Safety and Efficacy of Folfox4 + Weekly Cetuximab vs Folfox 4+Biweekly Cetuximab by Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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To assess the efficacy of FOLFOX4 in combination with cetuximab, weekly and FOLFOX4 in combination with cetuximab, biweekly.

Detailed Description
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This multicenter randomized phase II study will enroll approximately 150 patients with metastatic Colorectal Cancer. Patients are randomized in Arm A(FOLFOX4 in combination with weekly Cetuximab) or Arm B (FOLFOX4 in combination with biweekly Cetuximab). Both efficacy and safety data will be collected. The investigator will assess response to treatment every 8 weeks based on the imaging. Following permanent treatment cessation, patients will be followed-up for survival.

Official Title
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A Randomized, Open-label Phase II Study Evaluating the Efficacy and Safety of FOLFOX4 + Weekly Cetuximab Versus FOLFOX4+ Biweekly Cetuximab as First-line Therapy in Patients With Metastatic Colorectal Cancer.

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFOX4 (Oxaliplatin), Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Male or female ≥ 18 years of age Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum Metastatic colorectal carcinoma not suitable for curative-intent resection- Availability of tumor sample (or able and willing to provide tumor sample) for EGFR assessment Presence of at least one lesion measurable unidimensionally by CT scan or MRI. (Target lesion(s) must not lie within an irradiated area) Karnofsky performance status of > 80 at study entry Leucocytes ≥ 3.0 x 10 9/L and neutrophils ≥1.5 x 10 9/L, platelets ≥ 100 x 10 9/L, and hemoglobin ≥ 9 g/dL. Bilirubin ≥ 1.5 x ULN ASAT and ALAT ≤ 2.5 x ULN (≤5 x ULN if liver metastasis are present) Serum creatinine ≤ 1.5 x ULN Exclusion Criteria: Brain metastasis (known or suspected) Previous chemotherapy for metastatic disease. Prior adjuvant chemotherapy is allowed if the chemotherapy treatment free interval is > 6 months. Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol Any investigational agent(s) within 4 weeks prior to entry Previous exposure to EGFR-pathway targeting therapy Clinically relevant coronary artery disease or a history of a myocardial infarction within the last 12 months Acute or subacute intestinal occlusion or history of inflammatory bowel disease Pre-existing neuropathy > grade 1. In case of prior oxaliplatin containing adjuvant chemotherapy: pre-existing neuropathy ≥ 1. Known grade 3 or 4 allergic reaction to any of the components of the treatment. Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 5 years will be allowed to enter the trial) Pregnancy or lactation Inadequate contraception (male or female patients) if of childbearing or procreational potential Known drug abuse/ alcohol abuse Legal incapacity or limited legal capacity Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>FOLFOX4: Oxaliplatin 85 mg/m² d1 Leucovorin 200 mg/m² d1+d2, followed by Bolus 5FU 400 mg/m², followed by Infusional 5FU 600 mg/m²,over 22 hours, every 2 weeks Cetuximab is administered to arm A of the study as an infusion with initial dose 400 mg/m² in week 1 followed by weekly doses of 250 mg/m². | Drug: FOLFOX4 (Oxaliplatin), Cetuximab<br>* Arm A FOLFOX4: Oxaliplatin 85 mg/m² d1 Leucovorin 200 mg/m² d1+d2, followed by Bolus 5FU 400 mg/m², followed by Infusional 5FU 600 mg/m²,over 22 hours, every 2 weeks Cetuximab is administered to arm A of the study as an infusion with initial dose 400 mg/m² in week 1 followed by weekly doses of 250 mg/m². Arm B FOLFOX4: Oxaliplatin 85 mg/m² d1 Leucovorin 200 mg/m² d1+d2, followed by Bolus 5FU 400 mg/m² , followed by Infusional 5FU 600 mg/m², over 22 hours, every 2 weeks Cetuximab is administered to arm B of the study as infusions of 500 mg/m² every two weeks.<br>|
| Active Comparator: B<br>FOLFOX4: Oxaliplatin 85 mg/m² d1 Leucovorin 200 mg/m² d1+d2, followed by Bolus 5FU 400 mg/m² , followed by Infusional 5FU 600 mg/m², over 22 hours, every 2 weeks Cetuximab is administered to arm B of the study as infusions of 500 mg/m² every two weeks. | Drug: FOLFOX4 (Oxaliplatin), Cetuximab<br>* Arm A FOLFOX4: Oxaliplatin 85 mg/m² d1 Leucovorin 200 mg/m² d1+d2, followed by Bolus 5FU 400 mg/m², followed by Infusional 5FU 600 mg/m²,over 22 hours, every 2 weeks Cetuximab is administered to arm A of the study as an infusion with initial dose 400 mg/m² in week 1 followed by weekly doses of 250 mg/m². Arm B FOLFOX4: Oxaliplatin 85 mg/m² d1 Leucovorin 200 mg/m² d1+d2, followed by Bolus 5FU 400 mg/m² , followed by Infusional 5FU 600 mg/m², over 22 hours, every 2 weeks Cetuximab is administered to arm B of the study as infusions of 500 mg/m² every two weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint of the trial is: • Objective response (CR/PR), as assessed by RECIST criteria | Objective response (partial or complete) will be assessed using RECIST criteria. The objective response rate (defined as the rate of subjects with complete response (CR) or partial response (PR)) will be estimated and associated exact two-sided 95% confidence limit (Clopper-Pearson) will be calculated. In addition to the estimates within each treatment group odds ratios and associated 95% CI will be calculated using the Cochran Mantel-Haenszel procedure. | The objective response rate - defined as the rate of subjects with complete response (CR) or partial response (PR) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Progression Free Survival (PFS) • Overall survival • Safety/Adverse events Safety | Secondary objectives are the estimation of differences in PFS and overall survival. | he rate of subjects with complete response (CR) or partial response (PR) |