A Phase III Study of 2nd-line XELIRI ± Bevacizumab vs. FOLFIRI ± Bevacizumab in mCRC

Study Overview
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Brief Summary
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The primary purpose of this study is to determine the non-inferiority of overall survival XELIRI with or without Bevacizumab compared with FOLFIRI with or without Bevacizumab as Second-line therapy in Patient with Metastatic Colorectal Cancer.

Detailed Description
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Primary endpoint: Overall survival (OS), Secondary endpoints: Progression-free survival (PFS), Time to treatment failure (TTF), Overall response rate (ORR),Disease Control Rate (DCR), Relative dose intensity, Safety, and Correlation between UGT1A1 genotype and Safety.

Official Title
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A Multinational, Randomized, Phase III Study of XELIRI With/Without Bevacizumab Versus FOLFIRI With/Without Bevacizumab As Second-line Therapy in Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Neoplasms, Neoplasm Metastasis, Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: CPT-11 (Irinotecan)
* Drug: 5-FU Bolus
* Drug: 5-FU Infusion
* Drug: l-LV (dl-LV)
* Biological: bevacizumab
* Drug: CPT-11 (Irinotecan)
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed inoperable colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer. Age ≥20 years at the time of informed consent ECOG performance status (PS) of 0-2 Written informed consent prior to study-specific screening procedures Life expectancy of at least 90 days Withdrawal from first-line chemotherapy (regardless of containing molecular-targeted drugs) for metastatic colorectal cancer due to intolerable toxicity or progressive disease, or relapse within 180 days after the last dose of adjuvant chemotherapy. Adequate organ function according to following laboratory values obtained within 14 days before enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test) Neutrophil count: ≥1500/mm3 Platelet count: ≥10.0 x 104/mm3 Hemoglobin: ≥9.0 g/dL Total bilirubin: ≤1.5 mg/dL AST, ALT: ≤100 IU/L (≤200 IU/I if liver metastases present) Serum creatinine: ≤1.5 mg/dL Exclusion Criteria: History of other malignancy with a disease-free interval <5 years (other than curatively treated cutaneous basal cell carcinoma, curatively treated carcinoma in situ of the cervix, and gastroenterological cancer confirmed to be cured by endoscopic mucosal resection) With massive pleural effusion or ascites requiring intervention Radiological evidence of brain tumor or brain metastases Active infection including hepatitis Any of the following complication: i) Gastrointestinal bleeding or gastrointestinal obstruction (including paralytic ileus) ii) Symptomatic heart disease (including unstable angina, myocardial infarction, and heart failure) iii) Interstitial pneumonia or pulmonary fibrosis iv) Uncontrolled diabetes mellitus v) Uncontrolled diarrhea (that interferes with daily activities despite adequate therapy) Any of the following medical history: Myocardial infarction: History of one episode within one year before enrollment or two or more lifetime episodes i) Serious hypersensitivity to any of the study drugs ii) History of adverse reaction to fluoropyrimidines suggesting dihydropyrimidine dehydrogenase (DPD) deficiency Previous treatment with irinotecan hydrochloride Current treatment with atazanavir sulfate Previous treatment with tegafur, gimeracil, and oteracil potassium within seven days before enrollment Pregnant or lactating females, and males and females unwilling to use contraception Requires continuous treatment with systemic steroids Psychiatric disability that would preclude study compliance Otherwise determined by the investigator to be unsuitable for participation in the study Concurrent gastrointestinal perforation or history of gastrointestinal perforation with 1 year before enrollment History of pulmonary hemorrhage/hemoptysis ≥ Grade 2 (defined as bright red blood of at least 2.5mL) within 1 month prior to enrollment. History of laparotomy, thoracotomy, or intestinal resection within 28 days before enrollment Unhealed wound (except suture wounds from implantation of a central venous port), gastrointestinal ulcer, or traumatic fracture Current or recent (within 1 year) thromboembolism or cerebrovascular disease Currently receiving or requires anticoagulation therapy (> 325 mg/day of aspirin) Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR ≥1.5 within 14 days before enrollment) Uncontrolled hypertension Urine dipstick for proteinuria >+2

