Clinical trial NCT01478594: A Study Combining mFOLFOX6 With Tivozanib or Bevacizumab in Patients With Metastatic Colorectal Cancer as First Line Therapy
Official title: A Phase 2, Open Label, Multicenter, Randomized Trial Comparing Tivozanib in Combination With mFOLFOX6 to Bevacizumab in Combination With mFOLFOX6, In Stage IV Metastatic Colorectal Cancer (mCRC) Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: metastatic colorectal cancer
Avastin
bevacizumab
tivozanib
mFOLFOX6
BATON-CRC
AV951
ASP4130
Lead sponsor: AVEO Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2011-11-23
Enrollment: 265
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to compare the progression free survival (PFS), overall survival (OS), objective response rate (ORR), time to treatment failure (TTF), duration of response (DoR), quality of life, safety and tolerability of tivozanib in combination with mFOLFOX6 and bevacizumab in combination with mFOLFOX6.

Detailed description: Imaging scans (computed tomography \[CT\]/magnetic resonance imaging \[MRI\]) to assess disease progression were to be completed within 28 days prior to first study drug administration, approximately every 8 weeks for the first 18 months and then approximately every 12 weeks until the patient showed progressive disease (PD) per the investigator, withdrew consent, was lost to follow-up or died. Per the original protocol, all patients were to be contacted by the study site every 12 weeks for survival following the end-of-treatment visit until death or for no more than 3 years after the end-of-treatment visit.

The interim futility analysis was conducted in December 2013, based on a pre-specified analysis cutoff date of 13 September 2013. The study was brought to a close as specified in the protocol due to the results of the interim futility analysis and only those participants who were deriving benefit (per the treating physician) from their current treatment remained on study until one of the discontinuation criteria was met.

Given the early closure of the study, no updated or additional efficacy analyses were performed after the interim analysis. A biomarker analysis was conducted in January 2014, based on the data from the cutoff date of 13 September 2013. The safety analysis was updated with a new cutoff date of 28 February 2014.

Eligibility criteria: Inclusion Criteria:

* Documented diagnosis of metastatic colorectal cancer
* One measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* No prior systemic chemotherapy for advanced colorectal cancer; no fluorouracil containing adjuvant therapy in previous 6 months
* Eastern Cooperative Oncology Group (ECOG) status of 0 or 1

Exclusion Criteria:

* Any prior Vascular Endothelial Growth Factor (VEGF)-directed therapy or any other agent or investigational agent targeting the VEGF pathway
* Primary Central Nervous System (CNS) malignancies or CNS metastases
* Hematologic abnormalities:

  * Hemoglobin \< 9.0 g/dL,
  * Absolute neutrophil count (ANC) \< 2000 per mm\^3,
  * Platelet count \< 100,000 per mm\^3,
  * Prothrombin (PT) or Partial Thromboplastin Time (PTT) \> 1.5 X Upper Limit of Normal (ULN)
* Serum chemistry abnormalities:

  * Total bilirubin \> 1.5 X ULN,
  * Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) \> 2.5 X ULN,
  * Alkaline phosphatase \> 2.5 X ULN,
  * Serum albumin \< 2.0 g/dL,
  * Creatinine \> 1.5 X ULN,
  * Proteinuria \> 2+ by urine dipstick
* Significant cardiovascular disease
* Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug
* Non-healing wound, bone fracture, or skin ulcer
* Inadequate recovery from any prior surgical procedure or major surgical procedure within 8 weeks prior to administration, or anticipation of major surgical procedure during the course of the study
* History of significant gastrointestinal (GI) toxicity, diarrhea, or stomatitis within the last 6 weeks
* An active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug
* Serious/active infection or infection requiring antibiotics
* Significant bleeding disorders within 6 months prior to administration of first dose of study drug
* Active second primary malignancy, other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. Subject is not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for \> 5 years
* History of allergic reactions, or intolerance, attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, history of Grade 3 hypersensitivity to oxaliplatin, history of allergic reaction to folic acid
* Female subject is pregnant or lactating
* Known history of genetic or acquired immune suppression disease including Human Immunodeficiency Virus (HIV); subjects on immune suppressive therapy for organ transplant
* Inability to swallow pills, malabsorption syndrome or gastrointestinal disease, major resection of the stomach or small bowel, or gastric bypass
* Uncontrolled neuro-psychiatric disorder or altered mental status
* Peripheral neuropathy ≥ Grade 2
* Participating in another interventional protocol

