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

• Sponsor: AVEO Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01478594
• Collaborator: (none)
• Enrollment: 265
• Locations: 73
• Arms: 2
• Duration (Months): 37
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Tivozanib; Drug: Bevacizumab; Drug: mFOLFOX6	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 265 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Dec 1, 2011
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tivozanib + mFOLFOX6 Participants received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received modified FOLFOX6 (mFOLFOX6) chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Drug: Tivozanib; Capsules for oral administration; Other Names: AV951 ASP4130 ; Drug: mFOLFOX6; 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.
Active Comparator: Bevacizumab + mFOLFOX6 Participants received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Drug: Bevacizumab; Solution for intravenous infusion; Other Names: Avastin ; Drug: mFOLFOX6; 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner MD Anderson Cancer Research Center	Gilbert	Arizona	United States	85234
2	Genesis Cancer Center	Hot Springs	Arizona	United States	71913
3	Arizona Clinical Research Center	Tucson	Arizona	United States	85715
4	University of California San Diego-Morris Cancer Center	La Jolla	California	United States	92093
5	UC Irvine Medical Center, Division of Hematology/Oncology	Orange	California	United States	92868
6	Desert Hematology Oncology Medical Group, Inc.	Rancho Mirage	California	United States	92270
7	Mountain Blue Cancer Care Center	Golden	Colorado	United States	80033
8	University of Florida, Davis Cancer Center (VA)	Gainesville	Florida	United States	32610
9	Cleveland Clinic Florida	Weston	Florida	United States	33331
10	Queen's Medical Center	Honolulu	Hawaii	United States	96813
11	University of Hawaii	Honolulu	Hawaii	United States	96813
12	Kaiser Foundation Hospitals	Honolulu	Hawaii	United States	96819
13	Northwestern University	Chicago	Illinois	United States	60611
14	Illinios Cancer Care	Peoria	Illinois	United States	61615
15	Investigative Clinical Research of Indiana, LLC	Indianapolis	Indiana	United States	46260
16	Horizon Oncology Research, Inc.	Lafayette	Indiana	United States	47905
17	Associates of Oncology Hematology, P.C.	Rockville	Maryland	United States	20850
18	University of Michigan Health	Ann Arbor	Michigan	United States	48109
19	NYU Cancer Institute	New York	New York	United States	10016
20	Alamance Regional Medical Center	Burlington	North Carolina	United States	27215
21	Tri Country Hematology / Oncology	Canton	Ohio	United States	44718
22	Signal Point Clinical Research Center, LLC	Middletown	Ohio	United States	45042
23	Cancer Care Associates	Tulsa	Oklahoma	United States	74136
24	Oregon Health and Science University	Portland	Oregon	United States	97239
25	Oncology Hematology of Lehigh Valley	Bethlehem	Pennsylvania	United States	18015
26	Northern Utah Associates	Ogden	Utah	United States	84403
27	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
28	St George Hospital	Kogarah	New South Wales	Australia	2217
29	Tweed Hospital	Tweed Heads	New South Wales	Australia	2485
30	Calvary Mater Newcastle	Waratah	New South Wales	Australia	2298
31	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
32	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
33	Ballarat Health Services	Ballarat	Victoria	Australia	3350
34	Cabrini Hospital Malvern	Malvern	Victoria	Australia	3144
35	Border Medical Oncology	Wodonga	Victoria	Australia	3690
36	Medizinische Universitat Graz	Graz		Austria	8036
37	Salzburger Landesklinken	Salzburg		Austria	5020
38	Klinikum Wels-Grieskirchen GmbH	Wels		Austria	4600
39	Ziekenhuisnetwerk Antwerpen - AZ Middelheim	Antwerpen		Belgium	2020
40	Imelda VZW	Bonheiden		Belgium	2820
41	AZ Sint-Lucas Brugge	Brugge		Belgium	8310
42	AZ Groeninge - Campus Sint-Niklaas	Kortrijk		Belgium	8500
43	British Columbia Cancer Agency	Vancouver	British Columbia	Canada	V5Z 4E6
44	QEII Health Science Centre	Halifax	Nova Scotia	Canada	B3H 2Y9
45	Hopital De La Cite-De-La-Sante	Laval	Quebec	Canada	H7M 3L9
46	Hopital Saint-Luc - Pavillon Principal	Montreal	Quebec	Canada	H2X 3J4
47	Chuq Centre Hospitalier Universitaire De Quebec	Quebec		Canada	G1R 2J6
48	Masarykuv onkologicky ustav	Brno		Czech Republic	656 53
49	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czech Republic	500 05
50	Tampereen yliopistollinen sairaala	Tampere		Finland	FI-33520
51	Turun yliopistollinen keskussairaala	Turku		Finland	FI-20520
52	Orszagos Onkologiai Intezet	Budapest		Hungary	1122
53	Petz Aladar Megyei Oktato Korhaz	Gyor		Hungary	9024
54	Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza	Gyula		Hungary	5700
55	Fejer Megyei Szent Gyorgy Korhaz	Szekesfehervar		Hungary	8000
56	Azienda Ospedaliero- Universitaria di Bologna - Policlinico S.Orsola-Malpighi	Bologna		Italy	40128
57	Fondazione del Piemonte per I'Oncologia IRCC	Candiolo		Italy	10060
58	IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro	Genova		Italy	16132
59	Istituto Clinico Humanitas	Rozzano (MI)		Italy	20089
60	Amphia Ziekenhuis	Breda		Netherlands	4819 EV
61	Hospital Universitario Miguel Servet	Zaragoza	Aragon	Spain	50009
62	Hospital Universitario Marques de Valdecilla	Santander	Cantabria	Spain	39008
63	Corporacio Sanitaria Parc Tauli	Sabadell	Cataluna	Spain	08208
64	Hospital Mutua de Terrassa	Terrassa	Cataluna	Spain	08221
65	Centro Oncologico de Galicia	Galicia		Spain	15009
66	Centro Integral Oncologico Clara Campal	Madrid		Spain	28050
67	Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 2QQ
68	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
69	Beatson West of Scotland Cancer Center	Glasgow		United Kingdom	G12 0YN
70	University College Hospital	London		United Kingdom	NW1 2BU
71	Maidstone Hospital	Maidstone		United Kingdom	ME16 9QQ
72	Christie Hospital	Manchester		United Kingdom	M20 4BX
73	Peterborough and Stamford Hospitals NHS Foundation Trust	Peterborough		United Kingdom	PE3 6DA

Sponsors and Collaborators

• AVEO Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, AVEO Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AVEO Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01478594
• Other Study ID Numbers: 4130-CL-0201; 2011-003502-24
• First Posted: Nov 23, 2011
• Last Update Posted: Jul 8, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by AVEO Pharmaceuticals, Inc.: metastatic colorectal cancer; Avastin; bevacizumab; tivozanib; mFOLFOX6; BATON-CRC; AV951; ASP4130
• Additional relevant MeSH terms: Colorectal Neoplasms; Bevacizumab

Study Results

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 Detail	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).

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each 28-day cycle for 21 days followed by 7 days off treatment. Participants also received modified FOLFOX6 (mFOLFOX6) chemotherapy consisting of oxaliplatin, 85 mg/m^2, leucovorin 400 mg/m^2, and 5-fluorouracil 400 mg/m^2 bolus then 2400 mg/m^2 every 2 weeks on Days 1 and 15 of each cycle.	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.
Period Title: Overall Study
STARTED	177	88
Treated	177	87
COMPLETED	112	60
NOT COMPLETED	65	28

Baseline Characteristics

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	177	88	265
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (9.58)	62.6 (11.17)	62.2 (10.12)
Sex: Female, Male (Count of Participants)
Female	59 33.3%	33 37.5%	92 34.7%
Male	118 66.7%	55 62.5%	173 65.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 3.4%	2 2.3%	8 3%
Not Hispanic or Latino	170 96%	86 97.7%	256 96.6%
Unknown or Not Reported	1 0.6%	0 0%	1 0.4%
Race/Ethnicity, Customized (participants) [Number]
White	169 95.5%	85 96.6%	254 95.8%
Black or African American	2 1.1%	0 0%	2 0.8%
Asian	3 1.7%	2 2.3%	5 1.9%
Native Hawaiian or other Pacific Islander	1 0.6%	1 1.1%	2 0.8%
Other	2 1.1%	0 0%	2 0.8%
Region of Enrollment (participants) [Number]
United States	44 24.9%	26 29.5%	70 26.4%
Hungary	24 13.6%	8 9.1%	32 12.1%
Czech Republic	12 6.8%	9 10.2%	21 7.9%
Canada	13 7.3%	4 4.5%	17 6.4%
Finland	5 2.8%	1 1.1%	6 2.3%
Spain	22 12.4%	8 9.1%	30 11.3%
Belgium	10 5.6%	9 10.2%	19 7.2%
Austria	8 4.5%	3 3.4%	11 4.2%
Australia	15 8.5%	9 10.2%	24 9.1%
Netherlands	1 0.6%	1 1.1%	2 0.8%
United Kingdom	19 10.7%	7 8%	26 9.8%
Italy	4 2.3%	3 3.4%	7 2.6%
Eastern Cooperative Oncology Group (ECOG) performance status (participants) [Number]
ECOG Performance Status 0	95 53.7%	58 65.9%	153 57.7%
ECOG Performance Status 1	82 46.3%	30 34.1%	112 42.3%
ECOG Performance Status 2	0 0%	0 0%	0 0%
ECOG Performance Status 3	0 0%	0 0%	0 0%
ECOG Performance Status 4	0 0%	0 0%	0 0%
Lactate dehydrogenase (LDH) Status (participants) [Number]
< 1.5 Upper Limit of Normal	127 71.8%	64 72.7%	191 72.1%
≥ 1.5 Upper Limit of Normal	50 28.2%	24 27.3%	74 27.9%
Origin of Cancer (participants) [Number]
Rectal	53 29.9%	24 27.3%	77 29.1%
Colon	124 70.1%	64 72.7%	188 70.9%
Number of metastatic sites/organs (participants) [Number]
1	56 31.6%	30 34.1%	86 32.5%
2	80 45.2%	34 38.6%	114 43%
3	29 16.4%	21 23.9%	50 18.9%
≥ 4	12 6.8%	3 3.4%	15 5.7%
Kirsten rat sarcoma (KRAS) Mutation Status (participants) [Number]
Wild-type	33 18.6%	21 23.9%	54 20.4%
Mutant	23 13%	16 18.2%	39 14.7%
Unknown	121 68.4%	51 58%	172 64.9%
Time Since Initial Diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	9.41 (20.473)	10.88 (21.055)	9.90 (20.640)
Number of metastatic sites at screening (metastatic sites) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [metastatic sites]	2.0 (1.02)	2.0 (0.85)	2.0 (0.97)

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants.

