PEAK: Panitumumab Plus mFOLFOX6 vs. Bevacizumab Plus mFOLFOX6 for First Line Treatment of Metastatic Colorectal Cancer (mCRC) Patients With Wild-Type Kirsten Rat Sarcoma-2 Virus (KRAS) Tumors

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to estimate the treatment effect on progression-free survival (PFS) of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy in patients with tumors expressing wild-type KRAS, unresectable mCRC.

Official Title
-----------------
A Randomized, Multicenter, Phase 2 Study to Compare the Efficacy of Panitumumab in Combination With mFOLFOX6 to the Efficacy of Bevacizumab in Combination With mFOLFOX6 in Patients With Previously Untreated, KRAS Wild-Type, Unresectable, Metastatic Colorectal Cancer

Conditions
-----------------
Colon Cancer, Colorectal Cancer, Rectal Cancer, Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Panitumumab
* Drug: Bevacizumab
* Drug: mFOLFOX6


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum in patients with unresectable metastatic (M1) disease Patients with at least 1 uni-dimensionally measurable lesion of at least 10 mm per modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines Wild-type KRAS tumor status confirmed by an Amgen approved central laboratory or an experienced laboratory (local laboratory) per local regulatory guidelines using a validated test method Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 Men or women 18 years of age or older Adequate hematologic, renal, hepatic, metabolic, and coagulation function Exclusion Criteria: History of prior or concurrent central nervous system (CNS) metastases Prior chemotherapy or other systemic anticancer therapy for treatment of metastatic colorectal carcinoma Clinically significant cardiac disease Clinically significant peripheral sensory neuropathy Active inflammatory bowel disease Recent gastroduodenal ulcer to be active or uncontrolled History of interstitial lung disease Recent pulmonary embolism, deep vein thrombosis, or other significant venous event Pre-existing bleeding diathesis and/or coagulopathy with exception of well-controlled anticoagulation therapy Recent major surgical procedure, open biopsy, or significant traumatic injury not yet recovered from prior major surgery.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panitumumab Plus mFOLFOX6<br>Participants received 6 mg/kg panitumumab administered by intravenous (IV) infusion and modified FOLFOX6 (mFOLFOX6) chemotherapy regimen consisting of oxaliplatin (85 mg/m^2), leucovorin (400 mg/m^2) and 5-fluorouracil (5-FU) (2400 mg/m^2) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death. | Drug: Panitumumab<br>* Panitumumab is a fully human immunoglobulin G (IgG)2 monoclonal antibody antagonist directed against human Epidermal Growth Factor receptor (EGFr).<br>* Other names: Vectibix;Drug: mFOLFOX6<br>* mFOLFOX6 regimen is a combination therapy of oxaliplatin (85 mg/m^2) administered as a 2-hour infusion on Day 1; leucovorin (400 mg/m^2) administered as a 2-hour infusion on Day 1; followed by a loading dose of 5-fluorouracil (5-FU; 400 mg/m^2) IV bolus administered over approximately 2 to 4 minutes on Day 1, then 5- FU (2400 mg/m^2) via ambulatory pump administered for a period of 46 to 48 hours.<br>|
| Active Comparator: Bevacizumab Plus mFOLFOX6<br>Participants received 5 mg/kg bevacizumab administered by IV infusion and the mFOLFOX6 regimen consisting of oxaliplatin (85 mg/m^2), leucovorin (400 mg/m^2), followed by 5-FU (2400 mg/m^2) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death. | Drug: Bevacizumab<br>* Bevacizumab is a humanized monoclonal IgG1 antibody that is directed against Vascular Endothelial Growth Factor (VEGF).<br>* Other names: Avastin;Drug: mFOLFOX6<br>* mFOLFOX6 regimen is a combination therapy of oxaliplatin (85 mg/m^2) administered as a 2-hour infusion on Day 1; leucovorin (400 mg/m^2) administered as a 2-hour infusion on Day 1; followed by a loading dose of 5-fluorouracil (5-FU; 400 mg/m^2) IV bolus administered over approximately 2 to 4 minutes on Day 1, then 5- FU (2400 mg/m^2) via ambulatory pump administered for a period of 46 to 48 hours.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Percentage of Participants With an Objective Response | Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator's review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Duration of Response | For participants with a confirmed objective response, the time from first confirmed objective response to radiologic disease progression per modified RECIST 1.0 criteria or death. For participants who responded and have not progressed or died, duration of response was censored at their last evaluable disease assessment date. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Time to Disease Progression | Time to progression (TTP) is defined as the time from randomization to the date of radiologic disease progression per modified RECIST 1.0 criteria. Participants not meeting criteria for disease progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Time to Initial Objective Response | For participants with a confirmed objective response, the time from randomization to the date of first confirmed objective response. Assessments are based on the investigator's review of scans using a modified-RECIST v1.0. An objective response is defined as a best tumor response of complete or partial response. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Resection Rate | The resection rate was defined as the percentage of participants with a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Progression-free Survival (PFS) in Participants With Wild-type Rat Sarcoma Viral Oncogene Homolog (RAS) | PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Progression-free Survival (PFS) in Participants With Wild-type RAS / V-raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) | PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Overall Survival in Participants With Wild-type RAS | Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Overall Survival in Participants With Wild-type RAS / BRAF | Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Percentage of Participants With an Objective Response for Participants With Wild-type RAS | Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator's review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Percentage of Participants With an Objective Response for Participants With Wild-type RAS / BRAF | Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator's review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. | From randomization until the data cutoff date of 30 May 2012; median follow-up time was 60 weeks. | 
| Number of Participants With Adverse Events (AEs) | Severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0, with the exception of some dermatology/skin adverse events that were graded using CTCAE v3.0 with modifications. Fatal adverse events are classified as grade 5. Serious adverse events include any event that is fatal, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or other significant medical hazard. Treatment-related AEs were those that the investigator considered a reasonable possibility that might have been caused by study drug. | The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date. The median time frame is 8.0 months for Panitumumab Plus mFOLFOX arm and 7.3 months for Bevacizumab Plus mFOLFOX6 arm. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
First-Line, Colon Cancer, Colorectal Cancer, Rectal Cancer, Panitumumab, Vectibix, modified FOLFOX 6, mFOLFOX 6, FOLFOX, Bevacizumab, Avastin, metastatic