Colorectal Cancer
Conditions
Keywords
metastatic colorectal cancer, Avastin, bevacizumab, tivozanib, mFOLFOX6, BATON-CRC, AV951, ASP4130
Brief summary
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
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.
Interventions
DRUGTivozanib
Capsules for oral administration
DRUGBevacizumab
Solution for intravenous infusion
DRUGmFOLFOX6
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.
Sponsors
AVEO Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed Progression-Free Survival (PFS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| Health Related Quality of Life (HRQoL) | 3 years | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR) | 3 years | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Finland, Hungary, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were at least 18 years of age with Stage IV metastatic colorectal cancer (mCRC) and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1).
Pre-assignment details
Participants were randomized in a 2:1 ratio (tivozanib to bevacizumab) and stratified by lactate dehydrogenase (LDH) status (\< 1.5 x the upper limit of normal \[ULN\] or \> 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or \> 2).
Participants by arm
| Arm | Count |
|---|---|
| Tivozanib + mFOLFOX6 Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle. | 177 |
| Bevacizumab + mFOLFOX6 Participants received 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. | 88 |
| Total | 265 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 45 | 18 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Randomized but Never Received Study Drug | 0 | 1 |
| Overall Study | Study Closed by Sponsor | 8 | 5 |
| Overall Study | Withdrawal by Subject | 9 | 3 |
Baseline characteristics
| Characteristic | Tivozanib + mFOLFOX6 | Bevacizumab + mFOLFOX6 | Total |
|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 9.58 | 62.6 years STANDARD_DEVIATION 11.17 | 62.2 years STANDARD_DEVIATION 10.12 |
| Eastern Cooperative Oncology Group (ECOG) performance status ECOG Performance Status 0 | 95 participants | 58 participants | 153 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status ECOG Performance Status 1 | 82 participants | 30 participants | 112 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status ECOG Performance Status 2 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status ECOG Performance Status 3 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status ECOG Performance Status 4 | 0 participants | 0 participants | 0 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 170 Participants | 86 Participants | 256 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Kirsten rat sarcoma (KRAS) Mutation Status Mutant | 23 participants | 16 participants | 39 participants |
| Kirsten rat sarcoma (KRAS) Mutation Status Unknown | 121 participants | 51 participants | 172 participants |
| Kirsten rat sarcoma (KRAS) Mutation Status Wild-type | 33 participants | 21 participants | 54 participants |
| Lactate dehydrogenase (LDH) Status < 1.5 Upper Limit of Normal | 127 participants | 64 participants | 191 participants |
| Lactate dehydrogenase (LDH) Status ≥ 1.5 Upper Limit of Normal | 50 participants | 24 participants | 74 participants |
| Number of metastatic sites at screening | 2.0 metastatic sites STANDARD_DEVIATION 1.02 | 2.0 metastatic sites STANDARD_DEVIATION 0.85 | 2.0 metastatic sites STANDARD_DEVIATION 0.97 |
| Number of metastatic sites/organs 1 | 56 participants | 30 participants | 86 participants |
| Number of metastatic sites/organs 2 | 80 participants | 34 participants | 114 participants |
| Number of metastatic sites/organs 3 | 29 participants | 21 participants | 50 participants |
| Number of metastatic sites/organs ≥ 4 | 12 participants | 3 participants | 15 participants |
| Origin of Cancer Colon | 124 participants | 64 participants | 188 participants |
| Origin of Cancer Rectal | 53 participants | 24 participants | 77 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 2 participants | 5 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 169 participants | 85 participants | 254 participants |
| Region of Enrollment Australia | 15 participants | 9 participants | 24 participants |
| Region of Enrollment Austria | 8 participants | 3 participants | 11 participants |
| Region of Enrollment Belgium | 10 participants | 9 participants | 19 participants |
| Region of Enrollment Canada | 13 participants | 4 participants | 17 participants |
| Region of Enrollment Czech Republic | 12 participants | 9 participants | 21 participants |
| Region of Enrollment Finland | 5 participants | 1 participants | 6 participants |
| Region of Enrollment Hungary | 24 participants | 8 participants | 32 participants |
| Region of Enrollment Italy | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Spain | 22 participants | 8 participants | 30 participants |
| Region of Enrollment United Kingdom | 19 participants | 7 participants | 26 participants |
| Region of Enrollment United States | 44 participants | 26 participants | 70 participants |
| Sex: Female, Male Female | 59 Participants | 33 Participants | 92 Participants |
| Sex: Female, Male Male | 118 Participants | 55 Participants | 173 Participants |
| Time Since Initial Diagnosis | 9.41 months STANDARD_DEVIATION 20.473 | 10.88 months STANDARD_DEVIATION 21.055 | 9.90 months STANDARD_DEVIATION 20.64 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 175 / 177 | 85 / 87 |
| serious Total, serious adverse events | 82 / 177 | 42 / 87 |
Outcome results
Primary
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.