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	177	88
Median (95% Confidence Interval) [months]	9.4	10.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
	Comments	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%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.706
	Comments
	Method	Log Rank
	Comments	Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.091
	Confidence Interval	(2-Sided) 95%; 0.693 to 1.718
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Analysis was not performed due to study closure.

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	0	0

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	177	88
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.754
	Comments
	Method	Log Rank
	Comments	Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.116
	Confidence Interval	(2-Sided) 95%; 0.561 to 2.218
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	Participants received 1.5 m 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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	177	88
Number [percentage of participants]	45.2 25.5%	43.2 49.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.718
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).

5. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Participants with a best overall response of complete response (CR) or partial response (PR).

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	80	38
Median (95% Confidence Interval) [months]	7.4	9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.437
	Comments
	Method	Log Rank
	Comments	Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.389
	Confidence Interval	(2-Sided) 95%; 0.604 to 3.194
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.

6. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	177	88
Median (95% Confidence Interval) [months]	5.5	5.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab + mFOLFOX6
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.967
	Comments
	Method	Log Rank
	Comments	Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.006
	Confidence Interval	(2-Sided) 95%; 0.746 to 1.358
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR presented for the stratified analysis, which was based on the Cox proportional hazards model. Assuming proportional hazards, an HR < 1 indicates a reduction in the HR in favor of tivozanib.

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Analysis was not performed due to study closure.

Arm/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	0	0

8. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Tivozanib + mFOLFOX6	Bevacizumab + mFOLFOX6
Arm/Group Description	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.	Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	177	87
Any adverse event	177 100%	87 98.9%
CTCAE Grade 3 or higher	156 88.1%	76 86.4%
Any tivozanib/bevacizumab-related adverse event	158 89.3%	74 84.1%
Any mFOLFOX6-related adverse event	169 95.5%	84 95.5%
Any tivozanib/bevacizumab and mFOLFOX6-related AE	138 78%	59 67%
Any tivozanib/bevacizumab-related AE ≥ Grade 3	104 58.8%	31 35.2%
Any mFOLFOX6-related AE ≥ Grade 3	126 71.2%	61 69.3%
Any tiv/bev and mFOLFOX6-related AE ≥ Grade 3	75 42.4%	23 26.1%
Any AE with an outcome of death	8 4.5%	2 2.3%
Any tivozanib/bevacizumab-related AE of death	3 1.7%	2 2.3%
Any mFOLFOX6-related AE outcome of death	3 1.7%	2 2.3%
Any tiv/bev & mFOLFOX6-related AE outcome of death	3 1.7%	2 2.3%
Any serious adverse event (SAE)	82 46.3%	42 47.7%
Any tivozanib/bevacizumab-related SAE	38 21.5%	15 17%
Any mFOLFOX6-related SAE	45 25.4%	23 26.1%
Any tivozanib/bevacizumab and mFOLFOX6-related SAE	30 16.9%	11 12.5%
AE leading to tiv/bev discontinuation	73 41.2%	30 34.1%
AE leading to tivozanib/bevacizumab interruption	138 78%	63 71.6%

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Tivozanib: LDH < 1.5 ULN	Tivozanib: LDH ≥ 1.5 ULN	Bevacizumab: LDH < 1.5 ULN	Bevacizumab : LDH ≥ 1.5 ULN
Arm/Group Description	Participants with LDH status < 1.5 ULN 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.	Participants with LDH status ≥ 1.5 ULN 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.	Participants with LDH status < 1.5 ULN received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with LDH status ≥ 1.5 ULN received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	127	50	64	24
Number [participants]	42 23.7%	24 27.3%	16 6%	13 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.331
	Confidence Interval	(2-Sided) 95%; 0.746 to 2.375
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.575
	Confidence Interval	(2-Sided) 95%; 0.285 to 1.160
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

10. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: VEGF-A < Median	Tivozanib: VEGF-A ≥ Median	Bevacizumab: VEGF-A < Median	Bevacizumab: VEGF-A ≥ Median
Arm/Group Description	Participants with VEGF-A levels < median 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 mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-A levels ≥ median 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 mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-A levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-A levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	54	54	29	26
Number [participants]	20 11.3%	24 27.3%	6 2.3%	12 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.608
	Confidence Interval	(2-Sided) 95%; 0.635 to 4.073
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.755
	Confidence Interval	(2-Sided) 95%; 0.375 to 1.521
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

11. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: VEGF-C < Median	Tivozanib: VEGF-C ≥ Median	Bevacizumab: VEGF-C < Median	Bevacizumab: VEGF-C ≥ Median
Arm/Group Description	Participants with VEGF-C levels < median 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.	Participants with VEGF-C levels ≥ median 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.	Participants with VEGF-C levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-C levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	52	56	27	28
Number [participants]	15 8.5%	29 33%	8 3%	10 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.877
	Confidence Interval	(2-Sided) 95%; 0.366 to 2.100
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.275
	Confidence Interval	(2-Sided) 95%; 0.614 to 2.646
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

12. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: VEGF-C/VEGF-A < Median	Tivozanib: VEGF-C/VEGF-A ≥ Median	Bevacizumab: VEGF-C/VEGF-A < Median	Bevacizumab: VEGF-C/VEGF-A ≥ Median
Arm/Group Description	Participants with VEGF-C/VEGF-A ratio < median 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 mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-C/VEGF-A ratio ≥ median 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 mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-C/VEGF-A ratio < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-C/VEGF-A ratio ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	53	55	26	29
Number [participants]	21 11.9%	23 26.1%	11 4.2%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.721
	Confidence Interval	(2-Sided) 95%; 0.345 to 1.507
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.597
	Confidence Interval	(2-Sided) 95%; 0.672 to 3.795
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

13. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: sVEGFR-2 < Median	Tivozanib: sVEGFR-2 ≥ Median	Bevacizumab: sVEGFR-2 < Median	Bevacizumab: sVEGFR-2 ≥ Median
Arm/Group Description	Participants with sVEGFR-2 levels < median 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.	Participants with sVEGFR-2 levels ≥ median 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.	Participants with sVEGFR-2 levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with sVEGFR-2 levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	46	62	27	28
Number [participants]	15 8.5%	29 33%	5 1.9%	13 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.627
	Confidence Interval	(2-Sided) 95%; 0.580 to 4.564
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.779
	Confidence Interval	(2-Sided) 95%; 0.397 to 1.531
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

14. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: sVEGFR-3 < Median	Tivozanib: sVEGFR-3 ≥ Median	Bevacizumab: sVEGFR-3 < Median	Bevacizumab: sVEGFR-3 ≥ Median
Arm/Group Description	Participants with sVEGFR-3 levels < median 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.	Participants with sVEGFR-3 levels ≥ median 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.	Participants with sVEGFR-3 levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with sVEGFR-3 levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	50	58	30	25
Number [participants]	14 7.9%	30 34.1%	4 1.5%	14 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.946
	Confidence Interval	(2-Sided) 95%; 0.636 to 5.956
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.806
	Confidence Interval	(2-Sided) 95%; 0.422 to 1.538
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

15. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: IL-8 < Median	Tivozanib: IL-8 ≥ Median	Bevacizumab: IL-8 < Median	Bevacizumab: IL-8 ≥ Median
Arm/Group Description	Participants with IL-8 levels < median 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.	Participants with IL-8 levels ≥ median received 1.5 m 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.	Participants with IL-8 levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with IL-8 levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	53	55	27	28
Number [participants]	14 7.9%	30 34.1%	7 2.6%	11 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.776
	Confidence Interval	(2-Sided) 95%; 0.303 to 1.991
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.241
	Confidence Interval	(2-Sided) 95%; 0.615 to 2.501
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

16. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available serum protein samples

Arm/Group Title	Tivozanib: Neuropilin < Median	Tivozanib: Neuropilin ≥ Median	Bevacizumab: Neuropilin < Median	Bevacizumab: Neuropilin ≥ Median
Arm/Group Description	Participants with neuropilin levels < median 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.	Participants with neuropilin levels ≥ median 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.	Participants with neuropilin levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and FOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with neuropilin levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	53	55	30	25
Number [participants]	10 5.6%	34 38.6%	6 2.3%	12 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.950
	Confidence Interval	(2-Sided) 95%; 0.343 to 2.630
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.983
	Confidence Interval	(2-Sided) 95%; 0.503 to 1.918
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

17. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available tumor biopsy RNA samples

Arm/Group Title	Tivozanib: VEGF-A RNA < Median	Tivozanib: VEGF-A RNA ≥ Median	Bevacizumab: VEGF-A RNA < Median	Bevacizumab: VEGF-A RNA ≥ Median
Arm/Group Description	Participants with VEGF-A RNA levels < median 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.	Participants with VEGF-A RNA levels ≥ median 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.	Participants with VEGF-A RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-A RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	40	38	18	17
Number [participants]	13 7.3%	18 20.5%	7 2.6%	5 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.226
	Confidence Interval	(2-Sided) 95%; 0.468 to 3.214
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.232
	Confidence Interval	(2-Sided) 95%; 0.447 to 3.396
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

18. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available tumor biopsy RNA samples

