Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Dose escalation of cetuximab; Standard first line treatment with cetuximab + Folfiri
Intervention description: 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; 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 MeSH terms: Cetuximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 108.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colorectal cancer; K-Ras wildtype; first line metastatic; standard cetuximab + FOLFIRI; dose escalation cetuximab

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.
    

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.