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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck KGaA
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier:
NCT01251536
First received: December 1, 2010
Last updated: December 2, 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 2016
Estimated Primary Completion Date: March 2015 (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

Locations
Austria
Universitätsklinik für Innere medizin, Klinishe abteilung für hämatologie und Onkologie
Innsbruck, Austria
LKH Leoben, abteilung f. innere Medizin
Leoben, Austria
AKH Linz, Innere Medizin 3, Zentrum für Hämatologie und medizinishe Onkologie
Linz, Austria
Landeskrankenhaus Salzburg, Univ. Klinik für innere Medizin III, Universitätsklinikum der PMU
Salzburg, Austria
Krankenanstalt Rudolfstiftung, 1 medizinishe Abteilung
Wien, Austria
St Vincent Krankenhaus Betriebs GmbH
Zams, Austria
Belgium
Imelda Ziekenhuis
Bonheiden, Belgium
Cliniques Universitaires St Luc
Brussels, Belgium, 1200
Erasme Hospital
Brussels, Belgium, 1070
AZ Middelares Gent
Gent, Belgium
UZ Gent
Gent, Belgium
Centre Hospitalier de Jolimont-Lobbes, Oncology Médicale
Haine Saint Paul, Belgium
AZ Groeninge
Kortrijk, Belgium, 8500
UZ Gasthuisberg
Leuven, Belgium, 3000
CHC Saint Joseph
Liege, Belgium
AZ Sint Maarten Mechelen/Duffel
Mechelen, Belgium
H. Hartziekenhuis
Roeselare, Belgium, 8800
AZ Turnhout (Campus St Elisabeth)
Turnhout, Belgium
France
Hôpital Avicennes
Bobigny, France
Hôpital Saint-André
Bordeaux, France, 33000
Hopital Européen Georges Pompidou
Paris, France, 75015
Centre Eugène Marquis
Rennes Cedex, France, 35042
CHU Charles Nicolle
Rouen, France, 76031
Hungary
Medical Center of the University of Pecs
National Institute Oncology, Budapest, Hungary, 1122
State Health Center
Budapest, Hungary, 1062
Spain
Hospital Universitari Vall d'Hebron
Barcelona, Spain, 8035
Institut Català d'Oncologia
Barcelona, Spain
Hospital Universitario Marqués de Valdecilla
Santander, Spain
Hospital Universitario Virgen del Rocío
Sevilla, Spain
Hospital Clinico Universitario De Valencia
Valencia, Spain
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: December 2, 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
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Cetuximab
Antineoplastic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on March 30, 2015