Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer

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.

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.