Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer (Everest2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Universitaire Ziekenhuizen Leuven
Sponsor:
Collaborator:
Merck KGaA
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier:
NCT01251536
First received: December 1, 2010
Last updated: January 21, 2014
Last verified: January 2014
  Purpose

The purposes of this study are to determine whether administering escalating doses of cetuximab in patients with no early skin toxicity could delay the progression of disease in a significant proportion of patients and to study the molecular signatures of response.


Condition Intervention Phase
Colorectal Cancer
Drug: Dose escalation of cetuximab
Drug: Standard first line treatment with cetuximab + Folfiri
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two Arm Phase II Study of FOLFIRI in Combination With Standard or Escalating Dose of Cetuximab as First Line Treatment of K-Ras Wild Type Metastatic Colorectal Cancer: Everest 2

Resource links provided by NLM:


Further study details as provided by Universitaire Ziekenhuizen Leuven:

Primary Outcome Measures:
  • PFS rate at 9 months in the dose escalation arm [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    To provide a precise estimate (+/- 10%) of the progression-free survival rate at 9 months, in patients without skin toxicity at 3 weeks (according to NCI CTCAE v. 4.0), treated with FOLFIRI + escalating dose of cetuximab (arm A). It is expected that the PFS rate will be similar to that observed after standard cetuximab treatment + FOLFIRI in patients with grade 1-4 skin toxicity in a K-Ras wild type population (CRYSTAL study)


Secondary Outcome Measures:
  • Safety profile (NCI-CTCAE v. 4.0) of the combination in treatment arms [ Time Frame: 3.5 years ] [ Designated as safety issue: Yes ]

    To evaluate PFS, OS, overall response and response rate in liver-limited disease, disease control rate, duration of response, general resection rate and R0 resection rate for metastatic lesions, skin toxicity, general safety, biomarkers, proteomics, expression profiling, mutations in each of the treatment arms.

    To evaluate pharmacokinetic parameters in patients in both treatment arms in selected centers


  • Skin toxicity and correlations between outcome, PK and dose escalations [ Time Frame: 3.5 years ] [ Designated as safety issue: Yes ]
  • Overall response and response rate in liver-limited disease [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  • Disease control rates [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  • Progression free survival and overall survival [ Time Frame: 6 years ] [ Designated as safety issue: No ]
  • R0 resection rate for metastatic lesions [ Time Frame: 3.5 years ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic parameters in patients in both treatment arms in selected centers only [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]
  • To perform biomarker analyses: proteomics, microarray and PCR studies on plasma and tumour respectively, in both treatment arms. [ Time Frame: 3.5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 375
Study Start Date: December 2010
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Arm B - standard dose of cetuximab
Patients with skin toxicity grade 1-4 or other significant toxicity who are not eligible for dose escalation will continue on the standard dose of cetuximab 250 mg/m2 weekly
Drug: Standard first line treatment with cetuximab + Folfiri

Dose, frequency & treatment mode: 400 mg/m2 (loading at day 1) followed by 250 mg/m2 weekly (at day 8 and 15)

Arm allocation at day 22:

Patients with skin toxicity grade 1-4 or other significant toxicity who are not eligible for dose escalation will continue on the standard dose of cetuximab: 250 mg/m2 weekly.

Other Name: Erbitux
Experimental: Arm A - dose escalation of cetuximab
Patients with skin toxicity grade 0 will follow an increasing dose schedule: on days 22 and 29 they will receive 350 mg/m2 and from day 36 onwards, 500 mg/m2 weekly.
Drug: Dose escalation of cetuximab

Dose, frequency & treatment mode: 400 mg/m2 (loading at day 1) followed by 250 mg/m2 weekly (at day 8 and 15)

Arm allocation at day 22:

Patients with skin toxicity grade 0 will follow an increasing dose schedule: on days 22 and 29 they will receive 350 mg/m2 and from day 36 onwards, 500 mg/m2 weekly

Other Name: Erbitux

Detailed Description:

Colorectal carcinoma (CRC) is the third most common form of cancer worldwide and remains a leading malignancy both in incidence and mortality.