Primary outcomes:
measure: Investigator-assessed Progression-Free Survival (PFS)
timeFrame: From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.
Secondary outcomes:
measure: Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)
timeFrame: 3 years
measure: Overall Survival (OS)
timeFrame: 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.
measure: Objective Response Rate (ORR)
timeFrame: 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.
measure: Duration of Response (DoR)
timeFrame: 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.
measure: Time to Treatment Failure (TTF)
timeFrame: 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.
measure: Health Related Quality of Life (HRQoL)
timeFrame: 3 years
measure: Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)
timeFrame: 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.
measure: Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level
timeFrame: 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.
measure: Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level
timeFrame: 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.
measure: Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level
timeFrame: 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.
measure: Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio
timeFrame: 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.
measure: Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level
timeFrame: 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.
measure: Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level
timeFrame: 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.
measure: Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level
timeFrame: 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.
measure: Progression-Free Survival Events by Serum Neuropilin Level
timeFrame: 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.
measure: Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level
timeFrame: 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.
measure: Progression-Free Survival Events by Tumor VEGF-C RNA Level
timeFrame: 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.
measure: Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio
timeFrame: 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.
measure: Progression-Free Survival Events by Tumor VEGF-D RNA Level
timeFrame: 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.
measure: Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level
timeFrame: 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.
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Research Center
state: Arizona
city: Hot Springs
country: United States
facility: Genesis Cancer Center
state: Arizona
city: Tucson
country: United States
facility: Arizona Clinical Research Center
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego-Morris Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center, Division of Hematology/Oncology
state: California
city: Rancho Mirage
country: United States
facility: Desert Hematology Oncology Medical Group, Inc.
state: California
city: Golden
country: United States
facility: Mountain Blue Cancer Care Center
state: Colorado
city: Gainesville
country: United States
facility: University of Florida, Davis Cancer Center (VA)
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Honolulu
country: United States
facility: Kaiser Foundation Hospitals
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Peoria
country: United States
facility: Illinios Cancer Care
state: Illinois
city: Indianapolis
country: United States
facility: Investigative Clinical Research of Indiana, LLC
state: Indiana
city: Lafayette
country: United States
facility: Horizon Oncology Research, Inc.
state: Indiana
city: Rockville
country: United States
facility: Associates of Oncology Hematology, P.C.
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Health
state: Michigan
city: New York
country: United States
facility: NYU Cancer Institute
state: New York
city: Burlington
country: United States
facility: Alamance Regional Medical Center
state: North Carolina
city: Canton
country: United States
facility: Tri Country Hematology / Oncology
state: Ohio
city: Middletown
country: United States
facility: Signal Point Clinical Research Center, LLC
state: Ohio
city: Tulsa
country: United States
facility: Cancer Care Associates
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Bethlehem
country: United States
facility: Oncology Hematology of Lehigh Valley
state: Pennsylvania
city: Ogden
country: United States
facility: Northern Utah Associates
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: Tweed Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Ballarat
country: Australia
facility: Ballarat Health Services
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital Malvern
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical Oncology
state: Victoria
city: Graz
country: Austria
facility: Medizinische Universitat Graz
city: Salzburg
country: Austria
facility: Salzburger Landesklinken
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen GmbH
city: Antwerpen
country: Belgium
facility: Ziekenhuisnetwerk Antwerpen - AZ Middelheim
city: Bonheiden
country: Belgium
facility: Imelda VZW
city: Brugge
country: Belgium
facility: AZ Sint-Lucas Brugge
city: Kortrijk
country: Belgium
facility: AZ Groeninge - Campus Sint-Niklaas
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Halifax
country: Canada
facility: QEII Health Science Centre
state: Nova Scotia
city: Laval
country: Canada
facility: Hopital De La Cite-De-La-Sante
state: Quebec
city: Montreal
country: Canada
facility: Hopital Saint-Luc - Pavillon Principal
state: Quebec
city: Quebec
country: Canada
facility: Chuq Centre Hospitalier Universitaire De Quebec
city: Brno
country: Czech Republic
facility: Masarykuv onkologicky ustav
city: Hradec Kralove
country: Czech Republic
facility: Fakultni nemocnice Hradec Kralove
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Turku
country: Finland
facility: Turun yliopistollinen keskussairaala
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz
city: Gyula
country: Hungary
facility: Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza
city: Szekesfehervar
country: Hungary
facility: Fejer Megyei Szent Gyorgy Korhaz
city: Bologna
country: Italy
facility: Azienda Ospedaliero- Universitaria di Bologna - Policlinico S.Orsola-Malpighi
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per I'Oncologia IRCC
city: Genova
country: Italy
facility: IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro
city: Rozzano (MI)
country: Italy
facility: Istituto Clinico Humanitas
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
state: Aragon
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli
state: Cataluna
city: Terrassa
country: Spain
facility: Hospital Mutua de Terrassa
state: Cataluna
city: Galicia
country: Spain
facility: Centro Oncologico de Galicia
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Center
city: London
country: United Kingdom
facility: University College Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Peterborough
country: United Kingdom
facility: Peterborough and Stamford Hospitals NHS Foundation Trust
Study officials:
affiliation: AVEO Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: