Clinical trial NCT00154102: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Epidermal Growth Factor Receptor (EGFR) Expressing Metastatic Colorectal Cancer
Keywords: Metastatic colorectal cancer
EGFR
Irinotecan
cetuximab
first-line treatment
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2005-09-12
Enrollment: 1221
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Progression-free Survival (PFS) Time - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Progression-free Survival Time (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Progression-free Survival Time (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments
timeFrame: 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 outcomes:
measure: Overall Survival Time (OS)
timeFrame: 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
measure: Overall Survival Time (KRAS Wild-Type Population)
timeFrame: 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
measure: Overall Survival Time (KRAS Mutant Population)
timeFrame: 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
measure: Best Overall Response Rate - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Best Overall Response Rate (KRAS Wild-Type Population) - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Best Overall Response Rate (KRAS Mutant Population) - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Disease Control Rate - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Duration of Response - Independent Review Committee (IRC) Assessments
timeFrame: 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
measure: Participants With No Residual Tumor After Metastatic Surgery
timeFrame: 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
measure: Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status
timeFrame: 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
measure: Quality of Life Assessment (EORTC QLQ-C30) Social Functioning
timeFrame: 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
measure: Safety - Number of Patients Experiencing Any Adverse Event
timeFrame: 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
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Research Site
city: Bedford Park
country: Australia
facility: Research Site
city: Darlinghurst
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Nedlands
country: Australia
facility: Research Site
city: West Perth
country: Australia
facility: Research Site
city: Woodville
country: Australia
facility: Research Site
city: Innsbruck
country: Austria
facility: Research Site
city: Klagenfurt
country: Austria
facility: Research Site
city: Kufstein
country: Austria
facility: Research Site
city: Salzburg
country: Austria
facility: Research Site
city: St. Pölten
country: Austria
facility: Research Site
city: St. Veit an der Glan
country: Austria
facility: Research Site
city: Wels
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Antwerpen
country: Belgium
facility: Research Site
city: Bonheiden
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Goiania
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Santo André
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site
city: Plovidiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Santiago-Las Condes
country: Chile
facility: Research Site
city: Santiago-Providencia
country: Chile
facility: Research Site
city: Chomutov
country: Czech Republic
facility: Research Site
city: Prague
country: Czech Republic
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Boulogne-Billancourt
country: France
facility: Research Site
city: Colmar
country: France
facility: Research Site
city: Grenoble
country: France
facility: Research Site
city: La Roche sur Yon
country: France
facility: Research Site
city: Lorient
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Nantes
country: France
facility: Research Sites
city: Perigueux
country: France
facility: Research Site
city: Rennes Cedex
country: France
facility: Research Site
city: Saint Gregoire
country: France
facility: Research Site
city: Strasbourg
country: France
facility: Research Site
city: Toulon
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Dortmund
country: Germany
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Düsseldorf
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Frankfurt am Main
country: Germany
facility: Research Site
city: Freiburg
country: Germany
facility: Research Site
city: Göttingen
country: Germany
facility: Research Site
city: Halle
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Homburg/Saar
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Oldenburg
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Alexandroupolis
country: Greece
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Heraklion
country: Greece
facility: Research Site
city: Pokfulam
country: Hong Kong
facility: Research Site
city: Shatin
country: Hong Kong
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Györ
country: Hungary
facility: Research Site
city: Kecskemét
country: Hungary
facility: Research Site
city: Pécs
country: Hungary
facility: Research Site
city: Ancona
country: Italy
facility: Research Site
city: Aviano
country: Italy
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Benevento
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Mantova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Modena
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Reggio Emilia
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Rozzano
country: Italy
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Mexico
country: Mexico
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Apeldoom
country: Netherlands
facility: Research Site
city: Blaricum
country: Netherlands
facility: Research Site
city: Den Haag
country: Netherlands
facility: Research Site
city: Roosendaal
country: Netherlands
facility: Research Site
city: Zwolle
country: Netherlands
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Gliwice
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Opole
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Warsaw
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Cluj Napoca
country: Romania
facility: Research Site
city: Iasi
country: Romania
facility: Research Site
city: Suceava
country: Romania
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Banska Bystrica
country: Slovakia
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Trnava
country: Slovakia
facility: Research Site
city: Zilina
country: Slovakia
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Durban
country: South Africa
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Port Elizabeth
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: A Coruna
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Cadiz
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Palma de Mallorca
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Changhua
country: Taiwan
facility: Research Site
city: Chiayi
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan
country: Taiwan
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Charkassy
country: Ukraine
facility: Research Site
city: Donetsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kiev
country: Ukraine
facility: Research Site
city: Krivoy Rog
country: Ukraine
facility: Research Site
city: Lugansk
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Uzhgorod
country: Ukraine
facility: Research Site
city: Zhaporozhye
country: Ukraine
facility: Research Site
city: Brighton
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Guildford
country: United Kingdom
facility: Research Site
city: Kent
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Peterborough
country: United Kingdom
facility: Research Site
city: Rhyl
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: University Hospital Gasthuisberg, Department Internal Medicine, Leuven, Belgium
name: Eric van Cutsem, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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
citation: 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
citation: 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.
citation: 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.
citation: 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.