Study Assessing Potential Predictive Tumor Markers in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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To estimate the progression free survival for subjects treated with panitumumab in combination with a chemotherapy regimen of oxaliplatin, 5-Fluorouracil (5-FU) and leucovorin (FOLFOX) as first-line chemotherapy regimen for subjects with metastatic colorectal cancer with WT (wild type) KRAS according to the IGFRp (protein receptor insulin growth factor) and MMP-7 (Matrilysin) expression.

Detailed Description
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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.

Official Title
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An Open Label, Phase II Study Assessing Potential Predictive Tumor Markers in Patients With Metastatic Colorectal Cancer and Wild Type K-RAS Tumor Treated With FOLFOX Plus Panitumumab as First-line Therapy

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Panitumumab + FOLFOX (DP)
* Drug: Panitumumab + FOLFOX (no-DP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Man or woman ≥ 18 years. Competent to comprehend, sign, and date an IEC-approved (Ethics Committee) informed consent form Histologically-confirmed metastatic adenocarcinoma of the colon or rectum by the investigator. Wild Type K-RAS colorectal cancer determined by the designated Central Laboratory prior to inclusion in the study in the primary tumor and/or at least one metastasis. At least 1 uni-dimensionally measurable lesion of at least > 10 mm with spiral CT per modified RECIST criteria 1.1. (Response Evaluation Criteria In Solid Tumors) Patients with the following characteristics will be included: Recurrence after adjuvant treatment with 5-fluorouracil/folinic acid or capecitabine +/- radiotherapy with a disease-free interval > than 6 months after its completion. Recurrence after adjuvant treatment with oxaliplatin +/- radiotherapy with a disease-free interval > than 12 months De novo diagnosis of the disease. Eastern Cooperative Oncology Group performance status of 0 or 1. Life expectancy ≥ 3 months Adequate bone marrow function Adequate Hepatic and metabolic functions Adequate Renal function Magnesium > LLN (Lower limit of Normal) Exclusion Criteria: Patients they have received prior systemic therapy for the treatment of metastatic colorectal carcinoma. Prior anti-EGFr antibody therapy (eg, cetuximab) or treatment small molecule EGFr tyrosine kinase inhibitors (eg, erlotinib) or EGFR signal transduction inhibitors. Patients who had resection of metastatic disease Central nervous system/brain metastases Prior malignant tumor in the last 5 years, except a history of basal cell carcinoma of the skin or pre-invasive cervical cancer. Unresolved toxicities from prior systemic therapy that, in the opinion of the investigator, does not qualify the patient for inclusion Presence of peripheral neuropathy (Common Toxicity Criteria (CTC) version 3.0 > grade 1), and of serious nonhealing wound, ulcer, or bone fracture. Hormonal therapy, immunotherapy or experimental or approved proteins/antibodies (eg, bevacizumab) ≤ 30 days before inclusion Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia. History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest CT scan Treatment for systemic infection within 14 days before initiating study treatment Acute or sub-acute intestinal occlusion and /or active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as > 4 loose stools per day). Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection Any investigational agent within 30 days before enrollment Subject who is pregnant or breast feeding Surgery (excluding diagnostic biopsy or central venous catheter placement) and/or radiotherapy within 14 days prior to inclusion in the study. Woman or man of childbearing potential not consenting to use adequate contraceptive precautions

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panitumumab + FOLFOX (DP)<br>Panitumumab and FOLFOX will be administered to patients with DP (MMP7+/p-IGF-IR) once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression. | Drug: Panitumumab + FOLFOX (DP)<br>* Panitumumab and FOLFOX will be administered to patients with DP once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression.<br>|
| Experimental: Panitumumab + FOLFOX (no-DP)<br>Panitumumab and FOLFOX will be administered to patients with no-DP (MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR) once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression. | Drug: Panitumumab + FOLFOX (no-DP)<br>* Panitumumab and FOLFOX will be administered to patients with no-DP (MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR) once every 14 days until 6 months of treatment or until disease progression (PD) or unacceptable toxicity. If patients have not progressed after 6 months of treatment with panitumumab and FOLFOX they will continue with panitumumab monotherapy until disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival time according to the MMP7 status (PFS) | 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-). | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | Time from first confirmed objective response to radiologic disease progression per modified RECIST criteria. | 5 years | 
| Time to response (TTR) | Time from randomization date to date of first confirmed objective response | 5 years | 
| Time to treatment failure (TtTF) | Time from enrolment to the date the decision was made to end the treatment phase for any reason. | 5 years | 
| Objective response rate (ORR) | 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. | 5 years | 
| Disease Control Rate (DCR) | 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. | 5 years | 
| Overall Survival (OS) | Time from randomization date to date of death. | 5 years | 
| Time To Progression (TTP) | Time from randomization date to date of radiologic disease progression per modified RECIST criteria. | 5 years | 
| Duration of Stable Disease (DoSD) | 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 | 5 years | 
| Incidence and severity of AEs | Incidence and severity of AEs (Common Toxicity Criteria version 3.0) | 5 years | 
| Molecular predictive markers for response. | Molecular predictive markers for response. | 5 years |