Time frame: 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.
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Investigator-assessed Progression-Free Survival (PFS) | 9.4 months |
| Bevacizumab + mFOLFOX6 | Investigator-assessed Progression-Free Survival (PFS) | 10.7 months |
Comparison: An interim futility analysis was to be performed when approximately 83 PFS events (50% of the total PFS events) were observed. The Lans DeMets beta spending function with an O'Brien-Fleming boundary was used to derive the futility boundary. If the hazard ratio (HR) for PFS was greater than 1.0581, enrollment was to be stopped. With this futility stopping rule, the adjusted study power was 78.6%.p-value: 0.70695% CI: [0.693, 1.718]Log Rank
Secondary
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.
Time frame: 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.
Population: Participants with a best overall response of complete response (CR) or partial response (PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Duration of Response (DoR) | 7.4 months |
| Bevacizumab + mFOLFOX6 | Duration of Response (DoR) | 9.3 months |
p-value: 0.43795% CI: [0.604, 3.194]Log Rank
Secondary
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.
Time frame: 3 years
Population: Analysis was not performed due to study closure.
Secondary
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.
Time frame: 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.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Objective Response Rate (ORR) | 45.2 percentage of participants |
| Bevacizumab + mFOLFOX6 | Objective Response Rate (ORR) | 43.2 percentage of participants |
p-value: 0.718Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 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.
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Overall Survival (OS) | NA months |
| Bevacizumab + mFOLFOX6 | Overall Survival (OS) | NA months |
p-value: 0.75495% CI: [0.561, 2.218]Log Rank
Secondary
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.
Time frame: 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.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level | 42 participants |
| Bevacizumab + mFOLFOX6 | Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level | 24 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level | 16 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level | 13 participants |
95% CI: [0.746, 2.375]
95% CI: [0.285, 1.16]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level | 14 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level | 30 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level | 7 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level | 11 participants |
95% CI: [0.303, 1.991]
95% CI: [0.615, 2.501]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Serum Neuropilin Level | 10 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Serum Neuropilin Level | 34 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Serum Neuropilin Level | 6 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Serum Neuropilin Level | 12 participants |
95% CI: [0.343, 2.63]
95% CI: [0.503, 1.918]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level | 20 participants |
| Bevacizumab + mFOLFOX6 | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level | 24 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level | 6 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level | 12 participants |
95% CI: [0.635, 4.073]
95% CI: [0.375, 1.521]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level | 15 participants |
| Bevacizumab + mFOLFOX6 | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level | 29 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level | 8 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level | 10 participants |
95% CI: [0.366, 2.1]
95% CI: [0.614, 2.646]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio | 21 participants |
| Bevacizumab + mFOLFOX6 | Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio | 23 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio | 11 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio | 7 participants |
95% CI: [0.345, 1.507]
95% CI: [0.672, 3.795]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level | 15 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level | 29 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level | 5 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level | 13 participants |
95% CI: [0.58, 4.564]
95% CI: [0.397, 1.531]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available serum protein samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level | 14 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level | 30 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level | 4 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level | 14 participants |
95% CI: [0.636, 5.956]
95% CI: [0.422, 1.538]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available tumor biopsy RNA samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level | 14 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level | 17 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level | 5 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level | 7 participants |
95% CI: [0.548, 4.32]
95% CI: [0.299, 1.85]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available tumor biopsy RNA samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level | 13 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level | 18 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level | 7 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level | 5 participants |
95% CI: [0.468, 3.214]
95% CI: [0.447, 3.396]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available tumor biopsy RNA samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-C RNA Level | 14 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-C RNA Level | 17 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-C RNA Level | 6 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-C RNA Level | 6 participants |
95% CI: [0.307, 2.1]
95% CI: [0.585, 3.873]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available tumor biopsy RNA samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio | 16 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio | 15 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio | 6 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio | 6 participants |
95% CI: [0.356, 2.385]
95% CI: [0.462, 3.22]
Secondary
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.