Arm/Group Title	Tivozanib: VEGF-C RNA < Median	Tivozanib: VEGF-C RNA ≥ Median	Bevacizumab: VEGF-C RNA < Median	Bevacizumab: VEGF-A RNA ≥ Median
Arm/Group Description	Participants with VEGF-C RNA levels < median 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.	Participants with VEGF-C RNA levels ≥ median 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.	Participants with VEGF-C RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-C RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	41	37	16	19
Number [participants]	14 7.9%	17 19.3%	6 2.3%	6 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.803
	Confidence Interval	(2-Sided) 95%; 0.307 to 2.100
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.505
	Confidence Interval	(2-Sided) 95%; 0.585 to 3.873
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

19. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available tumor biopsy RNA samples

Arm/Group Title	Tivozanib: VEGF-C/VEGF-A RNA < Median	Tivozanib: VEGF-C/VEGF-A RNA ≥ Median	Bevacizumab: VEGF-C/VEGF-A RNA < Median	Bevacizumab: VEGF-C/VEGF-A RNA ≥ Median
Arm/Group Description	Participants with VEGF-C/VEGF-A RNA ratio < median 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.	Participants with VEGF-C/VEGF-A RNA ratio ≥ median 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.	Participants with VEGF-C/VEGF-A RNA ratio < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-C/VEGF-A RNA ratio ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	38	40	16	19
Number [participants]	16 9%	15 17%	6 2.3%	6 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.921
	Confidence Interval	(2-Sided) 95%; 0.356 to 2.385
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.220
	Confidence Interval	(2-Sided) 95%; 0.462 to 3.220
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

20. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available tumor biopsy RNA samples

Arm/Group Title	Tivozanib: VEGF-D RNA < Median	Tivozanib: VEGF-D RNA ≥ Median	Bevacizumab: VEGF-D RNA < Median	Bevacizumab: VEGF-D RNA ≥ Median
Arm/Group Description	Participants with VEGF-D RNA levels < median 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.	Participants with VEGF-D RNA levels ≥ median 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.	Participants with VEGF-D RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with VEGF-D RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	42	36	14	21
Number [participants]	16 9%	15 17%	5 1.9%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.915
	Confidence Interval	(2-Sided) 95%; 0.334 to 2.512
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.384
	Confidence Interval	(2-Sided) 95%; 0.554 to 3.455
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

21. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Full analysis set with available tumor biopsy RNA samples

Arm/Group Title	Tivozanib: PIGF RNA < Median	Tivozanib: PIGF RNA ≥ Median	Bevacizumab: PIGF RNA < Median	Bevacizumab: PIGF RNA ≥ Median
Arm/Group Description	Participants with PIGF RNA levels < median 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.	Participants with PIGF RNA levels ≥ median 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.	Participants with PIGF RNA levels < median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.	Participants with PIGF RNA levels ≥ median received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
Measure Participants	39	39	17	18
Number [participants]	14 7.9%	17 19.3%	5 1.9%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib + mFOLFOX6, Bevacizumab: LDH < 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.538
	Confidence Interval	(2-Sided) 95%; 0.548 to 4.320
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + mFOLFOX6, Bevacizumab : LDH ≥ 1.5 ULN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.744
	Confidence Interval	(2-Sided) 95%; 0.299 to 1.850
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was calculated using an unadjusted Cox proportional hazard model including treatment arms as the covariate. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of Tivozanib arm.

