Clinical trial NCT01251536: Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: colorectal cancer
K-Ras wildtype
first line metastatic
standard cetuximab + FOLFIRI
dose escalation cetuximab
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2010-12-02
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: PFS Probability Rate at 9 Months in the Dose Escalation Arm
timeFrame: 9 months
Secondary outcomes:
measure: Progression Free Survival (PFS) Median Time
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Progression Free Survival (PFS) Median Time for Resected Patients
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio)
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Death Rates by 3 Years Follow-up
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Overall Survival (OS) Median Time
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Overall Survival (OS) Median Time for Resected Patients
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Overall Response
timeFrame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
measure: Overall Response in Patients With Liver-limited Disease
timeFrame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
measure: Disease Control
timeFrame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
measure: Disease Control in Patients With Liver-limited Disease
timeFrame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
measure: Duration of Response
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Duration of Response in Liver-limited Disease Patients
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Resections for Metastatic Lesions
timeFrame: Treatment + follow-up (3 years from database lock)
measure: R0 Rate (Free of Tumor After Resection for Metastatic Lesions)
timeFrame: Treatment + follow-up (3 years from database lock)
measure: Skin Toxicity (Safety)
timeFrame: From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.
measure: Laboratory Safety Assessments
timeFrame: From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.
measure: Deaths Till 30 Days From Last Cetuximab Administration
timeFrame: From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Universitätsklinik für Innere medizin, Klinishe abteilung für hämatologie und Onkologie
city: Leoben
country: Austria
facility: LKH Leoben, abteilung f. innere Medizin
city: Linz
country: Austria
facility: AKH Linz, Innere Medizin 3, Zentrum für Hämatologie und medizinishe Onkologie
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg, Univ. Klinik für innere Medizin III, Universitätsklinikum der PMU
city: Wien
country: Austria
facility: Krankenanstalt Rudolfstiftung, 1 medizinishe Abteilung
city: Zams
country: Austria
facility: St Vincent Krankenhaus Betriebs GmbH
city: Bonheiden
country: Belgium
facility: Imelda Ziekenhuis
city: Brussels
country: Belgium
facility: Erasme Hospital
city: Brussels
country: Belgium
facility: Cliniques Universitaires St Luc
city: Gent
country: Belgium
facility: AZ Middelares Gent
city: Gent
country: Belgium
facility: UZ Gent
city: Haine Saint Paul
country: Belgium
facility: Centre Hospitalier de Jolimont-Lobbes, Oncology Médicale
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Leuven
country: Belgium
facility: UZ Gasthuisberg
city: Liege
country: Belgium
facility: CHC Saint Joseph
city: Mechelen
country: Belgium
facility: AZ Sint Maarten Mechelen/Duffel
city: Roeselare
country: Belgium
facility: H. Hartziekenhuis
city: Turnhout
country: Belgium
facility: AZ Turnhout (Campus St Elisabeth)
city: Bobigny
country: France
facility: Hôpital Avicennes
city: Bordeaux
country: France
facility: Hôpital Saint-André
city: Paris
country: France
facility: Hopital Européen Georges Pompidou
city: Rennes Cedex
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: CHU Charles Nicolle
city: Budapest
country: Hungary
facility: State Health Center
city: Budapest
country: Hungary
facility: Medical Center of the University of Pecs , National Institute Oncology
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clinico Universitario De Valencia
Study officials:
affiliation: UZ Leuven
name: Eric Van Cutsem, MD
role: PRINCIPAL_INVESTIGATOR
References: