Study of Modified FOLFOX6 Plus or Minus Sorafenib in Stage IV Metastatic Colorectal Carcinoma (mCRC) Subjects

Study Overview
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Brief Summary
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To determine if sorafenib when added to chemotherapy will slow disease progression more than chemotherapy alone in patients previously untreated for metastatic colorectal cancer.

Official Title
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Phase 2b, DB, Randomized Study Evaluating Efficacy & Safety of Sorafenib Compared With Placebo When Administered in Combination With Modified FOLFOX6 for the Treatment of Metastatic CRC Subjects Previously Untreated for Stage IV Disease

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 (5-FU, levo-leucovorin, oxaliplatin)
* Drug: Matching placebo + mFOLFOX6 (5-FU, levo-leucovorin, oxaliplatin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of adenocarcinoma of the colon or rectum Tumor tissue sample available for KRAS and BRAF assessment Measurable metastatic Stage IV disease including at least one measurable lesion that has not previously been radiated No prior chemotherapy for metastatic CRC Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Life expectancy of at least 12 weeks Adequate bone marrow, liver, and renal function; adequate clotting parameters Exclusion Criteria: Prior treatment with sorafenib Clinical or radiographic evidence of brain metastasis Major surgery, surgical biopsy, or significant traumatic injury within 28 days of randomization; evidence or history of bleeding diathesis or coagulopathy Red blood cell (RBC), white blood cell (WBC), or platelet transfusions and/or growth factor use within 28 days before randomization Adjuvant therapy for CRC (Stage I, II, or III) completed within 12 months before randomization Serious, non-healing wound, ulcer, or bone fracture; Grade 3 or 4 hemorrhage within 28 days before randomization Use of anticoagulation therapy (low dose anticoagulation therapy to mitigate risk of thrombosis due to placement of a semi-permanent central venous port for administration of chemotherapy is allowed. The use of coumadin and related compounds is excluded.) Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 100 mmHg on repeated measurement) despite optimal medical management Thrombolic, embolic, venous, or arterial events (eg, cerebrovascular accident, including transient ischemic attacks) within 6 months before randomization Active cardiac disease including: Congestive heart failure Unstable angina or myocardial infarction within the 6 months before randomization Cardiac ventricular arrhythmias requiring antiarrhythmic treatment Peripheral neuropathy > Grade 1 (CTCAE) Known HIV infection or chronic hepatitis B or C infection Any active infection >/= Grade 2 (CTCAE) Any medical, psychological, or social condition that may interfere with the subject's participation in the study or evaluation of the study results Use of any investigational drug within 28 days or 5 half-lives of that drug, whichever is longer, before randomization Subjects with metastatic CRC who are currently candidates for surgery with curative intent

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6<br>Subjects will receive oral Sorafenib 400 mg twice daily (BID) continuously and intravenous (IV) mFOLFOX6 (5-FU 400 mg/m^2 bolus and 2400 mg/m^2 for 46-48 hrs; levo-leucovorin 200 mg/m^2; 85 mg/m^2 oxaliplatin) every 14 days until progressive disease (PD) | Drug: Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 (5-FU, levo-leucovorin, oxaliplatin)<br>* Subjects will receive oral Sorafenib 400 mg twice daily (BID) continuously and intravenous (IV) mFOLFOX6 (5-FU 400 mg/m^2 bolus and 2400 mg/m^2 for 46-48 hrs; levo-leucovorin 200 mg/m^2; 85 mg/m^2 oxaliplatin) every 14 days until progressive disease (PD)<br>|
| Placebo Comparator: Matching placebo + mFOLFOX6<br>Subjects will receive oral matching placebo 2 tablets BID continuously and IV mFOLFOX6 (5-FU 400 mg/m^2 bolus and 2400 mg/m^2 for 46-48 hrs; levo-leucovorin 200 mg/m^2; 85 mg/m^2 oxaliplatin) every 14 days until progressive disease | Drug: Matching placebo + mFOLFOX6 (5-FU, levo-leucovorin, oxaliplatin)<br>* Subjects will receive oral matching placebo 2 tablets BID continuously and IV mFOLFOX6 (5-FU 400 mg/m^2 bolus and 2400 mg/m^2 for 46-48 hrs; levo-leucovorin 200 mg/m^2; 85 mg/m^2 oxaliplatin) every 14 days until progressive disease<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression or death due to any cause, whichever occurred first. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Disease progression was defined as an increase of at least 20% in the sum of tumor lesions sizes. | From randomization of the first subject until 23 months later, assessed every 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact. | From randomization of the first subject until 33 months later. | 
| Time to Progression (TTP) | Time to progression (TTP) was defined as the time from date of randomization to disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Disease progression was defined as an increase of at least 20% in the sum of tumor lesions sizes. | From randomization of the first subject until 23 months later, assessed every 8 weeks. | 
| Overall Response | Overall response of a subject was defined as the best tumor response (Complete Response (CR) or Partial Response (PR)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes. | From randomization of the first subject until 23 months later, assessed every 8 weeks. | 
| Duration of Response | Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) was first documented or to the date of death, whichever occurred first according to Response Evaluation Criteria in Solid Tumors (RECIST). Subjects still having CR or PR and alive at the time of analysis were censored at their last date of tumor evaluation. CR was defined as disappearance of tumor lesions, PR as a decrease of at least 30% and PD as an increase of at least 20% in the sum of tumor lesions sizes. | From randomization of the first subject until 23 months later, assessed every 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer, Metastasis, Stage IV, Liver Metastasis