A Study of FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab

Study Overview
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Brief Summary
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This study is to verify the advantage of FOLFOXIRI plus cetuximab over FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors.

Detailed Description
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This study is to verify the advantage of FOLFOXIRI plus cetuximab over FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors. In this study the investigators employed deepness of response as a primary endpoint.

Official Title
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A Randomized Phase II Study to Investigate the Deepness of Response of FOLFOXIRI Plus Cetuximab (Erbitux) Versus FOLFOXIRI Plus Bevacizumab as the First-line Therapy in Metastatic Colorectal Cancer Patients With RAS Wild-type Tumors: DEEPER

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: fluorouracil
* Drug: Leucovorin
* Drug: irinotecan
* Drug: oxaliplatin
* Biological: bevacizumab
* Biological: cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed colorectal cancer RAS wild-type Measurable lesion by RECIST (Ver.1.1) No past history of chemotherapy in the case of unresectable primary lesion/distant metastasis/lymph node metastasis.In the case of recurrence, no treatment for the first recurrence lesion after operation Eastern Cooperative Oncology Group (ECOG) Performance status 0-1.The case >=71 years is PS0. Life expectancy of more than 6 months Patients have enough organ function for study treatment within 14 days before enrollment; White blood cell (WBC)>=3,000/mm3, <12,000/mm3. Neu>=1,500/mm3. Platelet count (PLT) >=10.0x104/mm3. Hb>=9.0g/dL. Total Bilirubin<=1.5x Upper Limited Normal (ULN) aspartate aminotransferase (AST) <=2.5xULN. alanine aminotransferase (ALT) <=2.5xULN. Creatinine<=1.5xULN. Proteinuria<=1+. prothrombin time-international normalized ratio (PT-INR) <=1.5 Must be able to swallow tablets Written informed consent Exclusion Criteria: Synchronous multiple malignancy or metachronous multiple malignancy within 5 years disease free interval Lynch syndrome Brain metastases Infectious disease Interstitial lung disease or pulmonary fibrosis Comorbidity or history of serious heart failure History of thromboembolic events Cerebrovascular disease History of hemoptysis/hematemesis Uncontrolled hypertension (systolic BP>180mmHg, or diastolic BP>100mmHg) Sensory alteration or paresthesia interfering with function Large quantity of pleural, abdominal or cardiac effusion Severe comorbidity (renal failure, liver failure, hypertension, etc) Prior radiotherapy for primary and metastases leision Men/women who are unwilling to avoid pregnancy Women who are pregnant or breastfeeding Women with a positive pregnancy test History of severe allergy HBsAg positive or active viral hepatitis Administration of blood products/ Granulocyte-Colony Stimulating Factor (G-CSF), and blood transfusion within 14 days Surgical procedure or such as skin-open biopsy, trauma surgery, or other more intensive surgery within 28 days Systematic administration of antiplatelet drug or non steroid anti-inflammatory drugs (NSAIDs) Diathesis of bleeding (history of hemoptysis, including cavitation and/or necrosis in lung metastasis confirmed by imaging), coagulopathy History of gastrointestinal perforation within 1 year Unhealed traumatic bone fracture Uncontrolled diarrhea History of organ recipient Prior cetuximab/bevacizumab/Irinotecan/Oxaliplatin treatment (Adjuvant therapy by Oxaliplatin is excluded) Administration of atazanavir sulfate Jaundice Ileus or bowel obstruction Clinical diagnosis of Alzheimer's Disease Insulin dependent diabetes Thyroid disease Any other cases who are regarded as inadequate for study enrollment by investigators

Ages Eligible for Study
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Minimum Age: 20 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: FOLFOXIRI+Bmab<br>Patients in the FOLFOXIRI + Bmab group receive until 12 cycles of FOLFOXIRI plus bevacizumab, consisting of a 30-minute infusion of bevacizumab at a dose of 5 mg per kilogram, a 60-minute infusion of irinotecan at a dose of 150 mg per square meter, and a 120-minute infusion of oxaliplatin at a dose of 85 mg per square meter and a concomitant 120-minute infusion of leucovorin at a dose of 200 mg per square meter, followed by a 48-hour continuous infusion of fluorouracil to a total dose of 2400 mg per square meter. Cycles were repeated every 14 days. After 13 cycles, patients receive fluorouracil, leucovorin and bevacizumab every 14 days until disease progression. | Drug: fluorouracil<br> <br> * Other names: 5-FU;Drug: Leucovorin<br> <br> * Other names: Levofolinate;Drug: irinotecan<br> <br> * Other names: CPT-11;Drug: oxaliplatin<br> <br> * Other names: eloxatin;Biological: bevacizumab<br> <br> |
| Experimental: FOLFOXIRI+Cmab<br>Patients in the experimental group received until 12 cycles of FOLFOXIRI plus cetuximab, consisting of a 30-minute infusion of cetuximab first time at a dose of 400 mg per kilogram, after the second time at a dose of 250mg per kilogram, a 60-minute infusion of irinotecan at a dose of 150 mg per square meter, and a 120-minute infusion of oxaliplatin at a dose of 85 mg per square meter and a concomitant 120-minute infusion of leucovorin at a dose of 200 mg per square meter, followed by a 48-hour continuous infusion of fluorouracil to a total dose of 2400 mg per square meter. Cycles were repeated every 14 days. After 13 cycles, patients receive fluorouracil, leucovorin and cetuximab every 14 days until disease progression. | Drug: fluorouracil<br> <br> * Other names: 5-FU;Drug: Leucovorin<br> <br> * Other names: Levofolinate;Drug: irinotecan<br> <br> * Other names: CPT-11;Drug: oxaliplatin<br> <br> * Other names: eloxatin;Biological: cetuximab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best deepness of response | The maximum tumor shrinkage rates by Response Evaluation Criteria in Solid Tumors (RECIST) throughout the treatments | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early tumor shrinkage | The rates of tumor shrinkage by RECIST at 8 weeks | at 8 weeks | 
| Response rate |  | up to 2 years | 
| Deepness of response | The tumor shrinkage rates by RECIST at 4 months | at 4 months | 
| Overall survival |  | up to 2 years | 
| Progression free survival |  | up to 2 years | 
| Rate of curatively resected metastatic lesion |  | up to 2 years | 
| Number of adverse events |  | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bmab, FOLFOXIRI, Cmab