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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 78
- 试验地点
- 30
- 主要终点
- Progression-free survival time according to the MMP7 status (PFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •(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
- •Life expectancy ≥ 3 months
- •Adequate bone marrow function
- •Adequate Hepatic and metabolic functions
- •Adequate Renal function
- •Magnesium > LLN (Lower limit of Normal)
排除标准
- •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
研究组 & 干预措施
Panitumumab + FOLFOX (DP)
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.
干预措施: Panitumumab + FOLFOX (DP) (Drug)
Panitumumab + FOLFOX (no-DP)
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.
干预措施: Panitumumab + FOLFOX (no-DP) (Drug)
结局指标
主要结局
Progression-free survival time according to the MMP7 status (PFS)
时间窗: 5 years
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-).
次要结局
- Time to response (TTR)(5 years)
- Disease Control Rate (DCR)(5 years)
- Time To Progression (TTP)(5 years)
- Duration of Stable Disease (DoSD)(5 years)
- Duration of response (DOR)(5 years)
- Time to treatment failure (TtTF)(5 years)
- Molecular predictive markers for response.(5 years)
- Objective response rate (ORR)(5 years)
- Overall Survival (OS)(5 years)
- Incidence and severity of AEs(5 years)