Adverse Events

Time Frame	From the 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 arm and 162.0 days in the bevacizumab arm.
Arm/Group Title	Tivozanib + mFOLFOX6		Bevacizumab + mFOLFOX6
Arm/Group 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 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.
All Cause Mortality
	Tivozanib + mFOLFOX6		Bevacizumab + mFOLFOX6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tivozanib + mFOLFOX6		Bevacizumab + mFOLFOX6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	82/177 (46.3%)		42/87 (48.3%)
Blood and lymphatic system disorders
Febrile neutropenia	5/177 (2.8%)		2/87 (2.3%)
Neutropenia	3/177 (1.7%)		1/87 (1.1%)
Anaemia	2/177 (1.1%)		1/87 (1.1%)
Agranulocytosis	1/177 (0.6%)		0/87 (0%)
Thrombocytopenia	1/177 (0.6%)		0/87 (0%)
Thrombotic thrombocytopenic purpura	0/177 (0%)		1/87 (1.1%)
Cardiac disorders
Cardiac failure	2/177 (1.1%)		0/87 (0%)
Aortic valve disease	1/177 (0.6%)		0/87 (0%)
Atrial fibrillation	1/177 (0.6%)		2/87 (2.3%)
Cardiomyopathy	1/177 (0.6%)		0/87 (0%)
Cardiopulmonary failure	1/177 (0.6%)		0/87 (0%)
Intracardiac thrombus	1/177 (0.6%)		0/87 (0%)
Sinus bradycardia	1/177 (0.6%)		0/87 (0%)
Sinus tachycardia	1/177 (0.6%)		0/87 (0%)
Tachycardia	1/177 (0.6%)		1/87 (1.1%)
Endocrine disorders
Hyperthyroidism	1/177 (0.6%)		0/87 (0%)
Gastrointestinal disorders
Diarrhoea	7/177 (4%)		5/87 (5.7%)
Abdominal pain	5/177 (2.8%)		4/87 (4.6%)
Vomiting	5/177 (2.8%)		0/87 (0%)
Intestinal obstruction	4/177 (2.3%)		2/87 (2.3%)
Nausea	3/177 (1.7%)		0/87 (0%)
Ascites	2/177 (1.1%)		0/87 (0%)
Stomatitis	2/177 (1.1%)		0/87 (0%)
Abdominal distension	1/177 (0.6%)		1/87 (1.1%)
Abdominal pain upper	1/177 (0.6%)		0/87 (0%)
Anal ulcer	1/177 (0.6%)		0/87 (0%)
Colitis	1/177 (0.6%)		0/87 (0%)
Colonic obstruction	1/177 (0.6%)		1/87 (1.1%)
Constipation	1/177 (0.6%)		1/87 (1.1%)
Gastrointestinal haemorrhage	1/177 (0.6%)		0/87 (0%)
Haemorrhoidal haemorrhage	1/177 (0.6%)		0/87 (0%)
Ileus	1/177 (0.6%)		1/87 (1.1%)
Large intestinal obstruction	1/177 (0.6%)		0/87 (0%)
Small intestinal obstruction	1/177 (0.6%)		1/87 (1.1%)
Enteritis	0/177 (0%)		1/87 (1.1%)
Intestinal perforation	0/177 (0%)		1/87 (1.1%)
Large intestine perforation	0/177 (0%)		1/87 (1.1%)
Peritonitis	0/177 (0%)		1/87 (1.1%)
Pneumatosis intestinalis	0/177 (0%)		1/87 (1.1%)
General disorders
Pyrexia	4/177 (2.3%)		7/87 (8%)
Disease progression	3/177 (1.7%)		0/87 (0%)
Asthenia	2/177 (1.1%)		0/87 (0%)
Fatigue	2/177 (1.1%)		1/87 (1.1%)
Catheter site erythema	1/177 (0.6%)		0/87 (0%)
Device malfunction	1/177 (0.6%)		0/87 (0%)
General physical health deterioration	1/177 (0.6%)		1/87 (1.1%)
Localised oedema	1/177 (0.6%)		0/87 (0%)
Oedema	1/177 (0.6%)		0/87 (0%)
Stent malfunction	1/177 (0.6%)		0/87 (0%)
Chest pain	0/177 (0%)		1/87 (1.1%)
Malaise	0/177 (0%)		1/87 (1.1%)
Mucosal inflammation	0/177 (0%)		1/87 (1.1%)
Hepatobiliary disorders
Bile duct stenosis	1/177 (0.6%)		0/87 (0%)
Cholecystitis	1/177 (0.6%)		0/87 (0%)
Jaundice cholestatic	1/177 (0.6%)		0/87 (0%)
Hepatic haemorrhage	0/177 (0%)		1/87 (1.1%)
Immune system disorders
Drug hypersensitivity	1/177 (0.6%)		1/87 (1.1%)
Hypersensitivity	1/177 (0.6%)		0/87 (0%)
Infections and infestations
Sepsis	4/177 (2.3%)		4/87 (4.6%)
Lower respiratory tract infection	3/177 (1.7%)		1/87 (1.1%)
Device related infection	2/177 (1.1%)		3/87 (3.4%)
Arthritis bacterial	1/177 (0.6%)		0/87 (0%)
Bacteraemia	1/177 (0.6%)		0/87 (0%)
Gastroenteritis viral	1/177 (0.6%)		0/87 (0%)
Infection	1/177 (0.6%)		2/87 (2.3%)
Influenza	1/177 (0.6%)		1/87 (1.1%)
Neutropenic sepsis	1/177 (0.6%)		0/87 (0%)
Parotitis	1/177 (0.6%)		0/87 (0%)
Perihepatic abscess	1/177 (0.6%)		0/87 (0%)
Peritonitis bacterial	1/177 (0.6%)		0/87 (0%)
