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

Primary Purpose

Colorectal Cancer

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tivozanib
Bevacizumab
mFOLFOX6
Sponsored by
AVEO Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring metastatic colorectal cancer, Avastin, bevacizumab, tivozanib, mFOLFOX6, BATON-CRC, AV951, ASP4130

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Banner MD Anderson Cancer Research Center
  • Genesis Cancer Center
  • Arizona Clinical Research Center
  • University of California San Diego-Morris Cancer Center
  • UC Irvine Medical Center, Division of Hematology/Oncology
  • Desert Hematology Oncology Medical Group, Inc.
  • Mountain Blue Cancer Care Center
  • University of Florida, Davis Cancer Center (VA)
  • Cleveland Clinic Florida
  • Queen's Medical Center
  • University of Hawaii
  • Kaiser Foundation Hospitals
  • Northwestern University
  • Illinios Cancer Care
  • Investigative Clinical Research of Indiana, LLC
  • Horizon Oncology Research, Inc.
  • Associates of Oncology Hematology, P.C.
  • University of Michigan Health
  • NYU Cancer Institute
  • Alamance Regional Medical Center
  • Tri Country Hematology / Oncology
  • Signal Point Clinical Research Center, LLC
  • Cancer Care Associates
  • Oregon Health and Science University
  • Oncology Hematology of Lehigh Valley
  • Northern Utah Associates
  • Seattle Cancer Care Alliance
  • St George Hospital
  • Tweed Hospital
  • Calvary Mater Newcastle
  • Flinders Medical Centre
  • Royal Hobart Hospital
  • Ballarat Health Services
  • Cabrini Hospital Malvern
  • Border Medical Oncology
  • Medizinische Universitat Graz
  • Salzburger Landesklinken
  • Klinikum Wels-Grieskirchen GmbH
  • Ziekenhuisnetwerk Antwerpen - AZ Middelheim
  • Imelda VZW
  • AZ Sint-Lucas Brugge
  • AZ Groeninge - Campus Sint-Niklaas
  • British Columbia Cancer Agency
  • QEII Health Science Centre
  • Hopital De La Cite-De-La-Sante
  • Hopital Saint-Luc - Pavillon Principal
  • Chuq Centre Hospitalier Universitaire De Quebec
  • Masarykuv onkologicky ustav
  • Fakultni nemocnice Hradec Kralove
  • Tampereen yliopistollinen sairaala
  • Turun yliopistollinen keskussairaala
  • Orszagos Onkologiai Intezet
  • Petz Aladar Megyei Oktato Korhaz
  • Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza
  • Fejer Megyei Szent Gyorgy Korhaz
  • Azienda Ospedaliero- Universitaria di Bologna - Policlinico S.Orsola-Malpighi
  • Fondazione del Piemonte per I'Oncologia IRCC
  • IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro
  • Istituto Clinico Humanitas
  • Amphia Ziekenhuis
  • Hospital Universitario Miguel Servet
  • Hospital Universitario Marques de Valdecilla
  • Corporacio Sanitaria Parc Tauli
  • Hospital Mutua de Terrassa
  • Centro Oncologico de Galicia
  • Centro Integral Oncologico Clara Campal
  • Addenbrooke's Hospital
  • Western General Hospital
  • Beatson West of Scotland Cancer Center
  • University College Hospital
  • Maidstone Hospital
  • Christie Hospital
  • Peterborough and Stamford Hospitals NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tivozanib + mFOLFOX6

Bevacizumab + mFOLFOX6

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
November 21, 2011
Last Updated
June 9, 2015
Sponsor
AVEO Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01478594
Brief Title
A Study Combining mFOLFOX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First Line Therapy
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
September 2013 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AVEO Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
metastatic colorectal cancer, Avastin, bevacizumab, tivozanib, mFOLFOX6, BATON-CRC, AV951, ASP4130

