TWICE-IRI: Optimization of Second-line Therapy With Aflibercept, Irinotecan (Day 1 or Day 1,3), 5-Fluorouracile and Folinic Acid in Patients With Metastatic Colorectal Cancer. A Randomized Phase III Study.
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 202
- 试验地点
- 1
- 主要终点
- Overall response rate (ORR).
研究概览
简要总结
Optimization of second-line therapy with aflibercept, irinotecan (day1 or day 1,3), 5fluorouracile and folinic acid in patients with metastatic colorectal cancer. A randomized Phase III study.
详细描述
Background - Rationale Aflibercept The addition of aflibercept to the standard FOLFIRI regimen as second-line therapy was evaluated in a large phase III study (EFC10262-VELOUR). This combination significantly improved both PFS (4.7 to 6.9 months, HR=0.76; P=<0.001) and OS (12.1 to 13.5 months, HR=0.82; P=0.003). In the evaluable population (86.5%), the tumor response rate was also improved when adding aflibercept (ORR=19.8% [16.4-23.2]) to the FOLFIRI regimen (ORR=11.1% [8.5-13.8]).
Irinotecan The combination of aflibercept with FOLFIRI3, an optimized irinotecan-based regimen, was evaluated in 65 patients in a French multicentric retrospective cohort. (Carola C et al, WJCO 2018) In the cohort of irinotecan-naïve patients (n=30), the objective response rate was 43.3%, and the disease control rate 76.7%. Median PFS and OS were 11.3 months (95% CI 6.1-29.0) and 17.0 months (95% CI 13.0-17.3). The most common (>5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), hypertension (6.7%).
In the cohort of patients previously treated with irinotecan (n=35), the objective response rate was 34.3%, and the disease control rate 60.0%. Median PFS and OS were 5.7 months (95% CI 3.9-10.4) and 14.3 months (95% CI 12.8-19.5).
Table. FOLFIRI-aflibercept vs. FOLFIRI3-aflibercept: a cross-trial comparison FOLFIRI-aflibercept (VELOUR) FOLFIRI3-aflibercept (Irinotecan-naïve) N = 612 N = 30 Efficacy RR, % 19.3 vs 43.3 PFS, months 6.9 vs 11.3 OS, months 13.5 vs 17.0 Grade 3-4 AEs, % Any 83.4 vs 56.7 Neutropenia 36.7 vs 14.3 Diarrhea 19.3 vs 37.9 Mucositis 13.8 vs 10.4 Hypertension 19.3 vs 6.9 Discontinuation, % Progression 49.8 vs 36.7 Adverse event 26.6 vs 46.7
Study Objectives
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
- •Provision of signed and dated informed consent and stated willingness to comply with all study procedures and availability for the duration of the study, Signed, written Informed Consent Form (ICF),
- •Willing and able to comply with the protocol,
- •Age 18-75 years,
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1,
- •Life expectancy ≥ 3 months,
- •Histologically proven carcinoma of colon and/or rectum,
- •Confirmed unresectable metastatic disease,
- •At least one measurable and/or evaluable tumor metastasis on CT-scan or MRI per RECIST criteria version 1.1,
- •Prior oxaliplatin-based first-line therapy for metastatic disease (the use of prior bevacizumab or anti-EGFR mabs is allowed but not mandatory) - Less than 6 months from completion of any prior oxaliplatin-based adjuvant therapy can be considered as first-line therapy. Prior use of irinotecan in combination with oxaliplatin and 5FU as first-line therapy is allowed if the interval between the last administration of irinotecan and disease progression is at least 6 months (ie, irinotecan-free interval ≥6 months).
- •Negative urine and/or serum pregnancy test within 7 days before inclusion if female subject is of childbearing potential,
- •Clinical laboratory parameters adequate as follows:
- •Serum total bilirubin level ≤ 1.5 x upper normal limit (UNL),
- •Neutrophil count ≥ 1.5x109/L,
- •Platelet count ≥ 100x109/L,
- •Hemoglobin ≥ 9 g/dL,
- •Serum creatinine level ≤ 150µM,
- •Serum albumin ≥ 25 g/L,
- •Calcium ≥ 1 x ULN
- •Alkaline phosphatase (ALP) < 3 x ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN (in the case of liver metastases, <5 x ULN),
- •Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour,
- •For women of childbearing potential and for men, agreement to use an effective contraceptive method from the time of screening throughout the study until 6 months after administration of the last dose of any study medication. Highly effective contraceptive method consist of prior sterilization, inter-uterine device, intrauterine hormone-releasing system, oral or injectable contraceptives barrier methods, and/or true sexual abstinence),
- •Affiliation to French health care system.
