Randomized Phase 3 Study of Intermittent or Continuous Panitumumab Plus FOLFIRI for First-line Treatment of Patients With Unresectable Left Sided RAS/B-RAF Wild-type Metastatic Colorectal Cancer (IMPROVE-2 Trial)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- Time to Treatment Failure
研究概览
简要总结
The investigators hypothesize that intermittent first-line Panitumumab plus FOLFIRI is effective in first line as the same regimen given continuously, resulting in a Time to Treatment Failure (TTF) not inferior to that obtained with standard continuous regimen of Panitumumab plus FOLFIRI, in the treatment of metastatic left sided RAS/B-RAF wild-type colorectal cancer patients.
Correlative mechanistic studies on tissue and blood samples, liquid biopsies, could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti-EGFR treatment strategy.
详细描述
This study is a multicentric open label academic randomized phase-3 study. The study population will include untreated and unresectable left sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, eligible for first-line treatment. A total of 500 patients, 250 for arm, will be enrolled.
All patients will receive an induction treatment with Panitumumab as 60 minutes or 90 minutes for doses over 1000 mg intravenous infusion at the dosage of 6 mg/kg, given every two weeks, plus FOLFIRI chemotherapy as standard guidelines.
Before starting FOLFIRI plus Panitumumab, at the time of enrollment, patients will be immediately randomized electronically 1:1 to one of the two arms: standard continuous or exploratory intermittent treatment.
Induction treatment with FOLFIRI plus panitumumab will continue until progressive disease, unacceptable toxicity or informed consent withdrawal, or for up to 8 cycles.
At the end of induction treatment, in presence of complete or partial response, or stable disease, non-progressing patients will be allocated to one of the two pre-assigned arms:
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent to study procedures and to correlative studies.
- •Histologically proven left sided mCRC.
- •RAS/BRAF wild-type and pMMR and/or MSS status assessed at local centers according a validated method defined by EMA
- •Disease judged unresectable by the local multidisciplinary team
- •Patient candidate to receive Induction treatment with FOLFIRI plus panitumumab as per standard clinical practice
- •No prior treatments (chemotherapy, radiation or surgery) for mCRC. Surgery for primary CRC tumor before starting treatment is allowed.
- •Either sex aged ≥ 18
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
- •Imaging-documented measurable disease, according to RECIST 1.1 criteria.
- •Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory
- •Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.
- •Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN.
- •Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula).
- •Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range
排除标准
- •Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- •Prior chemotherapy or any other medical treatment for mCRC (previous adjuvant chemotherapy is allowed if terminated > 6 months previously).
- •Major surgical intervention within 4 weeks prior to enrollment.
- •Pregnancy and breast-feeding.
- •Any brain metastases.
- •Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD) or known UGT1A1 homozygosity.
- •Required dose reduction of 5-fluorouracil in the past for toxicity.
- •Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
- •History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form.
- •Participation in any interventional drug or medical device study within 30 days prior to treatment start.
- •Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.
- •History of interstitial pneumonitis or pulmonary fibrosis.
- •History of corneal perforation or ulceration keratitis
研究组 & 干预措施
CONTINUOUS ARM
Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal
干预措施: Panitumumab (Drug)
CONTINUOUS ARM
Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal
干预措施: Irinotecan (Drug)
CONTINUOUS ARM
Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal
干预措施: 5-fluorouracil (Drug)
CONTINUOUS ARM
Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal
干预措施: L-folinic acid (Drug)
INTERMITTENT ARM
Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.
干预措施: Panitumumab (Drug)
INTERMITTENT ARM
Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.
干预措施: Irinotecan (Drug)
INTERMITTENT ARM
Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.
干预措施: 5-fluorouracil (Drug)
INTERMITTENT ARM
Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.
干预措施: L-folinic acid (Drug)
结局指标
主要结局
Time to Treatment Failure
时间窗: up to 1 year last patients randomized
Time to treatment failure (TTF) is defined as the time from randomization to the objective disease progression by RECIST 1.1 criteria occurred during the treatment (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first, or a treatment delay \> 28 days for toxicity
次要结局
- Overall survival(up to 1 year last patients randomized)