Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer

NCT ID: NCT01251536

Last Updated: 2019-10-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-12-31
• Study Completion Date: 2019-07-31

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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. No comparison between arms was planned.

Group Type: OTHER

Standard first line treatment with cetuximab + Folfiri

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Dose escalation of cetuximab

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Erbitux; Erbitux

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eric Van Cutsem, MD

Role: PRINCIPAL_INVESTIGATOR

UZ Leuven

Locations

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

Vienna, , Austria

St Vincent Krankenhaus Betriebs GmbH

Zams, , Austria

Imelda Ziekenhuis

Bonheiden, , Belgium

Erasme Hospital

Brussels, , Belgium

Cliniques Universitaires St Luc

Brussels, , Belgium

AZ Middelares Gent

Ghent, , Belgium

UZ Gent

Ghent, , Belgium

Centre Hospitalier de Jolimont-Lobbes, Oncology Médicale

Haine-Saint-Paul, , Belgium

AZ Groeninge

Kortrijk, , Belgium

UZ Gasthuisberg

Leuven, , Belgium

CHC Saint Joseph

Liège, , Belgium

AZ Sint Maarten Mechelen/Duffel

Mechelen, , Belgium

H. Hartziekenhuis

Roeselare, , Belgium

AZ Turnhout (Campus St Elisabeth)

Turnhout, , Belgium

Hôpital Avicennes

Bobigny, , France

Hôpital Saint-André

Bordeaux, , France

Hopital Européen Georges Pompidou

Paris, , France

Centre Eugène Marquis

Rennes, , France

CHU Charles Nicolle

Rouen, , France

State Health Center

Budapest, , Hungary

Medical Center of the University of Pecs , National Institute Oncology

Budapest, , Hungary

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Institut Català d'Oncologia

Barcelona, , Spain

Hospital Universitario Marqués de Valdecilla

Santander, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

Hospital Clinico Universitario De Valencia

Valencia, , Spain

Countries

Austria; Belgium; France; Hungary; Spain

Other Identifiers

2009-009992-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

S51532

Identifier Type: -

Identifier Source: org_study_id