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
265 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tivozanib + mFOLFOX6
Arm Type
Experimental
Arm Description
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.
Arm Title
Bevacizumab + mFOLFOX6
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Tivozanib
Other Intervention Name(s)
AV951, ASP4130
Intervention Description
Capsules for oral administration
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
Solution for intravenous infusion
Intervention Type
Drug
Intervention Name(s)
mFOLFOX6
Intervention Description
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.
Primary Outcome Measure Information:
Title
Investigator-assessed Progression-Free Survival (PFS)
Description
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.
Secondary Outcome Measure Information:
Title
Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)
Description
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
Title
Overall Survival (OS)
Description
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.
Title
Objective Response Rate (ORR)
Description
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.
Title
Duration of Response (DoR)
Description
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.
Title
Time to Treatment Failure (TTF)
Description
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.
Title
Health Related Quality of Life (HRQoL)
Description
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
Title
Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)
Description
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.
Title
Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level
Description
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.
Title
Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level
Description
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.
Title
Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level
Description
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.
Title
Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio
Description
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.
Title
Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level
Description
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.
Title
Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level
Description
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.
Title
Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level
Description
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.
Title
Progression-Free Survival Events by Serum Neuropilin Level
Description
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.
Title
Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level
Description
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.
Title
Progression-Free Survival Events by Tumor VEGF-C RNA Level
Description
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.
Title
Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio
Description
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.
Title
Progression-Free Survival Events by Tumor VEGF-D RNA Level
Description
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.
Title
Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level
Description
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
AVEO Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Banner MD Anderson Cancer Research Center
City
Gilbert
State/Province
Arizona
ZIP/Postal Code
85234
Country
United States
Facility Name
Genesis Cancer Center
City
Hot Springs
State/Province
Arizona
ZIP/Postal Code
71913
Country
United States
Facility Name
Arizona Clinical Research Center
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85715
Country
United States
Facility Name
University of California San Diego-Morris Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
UC Irvine Medical Center, Division of Hematology/Oncology
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Desert Hematology Oncology Medical Group, Inc.
City
Rancho Mirage
State/Province
California
ZIP/Postal Code
92270
Country
United States
Facility Name
Mountain Blue Cancer Care Center
City
Golden
State/Province
Colorado
ZIP/Postal Code
80033
Country
United States
Facility Name
University of Florida, Davis Cancer Center (VA)
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Cleveland Clinic Florida
City
Weston
State/Province
Florida
ZIP/Postal Code
33331
Country
United States
Facility Name
Queen's Medical Center
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96813
Country
United States
Facility Name
University of Hawaii
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96813
Country
United States
Facility Name
Kaiser Foundation Hospitals
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96819
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Illinios Cancer Care
City
Peoria
State/Province
Illinois
ZIP/Postal Code
61615
Country
United States
Facility Name
Investigative Clinical Research of Indiana, LLC
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
Horizon Oncology Research, Inc.
City
Lafayette
State/Province
Indiana
ZIP/Postal Code
47905
Country
United States
Facility Name
Associates of Oncology Hematology, P.C.
City
Rockville
State/Province
Maryland
ZIP/Postal Code
20850
Country
United States
Facility Name
University of Michigan Health
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
NYU Cancer Institute
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Alamance Regional Medical Center
City
Burlington
State/Province
North Carolina
ZIP/Postal Code
27215
Country
United States
Facility Name
Tri Country Hematology / Oncology
City
Canton
State/Province