排除标准
- •History of arterial thrombotic event in the last 6 months (eg., myocardial infarction, cerebrovascular accident or transient ischemic attack),
- •Uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg despite optimal medical therapy), or history of hypertensive crisis, or hypertensive encephalopathy,
- •Prior use of aflibercept,
- •Adverse events from prior anticancer therapy grade ≥2 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0), except for neuropathy and alopecia,
- •Bowel obstruction, inflammatory bowel disease
- •Known DPD deficiency. If not known for the patient, testing for DPD should be done during the screening period (patients with uracilemia ≥16ng/mL are not eligible),
- •Known UGT1A1 deficiency (eg, Gilbert syndrome, Crigler-Najjar syndrome). If not known for the patient, genetic testing for UGT1A1 should be done during the screening period for patients with hyperbilirubinemia (ie, total bilirubin level >1xULN),
- •Active infection requiring intravenous antibiotics at the start of study treatment,
- •Known active infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV),
- •Known allergy or hypersensitivity to the active substance or ingredients of any study drug,
- •Women currently pregnant or breastfeeding,
- •Inability to comply with study and follow-up procedures as judged by the Investigator,
- •Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy)
- •Concomitant use of Saint John Wort herb (millepertuis), Yellow Fever vaccine, Live Attenuated Vaccines (LAV) and phenytoine
- •Treatment with any other investigational medicinal product within 28 days or 5 investigational agent half-lives (whichever is longer) prior to the start of study treatment,
- •Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring systemic therapy, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of study drugs that may affect the interpretation of the results, or that may render the subject at high risk for treatment complications.
- •Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for three years prior to study entry,
- •Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to start of study treatment, or anticipation of need for major surgical procedure during the course of the study.
- •Minor surgical procedure including placement of a vascular access device, within 2 days of start of study treatment,
- •History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to start study treatment.
- •Clinically significant active cardiac disease (including NYHA class III or IV congestive heart failure)
- •Venous thromboembolic event (including pulmonary embolism) grade 3 or 4 within 6 months prior to start study treatment.
研究组 & 干预措施
Aflibercept-FOLFIRI (arm 1)
- Aflibercept (D1) H0: 4mg/kg IV infusion over 60min (+ 2-minute window),
- Folinic acid (D1) H+1: 400mg/m² IV infusion over 120min (+ 2-minute window),
- Irinotecan (D1) H+1: 180mg/m² IV infusion over 60min (+ 2-minute window),
- 5-fluorouracile (D1) H+3: 400mg/m² IV infusion over 15min (+ 2-minute window),
- 5-fluorouracile (D1 to D3): H+3.5: 2400mg/m² IV infusion over 46 hours (+ 1hour window)
- H+49.5: End of treatment administration
干预措施: Aflibercept-FOLFIRI (Drug)
Aflibercept-mFOLFIRI3 (arm 2)
- Aflibercept (D1) H0: 4mg/kg IV infusion over 60min (+ 2-minute window),
- Folinic acid (D1) H+1: 400mg/m² IV infusion over 120min (+ 2-minute window),
- Irinotecan (D1 and D3) H+1 and H+49: 75mg/m² IV infusion over 60min (+ 2-minute window) on cycles 1 and 2, then 90mg/m² at cycle 3 and furthers in absence of AEs grade ≥2,
- 5-fluorouracile (D1 to D3) H+3: 2400mg/m² IV infusion over 46 hours (+ 1hour window)
- H+50: End of treatment administration
干预措施: Aflibercept-mFOLFIRI3 (Drug)
结局指标
主要结局
Overall response rate (ORR).
时间窗: 2 months
Tumor measurements will be obtained using CT-scans (or MRIs) of the thorax, abdomen, and pelvis at baseline then every 8 weeks (+/- one week) according to RECIST v1.1. At the investigator's discretion, tumor assessments may be repeated at any time if progressive disease is suspected. It is preferred that the scans for a patient are taken with the same technique (CT or MRI) throughout the study.
次要结局
- Disease control rate (DCR)(2 months)
- Progression-free survival (PFS)(2 months)
- Early response rate(2 months)
- Overall survival (OS)(time interval from randomization to the date of death from any cause. Assessed up to 13 months after the beginning of the study)
- Pathological response rate(2 months)
- Tolerance(2 weeks)
- HRQoL(2 months)
- Salvage surgery rate(2 months)
- Exploratory biomarkers(2 months)