In the light of existing knowledge, the investigators propose a phase II open label, two arm study in patients presenting with K-Ras wild-type metastatic colorectal tumours in the first line setting. The standard combination of irinotecan plus infusional 5-FU/LV (FOLFIRI) and cetuximab will be given to all patients entering the study. As the investigators hypothesize that increasing the dose of cetuximab might increase the intensity of skin reactions that directly correlates with outcome, in patients experiencing no skin toxicity, the dose of cetuximab will be escalated from 250 mg/m2 to 350 mg/m2 and then up to 500 mg/m2, in order to better define the effect of dose escalation in the first-line setting in a K-Ras wild type tumour population and in an attempt to increase efficacy.

Pharmacokinetic studies will be performed to document PK parameters of cetuximab in patients from both arms in selected centers.

Translational research studies are planned for all patients. Some more in depth molecular testing will be performed in a subset of patients from whom three serial tissue samples from accessible metastases by biopsy are available.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent (+ optional for PK and TR) must be given according to ICH/GCP and national/local regulations.
  2. Patient is at least 18 years of age.
  3. Patient's body weight is ≤ 120 kg.
  4. Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon or rectum, not in a previously irradiated area.
  5. K-Ras wild type tumour eligible for treatment with cetuximab.
  6. Unresectable metastatic disease.
  7. Life expectancy of at least 12 weeks.
  8. WHO ECOG performance status: 0 or 1.
  9. Effective contraception for both male and female patients if the risk of conception exists.
  10. Adequate organ function.
  11. Adequate bone marrow, hepatic and renal function (assessed within 14 days prior to study entry):

    • Hemoglobin > 10.0 g/dL, absolute neutrophil count > 1.5 x 109/L, platelet count > 100 x 109/L
    • ALAT, ASAT < 2.5 x ULN, up to < 5 x ULN in case of liver metastases
    • Alkaline phosphatase < 2.5 x ULN
    • Total bilirubin < 1.5 x ULN
    • Creatinine clearance > 50 mL/min (calculated according to Cockroft and Gault)

Exclusion Criteria:

  1. Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines +/-oxaliplatin based regimens allowed if stopped 6 months prior to registration on study).
  2. Prior treatment with EGFR inhibitor or chemotherapy with irinotecan in adjuvant settings.
  3. Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry.
  4. Administration of any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment.
  5. Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or hormone therapy not indicated in the study protocol.
  6. Any active dermatological condition > grade 1.
  7. Brain metastasis (known or suspected).
  8. Significant impairment of intestinal absorption (e.g. chronic diarrhea, inflammatory bowel disease).
  9. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection.
  10. Uncontrolled coronary artery disease and/or unstable angina, a history of a myocardial infarction within the last 12 months or heart failure NYHA class III or IV. High risk of uncontrolled arrhythmia.
  11. Known allergy or any other adverse reaction to any of the drugs or to any related compound.
  12. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
  13. Gilbert disease.
  14. Previous (within 5 years) or concurrent malignancies at other sites with the exception of surgically cured or adequately treated carcinoma in-situ of the cervix and basal cell carcinoma of the skin.
  15. Organ allografts requiring immunosuppressive therapy.
  16. Pregnancy (absence confirmed by serum/urine beta human choriongonadotrophin in pre-menopausal women) or breast-feeding.
  17. Medical, social or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01251536

Contacts
Contact: Eric Van Cutsem, MD +32 16 344 218 eric.vancutsem@uz.kuleuven.ac.be