Pneumonia	1/177 (0.6%)		1/87 (1.1%)
Skin infection	1/177 (0.6%)		0/87 (0%)
Staphylococcal infection	1/177 (0.6%)		0/87 (0%)
Subcutaneous abscess	1/177 (0.6%)		0/87 (0%)
Upper respiratory tract infection	1/177 (0.6%)		0/87 (0%)
Urosepsis	1/177 (0.6%)		0/87 (0%)
Wound infection	1/177 (0.6%)		0/87 (0%)
Cellulitis	0/177 (0%)		1/87 (1.1%)
Diverticulitis	0/177 (0%)		1/87 (1.1%)
Enterocolitis viral	0/177 (0%)		1/87 (1.1%)
Tooth abscess	0/177 (0%)		1/87 (1.1%)
Urinary tract infection	0/177 (0%)		1/87 (1.1%)
Injury, poisoning and procedural complications
Overdose	1/177 (0.6%)		0/87 (0%)
Wound necrosis	1/177 (0.6%)		0/87 (0%)
Alcohol poisoning	0/177 (0%)		1/87 (1.1%)
Laceration	0/177 (0%)		1/87 (1.1%)
Investigations
Alanine aminotransferase increased	1/177 (0.6%)		0/87 (0%)
Blood lactate dehydrogenase increased	1/177 (0.6%)		0/87 (0%)
C-reactive protein increased	1/177 (0.6%)		0/87 (0%)
Heart rate increased	1/177 (0.6%)		0/87 (0%)
International normalised ratio increased	1/177 (0.6%)		0/87 (0%)
Platelet count decreased	1/177 (0.6%)		0/87 (0%)
Troponin increased	1/177 (0.6%)		0/87 (0%)
White blood cell count decreased	1/177 (0.6%)		0/87 (0%)
Metabolism and nutrition disorders
Cachexia	1/177 (0.6%)		0/87 (0%)
Decreased appetite	1/177 (0.6%)		1/87 (1.1%)
Dehydration	1/177 (0.6%)		1/87 (1.1%)
Musculoskeletal and connective tissue disorders
Back pain	1/177 (0.6%)		0/87 (0%)
Intervertebral disc degeneration	1/177 (0.6%)		0/87 (0%)
Mobility decreased	1/177 (0.6%)		0/87 (0%)
Flank pain	0/177 (0%)		1/87 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Angiomyolipoma	1/177 (0.6%)		0/87 (0%)
Cancer pain	1/177 (0.6%)		0/87 (0%)
Duodenal neoplasm	1/177 (0.6%)		0/87 (0%)
Nervous system disorders
Reversible posterior leukoencephalopathy syndrome	2/177 (1.1%)		0/87 (0%)
Transient ischaemic attack	2/177 (1.1%)		0/87 (0%)
Aphasia	1/177 (0.6%)		0/87 (0%)
Cerebral haemorrhage	1/177 (0.6%)		0/87 (0%)
Headache	1/177 (0.6%)		1/87 (1.1%)
Monoparesis	1/177 (0.6%)		0/87 (0%)
Neuropathy peripheral	1/177 (0.6%)		0/87 (0%)
Syncope	1/177 (0.6%)		1/87 (1.1%)
Amnesia	0/177 (0%)		1/87 (1.1%)
Psychiatric disorders
Confusional state	1/177 (0.6%)		1/87 (1.1%)
Delirium	1/177 (0.6%)		1/87 (1.1%)
Depression	1/177 (0.6%)		0/87 (0%)
Renal and urinary disorders
Hydronephrosis	1/177 (0.6%)		0/87 (0%)
Renal failure	1/177 (0.6%)		1/87 (1.1%)
Renal failure acute	0/177 (0%)		2/87 (2.3%)
Reproductive system and breast disorders
Vaginal fistula	1/177 (0.6%)		0/87 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	7/177 (4%)		0/87 (0%)
Dyspnoea	3/177 (1.7%)		0/87 (0%)
Epistaxis	1/177 (0.6%)		0/87 (0%)
Hypoxia	1/177 (0.6%)		0/87 (0%)
Pneumonia aspiration	1/177 (0.6%)		0/87 (0%)
Pulmonary haemorrhage	1/177 (0.6%)		0/87 (0%)
Respiratory failure	1/177 (0.6%)		0/87 (0%)
Pneumonitis	0/177 (0%)		1/87 (1.1%)
Surgical and medical procedures
Anorectal operation	1/177 (0.6%)		0/87 (0%)
Chemotherapy	1/177 (0.6%)		0/87 (0%)
Vascular disorders
Hypertension	4/177 (2.3%)		0/87 (0%)
Deep vein thrombosis	3/177 (1.7%)		1/87 (1.1%)
Thrombosis	2/177 (1.1%)		0/87 (0%)
Hypertensive emergency	1/177 (0.6%)		0/87 (0%)
Subclavian vein thrombosis	1/177 (0.6%)		0/87 (0%)
Venous thrombosis	1/177 (0.6%)		0/87 (0%)
Embolism	0/177 (0%)		1/87 (1.1%)
Hypertensive crisis	0/177 (0%)		1/87 (1.1%)
Jugular vein thrombosis	0/177 (0%)		2/87 (2.3%)
Other (Not Including Serious) Adverse Events
	Tivozanib + mFOLFOX6		Bevacizumab + mFOLFOX6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	175/177 (98.9%)		85/87 (97.7%)
Blood and lymphatic system disorders
Neutropenia	93/177 (52.5%)		36/87 (41.4%)
Thrombocytopenia	54/177 (30.5%)		13/87 (14.9%)
Anaemia	20/177 (11.3%)		9/87 (10.3%)
Leukopenia	19/177 (10.7%)		9/87 (10.3%)
Endocrine disorders