Ohio
ZIP/Postal Code
44718
Country
United States
Facility Name
Signal Point Clinical Research Center, LLC
City
Middletown
State/Province
Ohio
ZIP/Postal Code
45042
Country
United States
Facility Name
Cancer Care Associates
City
Tulsa
State/Province
Oklahoma
ZIP/Postal Code
74136
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Oncology Hematology of Lehigh Valley
City
Bethlehem
State/Province
Pennsylvania
ZIP/Postal Code
18015
Country
United States
Facility Name
Northern Utah Associates
City
Ogden
State/Province
Utah
ZIP/Postal Code
84403
Country
United States
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
St George Hospital
City
Kogarah
State/Province
New South Wales
ZIP/Postal Code
2217
Country
Australia
Facility Name
Tweed Hospital
City
Tweed Heads
State/Province
New South Wales
ZIP/Postal Code
2485
Country
Australia
Facility Name
Calvary Mater Newcastle
City
Waratah
State/Province
New South Wales
ZIP/Postal Code
2298
Country
Australia
Facility Name
Flinders Medical Centre
City
Bedford Park
State/Province
South Australia
ZIP/Postal Code
5042
Country
Australia
Facility Name
Royal Hobart Hospital
City
Hobart
State/Province
Tasmania
ZIP/Postal Code
7000
Country
Australia
Facility Name
Ballarat Health Services
City
Ballarat
State/Province
Victoria
ZIP/Postal Code
3350
Country
Australia
Facility Name
Cabrini Hospital Malvern
City
Malvern
State/Province
Victoria
ZIP/Postal Code
3144
Country
Australia
Facility Name
Border Medical Oncology
City
Wodonga
State/Province
Victoria
ZIP/Postal Code
3690
Country
Australia
Facility Name
Medizinische Universitat Graz
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
Salzburger Landesklinken
City
Salzburg
ZIP/Postal Code
5020
Country
Austria
Facility Name
Klinikum Wels-Grieskirchen GmbH
City
Wels
ZIP/Postal Code
4600
Country
Austria
Facility Name
Ziekenhuisnetwerk Antwerpen - AZ Middelheim
City
Antwerpen
ZIP/Postal Code
2020
Country
Belgium
Facility Name
Imelda VZW
City
Bonheiden
ZIP/Postal Code
2820
Country
Belgium
Facility Name
AZ Sint-Lucas Brugge
City
Brugge
ZIP/Postal Code
8310
Country
Belgium
Facility Name
AZ Groeninge - Campus Sint-Niklaas
City
Kortrijk
ZIP/Postal Code
8500
Country
Belgium
Facility Name
British Columbia Cancer Agency
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 4E6
Country
Canada
Facility Name
QEII Health Science Centre
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3H 2Y9
Country
Canada
Facility Name
Hopital De La Cite-De-La-Sante
City
Laval
State/Province
Quebec
ZIP/Postal Code
H7M 3L9
Country
Canada
Facility Name
Hopital Saint-Luc - Pavillon Principal
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2X 3J4
Country
Canada
Facility Name
Chuq Centre Hospitalier Universitaire De Quebec
City
Quebec
ZIP/Postal Code
G1R 2J6
Country
Canada
Facility Name
Masarykuv onkologicky ustav
City
Brno
ZIP/Postal Code
656 53
Country
Czech Republic
Facility Name
Fakultni nemocnice Hradec Kralove
City
Hradec Kralove
ZIP/Postal Code
500 05
Country
Czech Republic
Facility Name
Tampereen yliopistollinen sairaala
City
Tampere
ZIP/Postal Code
FI-33520
Country
Finland
Facility Name
Turun yliopistollinen keskussairaala
City
Turku
ZIP/Postal Code
FI-20520
Country
Finland
Facility Name
Orszagos Onkologiai Intezet
City
Budapest
ZIP/Postal Code
1122
Country
Hungary
Facility Name
Petz Aladar Megyei Oktato Korhaz
City
Gyor
ZIP/Postal Code
9024
Country
Hungary
Facility Name
Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza
City
Gyula
ZIP/Postal Code
5700
Country
Hungary
Facility Name
Fejer Megyei Szent Gyorgy Korhaz
City
Szekesfehervar
ZIP/Postal Code
8000
Country
Hungary
Facility Name
Azienda Ospedaliero- Universitaria di Bologna - Policlinico S.Orsola-Malpighi
City
Bologna
ZIP/Postal Code
40128
Country
Italy
Facility Name
Fondazione del Piemonte per I'Oncologia IRCC
City
Candiolo
ZIP/Postal Code
10060
Country
Italy
Facility Name
IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro
City
Genova
ZIP/Postal Code
16132
Country
Italy
Facility Name
Istituto Clinico Humanitas
City
Rozzano (MI)
ZIP/Postal Code
20089
Country
Italy
Facility Name
Amphia Ziekenhuis
City
Breda
ZIP/Postal Code
4819 EV
Country
Netherlands
Facility Name
Hospital Universitario Miguel Servet
City
Zaragoza
State/Province
Aragon
ZIP/Postal Code
50009
Country
Spain
Facility Name
Hospital Universitario Marques de Valdecilla
City
Santander
State/Province
Cantabria
ZIP/Postal Code
39008
Country
Spain
Facility Name
Corporacio Sanitaria Parc Tauli
City
Sabadell
State/Province
Cataluna
ZIP/Postal Code
08208
Country
Spain
Facility Name
Hospital Mutua de Terrassa
City
Terrassa
State/Province
Cataluna
ZIP/Postal Code
08221
Country
Spain
Facility Name
Centro Oncologico de Galicia
City
Galicia
ZIP/Postal Code
15009
Country
Spain
Facility Name
Centro Integral Oncologico Clara Campal
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Facility Name
Addenbrooke's Hospital
City
Cambridge
ZIP/Postal Code
CB2 2QQ
Country
United Kingdom
Facility Name
Western General Hospital
City
Edinburgh
ZIP/Postal Code
EH4 2XU
Country
United Kingdom
Facility Name
Beatson West of Scotland Cancer Center
City
Glasgow
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Facility Name
University College Hospital
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom
Facility Name
Maidstone Hospital
City
Maidstone
ZIP/Postal Code
ME16 9QQ
Country
United Kingdom
Facility Name
Christie Hospital
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom
Facility Name
Peterborough and Stamford Hospitals NHS Foundation Trust
City
Peterborough
ZIP/Postal Code
PE3 6DA
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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