in 1st-line treatment of metastatic colorectal cancer: Quality of life (QoL) analysis of patients (pts) with KRAS wild-type (wt) tumours in the CRYSTAL trial. European Journal of Cancer Supplements. 2009 7(2):345
• Dercle L, Lu L, Lichtenstein P, Yang H, Wang D, Zhu J, Wu F, Piessevaux H, Schwartz LH, Zhao B. Impact of Variability in Portal Venous Phase Acquisition Timing in Tumor Density Measurement and Treatment Response Assessment: Metastatic Colorectal Cancer as a Paradigm. JCO Clin Cancer Inform. 2017 Nov;1:1-8. doi: 10.1200/CCI.17.00108.
• Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, Esser R, Lenz HJ, Heinemann V. Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol. 2017 Feb 1;3(2):194-201. doi: 10.1001/jamaoncol.2016.3797. Erratum In: JAMA Oncol. 2017 Dec 1;3(12):1742.
• Licitra L, Storkel S, Kerr KM, Van Cutsem E, Pirker R, Hirsch FR, Vermorken JB, von Heydebreck A, Esser R, Celik I, Ciardiello F. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer. 2013 Apr;49(6):1161-8. doi: 10.1016/j.ejca.2012.11.018. Epub 2012 Dec 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 5, 2007): 1221
• Original Enrollment (submitted: September 8, 2005): 1080
• Actual Study Completion Date: March 2011
• Actual Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, Czech Republic, Finland, France, Germany, Greece, Hong Kong, Hungary, Italy, Korea, Republic of, Mexico, Netherlands, Poland, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom
• Removed Location Countries: Estonia, Israel

Administrative Information

• NCT Number: NCT00154102
• Other Study ID Numbers: EMR 62202-013
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Monika Foerster, Merck Serono
• Original Responsible Party: Not Provided
• Current Study Sponsor: Merck KGaA, Darmstadt, Germany
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Merck KGaA, Darmstadt, Germany
• Verification Date: January 2017