A Two Arm Phase II Study of FOLFIRI in Combination With Standard or Escalating Dose of Cetuximab as First Line Treatment of K-Ras Wild Type Metastatic Colorectal Cancer: Everest 2
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 108
- 试验地点
- 30
- 主要终点
- PFS Probability Rate at 9 Months in the Dose Escalation Arm
研究概览
简要总结
The purposes of this study are to determine whether administering escalating doses of cetuximab in patients with no early skin toxicity could delay the progression of disease in a significant proportion of patients and to study the molecular signatures of response.
详细描述
Colorectal carcinoma (CRC) is the third most common form of cancer worldwide and remains a leading malignancy both in incidence and mortality.
In the light of existing knowledge, the investigators propose a phase II open label, two arm study in patients presenting with K-Ras wild-type metastatic colorectal tumours in the first line setting. The standard combination of irinotecan plus infusional 5-FU/LV (FOLFIRI) and cetuximab will be given to all patients entering the study. As the investigators hypothesize that increasing the dose of cetuximab might increase the intensity of skin reactions that directly correlates with outcome, in patients experiencing no skin toxicity, the dose of cetuximab will be escalated from 250 mg/m2 to 350 mg/m2 and then up to 500 mg/m2, in order to better define the effect of dose escalation in the first-line setting in a K-Ras wild type tumour population and in an attempt to increase efficacy.
Pharmacokinetic studies will be performed to document PK parameters of cetuximab in patients from both arms in selected centers.
Translational research studies are planned for all patients. Some more in depth molecular testing will be performed in a subset of patients from whom three serial tissue samples from accessible metastases by biopsy are available.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Written informed consent (+ optional for PK and TR) must be given according to ICH/GCP and national/local regulations.
- •Patient is at least 18 years of age.
- •Patient's body weight is ≤ 120 kg.
- •Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon or rectum, not in a previously irradiated area.
- •K-Ras wild type tumour eligible for treatment with cetuximab.
- •Unresectable metastatic disease.
- •Life expectancy of at least 12 weeks.
- •WHO ECOG performance status: 0 or
- •Effective contraception for both male and female patients if the risk of conception exists.
- •Adequate organ function.
- •Adequate bone marrow, hepatic and renal function (assessed within 14 days prior to study entry):
- •Hemoglobin > 10.0 g/dL, absolute neutrophil count > 1.5 x 109/L, platelet count > 100 x 109/L
- •ALAT, ASAT < 2.5 x ULN, up to < 5 x ULN in case of liver metastases
- •Alkaline phosphatase < 2.5 x ULN
- •Total bilirubin < 1.5 x ULN
- •Creatinine clearance > 50 mL/min (calculated according to Cockroft and Gault)
排除标准
- •Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines +/-oxaliplatin based regimens allowed if stopped 6 months prior to registration on study).
- •Prior treatment with EGFR inhibitor or chemotherapy with irinotecan in adjuvant settings.
- •Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry.
- •Administration of any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment.
- •Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or hormone therapy not indicated in the study protocol.
- •Any active dermatological condition > grade
- •Brain metastasis (known or suspected).
- •Significant impairment of intestinal absorption (e.g. chronic diarrhea, inflammatory bowel disease).
- •Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection.
- •Uncontrolled coronary artery disease and/or unstable angina, a history of a myocardial infarction within the last 12 months or heart failure NYHA class III or IV. High risk of uncontrolled arrhythmia.
- •Known allergy or any other adverse reaction to any of the drugs or to any related compound.
- •Known dihydropyrimidine dehydrogenase (DPD) deficiency.
- •Gilbert disease.
- •Previous (within 5 years) or concurrent malignancies at other sites with the exception of surgically cured or adequately treated carcinoma in-situ of the cervix and basal cell carcinoma of the skin.
- •Organ allografts requiring immunosuppressive therapy.
- •Pregnancy (absence confirmed by serum/urine beta human choriongonadotrophin in pre-menopausal women) or breast-feeding.
- •Medical, social or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent.
研究组 & 干预措施
Arm B - standard dose of cetuximab
Patients with skin toxicity grade 1-4 or other significant toxicity who are not eligible for dose escalation will continue on the standard dose of cetuximab 250 mg/m2 weekly. No comparison between arms was planned.
干预措施: Standard first line treatment with cetuximab + Folfiri (Drug)
Arm A - dose escalation of cetuximab
Patients with skin toxicity grade 0 will follow an increasing dose schedule: on days 22 and 29 they will receive 350 mg/m2 and from day 36 onwards, 500 mg/m2 weekly.
干预措施: Dose escalation of cetuximab (Drug)
结局指标
主要结局
PFS Probability Rate at 9 Months in the Dose Escalation Arm
时间窗: 9 months
A precise estimate (+/- 10%) of the probability of not having progression at 9 months. This measure is an estimation derived from the Kaplan-Meier algorithm and does not represent a dimple percentage of participants.
次要结局
- Duration of Response in Liver-limited Disease Patients(Treatment + follow-up (3 years from database lock))
- Progression Free Survival (PFS) Median Time(Treatment + follow-up (3 years from database lock))
- Progression Free Survival (PFS) Median Time for Resected Patients(Treatment + follow-up (3 years from database lock))
- Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio)(Treatment + follow-up (3 years from database lock))
- Death Rates by 3 Years Follow-up(Treatment + follow-up (3 years from database lock))
- Overall Survival (OS) Median Time(Treatment + follow-up (3 years from database lock))
- Overall Survival (OS) Median Time for Resected Patients(Treatment + follow-up (3 years from database lock))
- Overall Response(Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.)
- Overall Response in Patients With Liver-limited Disease(Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.)
- Disease Control(Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.)
- Disease Control in Patients With Liver-limited Disease(Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.)
- Duration of Response(Treatment + follow-up (3 years from database lock))
- Resections for Metastatic Lesions(Treatment + follow-up (3 years from database lock))
- R0 Rate (Free of Tumor After Resection for Metastatic Lesions)(Treatment + follow-up (3 years from database lock))
- Skin Toxicity (Safety)(From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.)
- Laboratory Safety Assessments(From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.)
- Deaths Till 30 Days From Last Cetuximab Administration(From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.)