A Study Combining mFOLFOX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First Line Therapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Tivozanib
* Drug: Bevacizumab
* Drug: mFOLFOX6


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tivozanib + mFOLFOX6<br>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. | Drug: Tivozanib<br>* Capsules for oral administration<br>* Other names: ASP4130;Drug: mFOLFOX6<br>* mFOLFOX6 regimen is a combination therapy of oxaliplatin 85 mg/m^2 administered as an intravenous bolus over 2 hours on Days 1 and 15, leucovorin calcium 400 mg/m^2 administered as an intravenous bolus over 2 hours on Days 1 and 15, fluorouracil 400 mg/m^2 administered as an intravenous bolus over 5 to 15 minutes on Days 1 and 15, then 2400 mg/m^2 continuous intravenous infusion over 46 hours on Days 1 to 3 and 15 to 17.<br>|
| Active Comparator: Bevacizumab + mFOLFOX6<br>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. | Drug: Bevacizumab<br>* Solution for intravenous infusion<br>* Other names: Avastin;Drug: mFOLFOX6<br>* mFOLFOX6 regimen is a combination therapy of oxaliplatin 85 mg/m^2 administered as an intravenous bolus over 2 hours on Days 1 and 15, leucovorin calcium 400 mg/m^2 administered as an intravenous bolus over 2 hours on Days 1 and 15, fluorouracil 400 mg/m^2 administered as an intravenous bolus over 5 to 15 minutes on Days 1 and 15, then 2400 mg/m^2 continuous intravenous infusion over 46 hours on Days 1 to 3 and 15 to 17.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed Progression-Free Survival (PFS) | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR) | The time from the date of randomization until the date of radiological disease progression assessed by the IRR or until death due to any cause, even in the absence of radiological progression. | 3 years | 
| Overall Survival (OS) | Overall survival (OS) is defined as the time from the date of randomization until the documented date of death. Participants still alive at the time of analysis were censored on the last day the participant was known to be alive. | 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) | Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) confirmed a minimum of four weeks apart based on RECIST 1.1 criteria. CR: Disappearance of all target and non-target lesions and no new lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and no progression of non-target lesions and no new lesions, or, disappearance of all target lesions and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits and no new lesions. | 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) | Duration of response (DoR) is defined as the time from the date of the first documented response of CR or PR (whichever is first recorded) to documented progression or death. If a participant did not progress or had not died at the time of analysis, the duration of response was censored at the date of last tumor assessment. Duration of response is only defined for participants whose best overall response was CR or PR. | 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) | Time to Treatment Failure (TTF) is defined as the time from randomization to last dose date of tivozanib/bevacizumab. If a participant discontinued treatment for any reason, the participant was considered as an event. Participants remaining on treatment at the time of analysis were censored at date of last dose. | 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) | Time to deterioration in HRQoL measured by Colorectal cancer (CRC) subscale of the Functional Assessment of cancer Therapy Colorectal (FACT-C) scale, change in score from baseline using the European Quality of Life - 5 Dimensions (EQ-5D) and Fact Colorectal Symptom Index (FCSI) were not evaluated due to study closure. | 3 years | 
| Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | An abnormality identified during a medical test is defined as an AE if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study medication or was clinically significant in the investigator's opinion. An AE was serious if it resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required or prolonged inpatient hospitalization or other medically important event. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute Common Terminology Criteria for Grading Adverse Events (NCI-CTCAE) Version 4.03 per the following: 1=mild; 2= moderate; 3= severe; 4= life threatening; 5=death. Treatment-related AEs were defined as events where the relationship to study drug was marked as probably or possibly, or was missing. | 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 Lactate Dehydrogenase (LDH) Level | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum lactate dehydrogenase status. | 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum vascular endothelial growth factor-A (VEGF-A) level. VEGF-A protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median 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-C (VEGF-C) Level | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C level. VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median 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 VEGF-C / VEGF-A Ratio | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C/VEGF-A ratio. VEGF-A and VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the ratio is expressed relative to the observed median. | 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-2 level. sVEGFR-2 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median 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 Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-3 level. sVEGFR-3 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median 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 Interleukin-8 (IL-8) Level | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum interleukin-8 level. IL-8 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum neuropilin level. Neuropilin protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median 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-A Ribonucleic Acid (RNA) Level | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-A RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C/VEGF-A RNA ratio. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-D RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median 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 | The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor PIGF RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic colorectal cancer, Avastin, bevacizumab, tivozanib, mFOLFOX6, BATON-CRC, AV951, ASP4130