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: FOLFIRI +/- Bevacizumab<br>Bevacizumab 5 mg/kg IV 90-30 min Day 1 CPT-11 180 mg/m2 (150 mg/m2) IV 90 min Day 1 l-LV (dl-LV) 200 mg/m2 (400 mg/m2) IV 120 min Day 1 5-FU - bolus 400 mg/m2 IV bolus Day 1 5-FU - infusional 2400 mg/m2 IV continuous (46 hours) Day 1 - 3 | Biological: Bevacizumab<br>* 5 mg/kg intravenously administered over 90 minutes (can be reduced to 30 minutes at the minimum) on day 1 of a 2-week cycle.<br>* Other names: Avastin;Drug: CPT-11 (Irinotecan)<br>* 150-180 mg/m2 intravenously administered over 90 minutes on day 1 of a 2-week cycle.<br>* Other names: Irinotecan;Drug: 5-FU Bolus<br>* 400 mg/m2 intravenous bolus on day 1 of a 2-week cycle.<br>* Other names: fluorouracil;Drug: 5-FU Infusion<br>* 2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle.<br>* Other names: fluorouracil;Drug: l-LV (dl-LV)<br>* 200 (dl-LV: 400) mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle.<br>* Other names: Leucovorin;|
| Experimental: XELIRI +/- Bevacizumab<br>Bevacizumab 7.5 mg/kg IV 90-30 min Day 1 CPT-11 200 mg/m2 (150 mg/m2) IV 90 min Day 1 Capecitabine 800 mg/m2 p.o. twice daily 14 Days consecutively | Biological: bevacizumab<br>* 7.5mg/kg IV intravenously administered over 90 minutes (can be reduced to 30 minutes at the minimum) on Day 1 of a 3-week cycle.<br>* Other names: Avastin;Drug: CPT-11 (Irinotecan)<br>* 150-200 mg/m2 intravenously administered over 90 minutes on day 1 of a 3-week cycle.<br>* Other names: Irinotecan;Drug: Capecitabine<br>* 1600mg/m2/day oral on day 1 (evening) to day 15 (morning)of a 3-week cycle.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time from the date of enrollment to death from any cause. | Assessed until 1.5 years after the last patient enrolment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Time from the date of enrollment to the earlier of the date of confirmed progression or death from any cause. | Assessed until 1.5 years after the last patient enrolment | 
| Time to treatment failure (TTF) | Time from the date of enrollment to the earlier of the date of confirmed progression, death from any cause, or discontinuation of protocol treatment. | Assessed until 1.5 years after the last patient enrolment | 
| Overall Response Rate (ORR) | Proportion of eligible patients with measurable lesions with a best overall response of CR or PR assessed by the attending physician. | Assessed at 6, 12 week and thereafter every 8 weeks | 
| Disease Control Rate (DCR) | Proportion of best overall response of CR, PR, or SD assessed by the attending physician. | Assessed at 6, 12 week and thereafter every 8 weeks | 
| Relative Dose Intensity | will be calculated for each drug to evaluate treatment compliance in the all-treated population during the observation period. | Assessed until final dosing to the last patient | 
| Incidence of Adverse Events (Adverse Reactions) | The incidence of worst-grade adverse events (toxicities) on study as graded by NCI-CTCAE v 4.0 will be determined by treatment arm in all treated patients for the following events. | Adverse events occurring within 30 days after treatment discontinuation will be followed until recovery | 
| Correlation between UGT1A1 genotype and safety | The incidence of worst-grade adverse events on study as graded by NCI-CTCAE v 4.0 will be determined by treatment arm and UGT1A1 genotype in all treated patients with a known UGT1A1 genotype profile | Adverse events occurring within 30 days after treatment discontinuation will be followed until recovery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AXEPT, Fluorouracil, CPT-11, XELIRI, Bevacizumab, FOLFIRI, Capecitabine, 2nd-line metastatic colorectal cancer