FIRE-5 -Study: Optimal Anti-EGFR Treatment of mCRC Patients With Low-Frequency RAS Mutation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 2
- 主要终点
- Overall Response Rate
研究概览
简要总结
The present hypothesis is that anti-EGFR agents are active in tumors with low-level RAS mutation when the majority of tumor cells is still sensitive. While response rate may be high and may reflect sensitivity to anti-EGFR agents, PFS is anticipated to be shorter than in RAS wild-type patients due to the faster development of resistance when sensitive cells are eradicated and when the RAS-mutant anti-EGFR resistant clones become predominant.
The characteristics of low-level RAS mutant tumors would be:
- Objective response rate (ORR) high (reflecting the sensitive clone)
- Progression-free survival (PFS) short (reflecting the more rapid outgrowth of RAS mutant clones)
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Histologically confirmed, UICC stage IV metastatic adenocarcinoma of the colon or rectum
- •Primarily non-resectable metastases or surgical resection refused by the patient
- •RAS mutation determined by the local pathology
- •ECOG performance status 0-2
- •Patients suitable for chemotherapy administration
- •Patient's written declaration of consent obtained
- •Estimated life expectancy > 3 months
- •Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria
- •Primary tumor tissue available and patient consents to storage and molecular and genetic profiling of tumor material. Molecular profiling of blood samples is optionally performed.
- •Adequate bone marrow function:
- •Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
- •Thrombocytes ≥ 100 x 109/L
- •Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
- •Adequate hepatic function:
- •Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
- •ALAT and ASAT ≤ 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT ≤ 5 x ULN)
- •Adequate renal function:
- •▫ Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50 mL/min
- •No previous chemotherapy for metastatic disease. Patient with need of immediate treatment (high tumor load, symptoms) may have received one application of FOLFIRI prior to study treatment.
排除标准
- •Previous chemotherapy for metastatic disease with the exception of one cycle of FOLFIRI (e.g. while waiting for the result of RAS mutation frequency).
- •Patients planned to be treated with FOLFOX or another oxaliplatin-based regimen as first-line treatment
- •Primarily resectable metastases and the patient agrees to resection
- •Grade III or IV heart failure (NYHA classification)
- •Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
- •Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
- •Participation in an investigational clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in the investigational clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest
- •Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, panitumumab, irinotecan, and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade ≥
- •Known hypersensitivity to Chinese hamster ovary cell (CHO) - cellular products or other recombinant human or humanised monoclonal antibodies
- •History of uncontrolled bronchial asthma
- •Patients with interstitial pneumonitis or pulmonary fibrosis
- •Patients with known brain metastasis
- •History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
- •Symptomatic peritoneal carcinomatosis
- •Severe, non-healing wounds, ulcers or bone fractures
- •Patients with acute or chronic infection requiring systemic therapy
- •Known history of positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- •Active or chronic Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive; serologic tests required in patients who receive study treatment).
- •Known DPD deficiency (specific screening not required)
- •Known glucuronidation deficiency (Gilbert's syndrome);(specific screening not required
- •Treatment with sorivudine or brivudine within 28 days before study enrollment or requirement for concomitant antiviral treatment with sorivudine or brivudine
- •History of a second primary malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively.
- •Known previous or ongoing alcohol or drug abuse
- •Pregnant or breast-feeding patients
- •Any other severe concomitant disease or disorder which, in the investigator's opinion, could influence the patient's ability to participate in the study or influence his/her safety during the study or interfere with interpretation of study results
- •Both, absent and restricted legal capacity
研究组 & 干预措施
RAS mutations frequency <= 7%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Panitumumab (Drug)
RAS mutations frequency <= 7%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Irinotecan (Drug)
RAS mutations frequency <= 7%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Folinic acid (Drug)
RAS mutations frequency <= 7%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: 5-FU (Drug)
RAS mutation frequency >7% to <=14%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Panitumumab (Drug)
RAS mutation frequency >7% to <=14%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Irinotecan (Drug)
RAS mutation frequency >7% to <=14%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Folinic acid (Drug)
RAS mutation frequency >7% to <=14%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: 5-FU (Drug)
RAS mutation frequency >14% to <=20%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Panitumumab (Drug)
RAS mutation frequency >14% to <=20%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Irinotecan (Drug)
RAS mutation frequency >14% to <=20%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: Folinic acid (Drug)
RAS mutation frequency >14% to <=20%
Panitumumab 6 mg/kg BW as 60-min i.v. infusion* D1
*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Followed by FOLFIRI regimen
- Irinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
- Folinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
- 5-FU 400 mg/m² BSA, bolus, D1
- 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
q day 14
干预措施: 5-FU (Drug)
结局指标
主要结局
Overall Response Rate
时间窗: up to 60 months
As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each arm of patients with defined low-frequency RAS mutation
次要结局
- Overall Survival (OS)(up to 60 months)
- Investigation of Early Tumor shrinkage (ETS) as an alternative early-on-treatment predictor of treatment efficacy(up to 48 months)
- Investigation of Depth of Response (DpR) to define the nadir of tumour response(up to 48 months)
- Progression free survival (PFS)(up to 60 months)
研究者
PD Dr. med. Volker Heinemann
Director of the CCC-Munich at the LMU Munich
Ludwig-Maximilians - University of Munich