Hypothyroidism	25/177 (14.1%)		1/87 (1.1%)
Eye disorders
Conjunctivitis	3/177 (1.7%)		5/87 (5.7%)
Gastrointestinal disorders
Diarrhoea	101/177 (57.1%)		49/87 (56.3%)
Nausea	97/177 (54.8%)		47/87 (54%)
Vomiting	59/177 (33.3%)		24/87 (27.6%)
Constipation	50/177 (28.2%)		32/87 (36.8%)
Abdominal pain	42/177 (23.7%)		16/87 (18.4%)
Stomatitis	36/177 (20.3%)		14/87 (16.1%)
Dyspepsia	23/177 (13%)		9/87 (10.3%)
Abdominal pain upper	13/177 (7.3%)		8/87 (9.2%)
Aphthous stomatitis	9/177 (5.1%)		1/87 (1.1%)
Dry mouth	9/177 (5.1%)		2/87 (2.3%)
Dysphagia	9/177 (5.1%)		3/87 (3.4%)
Rectal haemorrhage	7/177 (4%)		5/87 (5.7%)
Flatulence	6/177 (3.4%)		5/87 (5.7%)
General disorders
Fatigue	95/177 (53.7%)		45/87 (51.7%)
Mucosal inflammation	40/177 (22.6%)		28/87 (32.2%)
Asthenia	37/177 (20.9%)		17/87 (19.5%)
Pyrexia	17/177 (9.6%)		13/87 (14.9%)
Oedema peripheral	14/177 (7.9%)		6/87 (6.9%)
Temperature intolerance	11/177 (6.2%)		9/87 (10.3%)
Infusion related reaction	9/177 (5.1%)		3/87 (3.4%)
Pain	5/177 (2.8%)		5/87 (5.7%)
Chest pain	2/177 (1.1%)		5/87 (5.7%)
Immune system disorders
Hypersensitivity	3/177 (1.7%)		6/87 (6.9%)
Infections and infestations
Urinary tract infection	19/177 (10.7%)		11/87 (12.6%)
Nasopharyngitis	8/177 (4.5%)		6/87 (6.9%)
Upper respiratory tract infection	6/177 (3.4%)		5/87 (5.7%)
Investigations
Weight decreased	34/177 (19.2%)		7/87 (8%)
Neutrophil count decreased	14/177 (7.9%)		8/87 (9.2%)
Alanine aminotransferase increased	10/177 (5.6%)		3/87 (3.4%)
Aspartate aminotransferase increased	10/177 (5.6%)		4/87 (4.6%)
Platelet count decreased	10/177 (5.6%)		3/87 (3.4%)
Blood thyroid stimulating hormone increased	9/177 (5.1%)		0/87 (0%)
Metabolism and nutrition disorders
Decreased appetite	63/177 (35.6%)		24/87 (27.6%)
Hypokalaemia	20/177 (11.3%)		13/87 (14.9%)
Hypomagnesaemia	12/177 (6.8%)		2/87 (2.3%)
Dehydration	10/177 (5.6%)		7/87 (8%)
Hyperglycaemia	8/177 (4.5%)		5/87 (5.7%)
Musculoskeletal and connective tissue disorders
Back pain	26/177 (14.7%)		12/87 (13.8%)
Pain in extremity	11/177 (6.2%)		6/87 (6.9%)
Arthralgia	10/177 (5.6%)		5/87 (5.7%)
Myalgia	5/177 (2.8%)		5/87 (5.7%)
Muscle spasms	3/177 (1.7%)		5/87 (5.7%)
Neck pain	2/177 (1.1%)		6/87 (6.9%)
Nervous system disorders
Neuropathy peripheral	74/177 (41.8%)		34/87 (39.1%)
Paraesthesia	46/177 (26%)		20/87 (23%)
Headache	28/177 (15.8%)		12/87 (13.8%)
Dysgeusia	26/177 (14.7%)		18/87 (20.7%)
Peripheral sensory neuropathy	21/177 (11.9%)		13/87 (14.9%)
Dizziness	17/177 (9.6%)		6/87 (6.9%)
Dysaesthesia	12/177 (6.8%)		5/87 (5.7%)
Lethargy	11/177 (6.2%)		3/87 (3.4%)
Neurotoxicity	10/177 (5.6%)		3/87 (3.4%)
Hypoaesthesia	5/177 (2.8%)		5/87 (5.7%)
Amnesia	1/177 (0.6%)		5/87 (5.7%)
Psychiatric disorders
Insomnia	23/177 (13%)		15/87 (17.2%)
Anxiety	8/177 (4.5%)		6/87 (6.9%)
Renal and urinary disorders
Proteinuria	19/177 (10.7%)		5/87 (5.7%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	42/177 (23.7%)		13/87 (14.9%)
Epistaxis	33/177 (18.6%)		25/87 (28.7%)
Dyspnoea	26/177 (14.7%)		13/87 (14.9%)
Cough	20/177 (11.3%)		12/87 (13.8%)
Oropharyngeal pain	16/177 (9%)		6/87 (6.9%)
Hiccups	10/177 (5.6%)		2/87 (2.3%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	34/177 (19.2%)		7/87 (8%)
Alopecia	18/177 (10.2%)		14/87 (16.1%)
Rash	16/177 (9%)		4/87 (4.6%)
Pruritus	7/177 (4%)		7/87 (8%)
Hyperhidrosis	1/177 (0.6%)		5/87 (5.7%)
Vascular disorders
Hypertension	77/177 (43.5%)		25/87 (28.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data or after 18 months after database lock, whichever comes first. Sponsor must receive a site's manuscript at least 30 days prior to publication for review and comment. Sponsor may delay the publication for up to 60 days to seek patent protection.