A Phase 2, Open Label, Multicenter, Randomized Trial Comparing Tivozanib in Combination With mFOLFOX6 to Bevacizumab in Combination With mFOLFOX6, In Stage IV Metastatic Colorectal Cancer (mCRC) Subjects
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 265
- 试验地点
- 73
- 主要终点
- Investigator-assessed Progression-Free Survival (PFS)
研究概览
简要总结
The objective of this study is to compare the progression free survival (PFS), overall survival (OS), objective response rate (ORR), time to treatment failure (TTF), duration of response (DoR), quality of life, safety and tolerability of tivozanib in combination with mFOLFOX6 and bevacizumab in combination with mFOLFOX6.
详细描述
Imaging scans (computed tomography [CT]/magnetic resonance imaging [MRI]) to assess disease progression were to be completed within 28 days prior to first study drug administration, approximately every 8 weeks for the first 18 months and then approximately every 12 weeks until the patient showed progressive disease (PD) per the investigator, withdrew consent, was lost to follow-up or died. Per the original protocol, all patients were to be contacted by the study site every 12 weeks for survival following the end-of-treatment visit until death or for no more than 3 years after the end-of-treatment visit.
The interim futility analysis was conducted in December 2013, based on a pre-specified analysis cutoff date of 13 September 2013. The study was brought to a close as specified in the protocol due to the results of the interim futility analysis and only those participants who were deriving benefit (per the treating physician) from their current treatment remained on study until one of the discontinuation criteria was met.
Given the early closure of the study, no updated or additional efficacy analyses were performed after the interim analysis. A biomarker analysis was conducted in January 2014, based on the data from the cutoff date of 13 September 2013. The safety analysis was updated with a new cutoff date of 28 February 2014.
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
- •Documented diagnosis of metastatic colorectal cancer
- •One measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •No prior systemic chemotherapy for advanced colorectal cancer; no fluorouracil containing adjuvant therapy in previous 6 months
- •Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
排除标准
- •Any prior Vascular Endothelial Growth Factor (VEGF)-directed therapy or any other agent or investigational agent targeting the VEGF pathway
- •Primary Central Nervous System (CNS) malignancies or CNS metastases
- •Hematologic abnormalities:
- •Hemoglobin < 9.0 g/dL,
- •Absolute neutrophil count (ANC) < 2000 per mm^3,
- •Platelet count < 100,000 per mm^3,
- •Prothrombin (PT) or Partial Thromboplastin Time (PTT) > 1.5 X Upper Limit of Normal (ULN)
- •Serum chemistry abnormalities:
- •Total bilirubin > 1.5 X ULN,
- •Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) > 2.5 X ULN,
- •Alkaline phosphatase > 2.5 X ULN,
- •Serum albumin < 2.0 g/dL,
- •Creatinine > 1.5 X ULN,
- •Proteinuria > 2+ by urine dipstick
- •Significant cardiovascular disease
- •Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug
- •Non-healing wound, bone fracture, or skin ulcer
- •Inadequate recovery from any prior surgical procedure or major surgical procedure within 8 weeks prior to administration, or anticipation of major surgical procedure during the course of the study
- •History of significant gastrointestinal (GI) toxicity, diarrhea, or stomatitis within the last 6 weeks
- •An active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug
- •Serious/active infection or infection requiring antibiotics
- •Significant bleeding disorders within 6 months prior to administration of first dose of study drug
- •Active second primary malignancy, other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. Subject is not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for > 5 years
- •History of allergic reactions, or intolerance, attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, history of Grade 3 hypersensitivity to oxaliplatin, history of allergic reaction to folic acid
- •Female subject is pregnant or lactating
- •Known history of genetic or acquired immune suppression disease including Human Immunodeficiency Virus (HIV); subjects on immune suppressive therapy for organ transplant
- •Inability to swallow pills, malabsorption syndrome or gastrointestinal disease, major resection of the stomach or small bowel, or gastric bypass
- •Uncontrolled neuro-psychiatric disorder or altered mental status
- •Peripheral neuropathy ≥ Grade 2
- •Participating in another interventional protocol
研究组 & 干预措施
Tivozanib + mFOLFOX6
Participants received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received modified FOLFOX6 (mFOLFOX6) chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
干预措施: Tivozanib (Drug)
Tivozanib + mFOLFOX6
Participants received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received modified FOLFOX6 (mFOLFOX6) chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
干预措施: mFOLFOX6 (Drug)
Bevacizumab + mFOLFOX6
Participants received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
干预措施: Bevacizumab (Drug)
Bevacizumab + mFOLFOX6
Participants received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
干预措施: mFOLFOX6 (Drug)
结局指标
主要结局
Investigator-assessed Progression-Free Survival (PFS)
时间窗: From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
The time from the date of randomization until objective tumor progression or death due to any cause. Objective tumor progression was determined through radiological imaging and based on the requirements of the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1): Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. Participants who did not progress or had not died at the time of the analysis were censored at the date of last tumor assessment where non-progression was documented.
次要结局
- Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)(3 years)
- Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Overall Survival (OS)(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)(From first dose through 30 days after last dose of either tivozanib or bevacizumab, until the data cut-off date of 28 February 2014. The median duration of treatment was 168.0 days in the tivozanib (tiv) arm and 162.0 days in the bevacizumab (bev) arm.)
- Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Time to Treatment Failure (TTF)(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Objective Response Rate (ORR)(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Tumor VEGF-D RNA Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Duration of Response (DoR)(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Health Related Quality of Life (HRQoL)(3 years)
- Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Serum Neuropilin Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Tumor VEGF-C RNA Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)
- Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level(From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.)