Locations
Austria
Universitätsklinik für Innere medizin, Klinishe abteilung für hämatologie und Onkologie Recruiting
Innsbruck, Austria
Contact: Eisterer         
LKH Leoben, abteilung f. innere Medizin Recruiting
Leoben, Austria
Contact: Keil         
AKH Linz, Innere Medizin 3, Zentrum für Hämatologie und medizinishe Onkologie Recruiting
Linz, Austria
Contact: Fridrik         
Landeskrankenhaus Salzburg, Univ. Klinik für innere Medizin III, Universitätsklinikum der PMU Recruiting
Salzburg, Austria
Contact: Greil, MD         
Krankenanstalt Rudolfstiftung, 1 medizinishe Abteilung Recruiting
Wien, Austria
Contact: Kaufman         
St Vincent Krankenhaus Betriebs GmbH Recruiting
Zams, Austria
Contact: Woll, MD         
Belgium
Imelda Ziekenhuis Recruiting
Bonheiden, Belgium
Contact: Veerle Moons, MD       veerle.moons@imelda.be   
Cliniques Universitaires St Luc Recruiting
Brussels, Belgium, 1200
Contact: Marc Vandeneynde, Prof.Dr       Marc.Vandeneynde@uclouvain.be   
Erasme Hospital Recruiting
Brussels, Belgium, 1070
Contact: Jean-Luc Van Laethem, Prof.MD       JL.VanLaethem@erasme.ulb.ac.be   
AZ Middelares Gent Recruiting
Gent, Belgium
Contact       erik.vanderstraeten@azmmsj.be   
UZ Gent Recruiting
Gent, Belgium
Contact: Karen Geboes, MD       karen.geboes@uzgent.be   
Centre Hospitalier de Jolimont-Lobbes, Oncology Médicale Recruiting
Haine Saint Paul, Belgium
Contact: Thierry Delaunoit, MD       thierry.delaunoit@entitejolimontoise.be   
AZ Groeninge Recruiting
Kortrijk, Belgium, 8500
Contact: Philippe Vergauwe, Dr       philippe.vergauwe@azgroeninge.be   
UZ Gasthuisberg Recruiting
Leuven, Belgium, 3000
Contact: Van Cutsem       eric.vancutsem@uz.kuleuven.ac.be   
CHC Saint Joseph Recruiting
Liege, Belgium
Contact: Ghislain Houbiers       ghislain.houbiers@chc.be   
AZ Sint Maarten Mechelen/Duffel Recruiting
Mechelen, Belgium
Contact: Ferrante       Michel.Ferrante@emmaus.be   
H. Hartziekenhuis Recruiting
Roeselare, Belgium, 8800
Contact: Jochen Decaestecker, Dr       jdecaestecker@hhr.be   
AZ Turnhout (Campus St Elisabeth) Recruiting
Turnhout, Belgium
Contact: Jos Janssens    (0032) 14 40 68 05      
France
Hôpital Avicennes Recruiting
Bobigny, France
Contact: Gaetan Des Guetz, MD         
Hôpital Saint-André Recruiting
Bordeaux, France, 33000
Contact: Denis Smith         
C.R.L.C. Val d'Aurelle- Paul Lamarque Withdrawn
MONTPELLIER Cedex 5, France, 34298
Hopital Européen Georges Pompidou Recruiting
Paris, France, 75015
Contact: Philippe Rougier, MD         
Centre Eugène Marquis Recruiting
Rennes Cedex, France, 35042
Contact: Eveline Boucher, MD         
CHU Charles Nicolle Recruiting
Rouen, France, 76031
Contact: Pierre Michel, MD         
Hungary
Medical Center of the University of Pecs Recruiting
National Institute Oncology, Budapest, Hungary, 1122
Contact: Istvan Lang       lang@oncol.hu   
State Health Center Recruiting
Budapest, Hungary, 1062
Contact: Zsuzsanna Papai       zspapai@t-online.hu   
Fovárosi Szent László Kórház Not yet recruiting
Budapest, Hungary, 1097
Contact: György Bodoky, MD       bodokygy@hungarnet.hu   
Italy
Seconda Università degli Studi di Napoli Withdrawn
Napoli, Italy, 80131
Università Cattolica del Sacro Cuore Withdrawn
Roma, Italy, 168
Spain
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain, 8035
Contact: Teresa Macarulla, MD         
Institut Català d'Oncologia Recruiting
Barcelona, Spain
Contact: Salazar         
Hospital Universitario Marqués de Valdecilla Recruiting
Santander, Spain
Contact: Rivera, MD         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain
Contact: Carbonero, MD         
Hospital Clinico Universitario De Valencia Recruiting
Valencia, Spain
Contact: Cervantes         
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Merck KGaA
Investigators
Principal Investigator: Eric Van Cutsem, MD UZ Leuven
  More Information

No publications provided

Responsible Party: Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT01251536     History of Changes
Other Study ID Numbers: S51532, 2009-009992-36
Study First Received: December 1, 2010
Last Updated: January 21, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Belgium: Ethics Committee
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Ethics Committee
Italy: Ethics Committee
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Institutional Ethical Committee
Austria: Agency for Health and Food Safety
Austria: Ethikkommission

Keywords provided by Universitaire Ziekenhuizen Leuven:
colorectal cancer
K-Ras wildtype
first line metastatic
standard cetuximab + FOLFIRI
dose escalation cetuximab

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Cetuximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 28, 2014