Study Assessing Potential Predictive Tumor Markers in Metastatic Colorectal Cancer (PULSE)

• Progression-free survival time according to the MMP7 status (PFS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  To estimate the PFS by DP immunohistochemistry (IHC) expression in patients with wild-type KRAS mCRC treated with panitumumab and mFOLFOX6. Two groups are established by DP status (MMP7+/p-IGF-IR+ vs. MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR-).
  
  

• Duration of response (DOR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Time from first confirmed objective response to radiologic disease progression per modified RECIST criteria.
  
  
• Time to response (TTR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Time from randomization date to date of first confirmed objective response
  
  
• Time to treatment failure (TtTF) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Time from enrolment to the date the decision was made to end the treatment phase for any reason.
  
  
• Objective response rate (ORR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Incidence of either a confirmed CR or PR per modified RECIST criteria. CRs or PRs will be confirmed no less than 28 days after the criteria for response are first met. All subjects without a confirmed response will be considered non-responders.
  
  
• Disease Control Rate (DCR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Incidence of either a confirmed CR or PR or stable disease (SD) while in the treatment phase; subjects prematurely discontinuing without a post baseline tumor response assessment or subjects with an observed response that is not confirmed will be considered non-responders otherwise.
  
  
• Overall Survival (OS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Time from randomization date to date of death.
  
  
• Time To Progression (TTP) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Time from randomization date to date of radiologic disease progression per modified RECIST criteria.
  
  
• Duration of Stable Disease (DoSD) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Calculated for only those subjects with a best response of SD during the treatment period, time from enrolment to date of first observed PD or death due to PD (whichever comes first) in either the combination or monotherapy phases
  
  
• Incidence and severity of AEs [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  Incidence and severity of AEs (Common Toxicity Criteria version 3.0)
  
  
• Molecular predictive markers for response. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Molecular predictive markers for response.
  
  

By transactivation, phosphorylated insulin growth factor receptor I (p-IGF-IR) can activate epidermal growth factor receptor (EGFR). Matrilysin (MMP-7), can activate IGF-IR (insulin-like growth factor receptor ) by degrading IGFBP-3 (Insulin-like growth factor-binding protein 3) and releasing IGF-I (Insulin-like growth factor 1). Concomitant expression of MMP-7 and p-IGF-IR (using a specific monoclonal antibody (p-1316) recognizing the phosphorylated carboxy-terminal part of the IGF-IR) (DP (Double Positivity)) correlates with poor prognosis in WT KRAS patients treated with anti-EGFR antibodies plus irinotecan.The primary objective of this trial is to estimate the progression free survival (PFS) by DP (Double Positivity)immunohistochemistry (IHC) expression in patients with wild-type KRAS mCRC (metastatic colorectal cancer)treated with panitumumab and mFOLFOX6. Two groups are established by DP status (MMP7+/p-IGF-IR+ vs. MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR-). With a power of 80% and a bilateral alpha level of 0.05, assuming an accrual period of 12 months (m) and a follow-up period of 18 m, 40 patients are planned to be included in each group to detect a Hazard Ratio of 2. The median PFS of the DP group is expected to be 6 m and the total number of expected events is 56. Secondary objectives include disease control rate, duration of response, time to response and survival according the DP status. Neither interim analysis nor multiple comparison adjustment is planned.Treatment: Both groups will receive panitumumab 6 mg/kg and mFOLFOX6 every 2 weeks. If patients have not progressed after 6 m of treatment they will continue with panitumumab monotherapy until disease progression.