Time frame: 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.
Population: Full analysis set with available tumor biopsy RNA samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-D RNA Level | 16 participants |
| Bevacizumab + mFOLFOX6 | Progression-Free Survival Events by Tumor VEGF-D RNA Level | 15 participants |
| Bevacizumab: LDH < 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-D RNA Level | 5 participants |
| Bevacizumab : LDH ≥ 1.5 ULN | Progression-Free Survival Events by Tumor VEGF-D RNA Level | 7 participants |
95% CI: [0.334, 2.512]
95% CI: [0.554, 3.455]
Secondary
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.
Time frame: 3 years
Population: Analysis was not performed due to study closure.
Secondary
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.
Time frame: 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.
Population: The safety analysis set consisted of all randomized participants who received at least one dose of study drug (tivozanib or bevacizumab), analyzed according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any adverse event | 177 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related AE ≥ Grade 3 | 126 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tiv/bev & mFOLFOX6-related AE outcome of death | 3 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | CTCAE Grade 3 or higher | 156 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related adverse event | 158 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related adverse event | 169 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab and mFOLFOX6-related AE | 138 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related AE ≥ Grade 3 | 104 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tiv/bev and mFOLFOX6-related AE ≥ Grade 3 | 75 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any AE with an outcome of death | 8 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related AE of death | 3 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related AE outcome of death | 3 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any serious adverse event (SAE) | 82 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related SAE | 38 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related SAE | 45 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab and mFOLFOX6-related SAE | 30 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | AE leading to tiv/bev discontinuation | 73 participants |
| Tivozanib + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | AE leading to tivozanib/bevacizumab interruption | 138 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab and mFOLFOX6-related AE | 59 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any adverse event | 87 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related AE ≥ Grade 3 | 31 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related SAE | 23 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related AE ≥ Grade 3 | 61 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tiv/bev and mFOLFOX6-related AE ≥ Grade 3 | 23 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related AE outcome of death | 2 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any serious adverse event (SAE) | 42 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab and mFOLFOX6-related SAE | 11 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | AE leading to tiv/bev discontinuation | 30 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | AE leading to tivozanib/bevacizumab interruption | 63 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tiv/bev & mFOLFOX6-related AE outcome of death | 2 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | CTCAE Grade 3 or higher | 76 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any AE with an outcome of death | 2 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related adverse event | 74 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related SAE | 15 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any mFOLFOX6-related adverse event | 84 participants |
| Bevacizumab + mFOLFOX6 | Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs) | Any tivozanib/bevacizumab-related AE of death | 2 participants |
Secondary
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.
Time frame: 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.
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib + mFOLFOX6 | Time to Treatment Failure (TTF) | 5.5 months |
| Bevacizumab + mFOLFOX6 | Time to Treatment Failure (TTF) | 5.4 months |
p-value: 0.96795% CI: [0.746, 1.358]Log Rank