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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01478594
• Other study ID #: 4130-CL-0201
• Secondary ID: 2011-003502-24
• Status: Completed
• Phase: Phase 2
• First received: November 21, 2011
• Last updated: June 9, 2015
• Start date: December 2011
• Est. completion date: January 2015

Study information

• Verified date: June 2015
• Source: AVEO Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaBelgium: Federal Agency for Medicinal Products and Health ProductsUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyCzech Republic: State Institute for Drug ControlAustralia: Department of Health and Ageing Therapeutic Goods AdministrationItaly: The Italian Medicines AgencySpain: Ministry of Health and ConsumptionAustria: Agency for Health and Food SafetyFinland: Finnish Medicines AgencyHungary: National Institute of PharmacyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 265
• Est. completion date: January 2015
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• Tivozanib
Capsules for oral administration
• Bevacizumab
Solution for intravenous infusion
• 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.

Locations

Country	Name	City	State
Australia	Ballarat Health Services	Ballarat	Victoria
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	St George Hospital	Kogarah	New South Wales
Australia	Cabrini Hospital Malvern	Malvern	Victoria
Australia	Tweed Hospital	Tweed Heads	New South Wales
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Australia	Border Medical Oncology	Wodonga	Victoria
Austria	Medizinische Universitat Graz	Graz
Austria	Salzburger Landesklinken	Salzburg
Austria	Klinikum Wels-Grieskirchen GmbH	Wels
Belgium	Ziekenhuisnetwerk Antwerpen - AZ Middelheim	Antwerpen
Belgium	Imelda VZW	Bonheiden
Belgium	AZ Sint-Lucas Brugge	Brugge
Belgium	AZ Groeninge - Campus Sint-Niklaas	Kortrijk
Canada	QEII Health Science Centre	Halifax	Nova Scotia
Canada	Hopital De La Cite-De-La-Sante	Laval	Quebec
Canada	Hopital Saint-Luc - Pavillon Principal	Montreal	Quebec
Canada	Chuq Centre Hospitalier Universitaire De Quebec	Quebec
Canada	British Columbia Cancer Agency	Vancouver	British Columbia
Czech Republic	Masarykuv onkologicky ustav	Brno
Czech Republic	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Finland	Tampereen yliopistollinen sairaala	Tampere
Finland	Turun yliopistollinen keskussairaala	Turku
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Petz Aladar Megyei Oktato Korhaz	Gyor
Hungary	Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza	Gyula
Hungary	Fejer Megyei Szent Gyorgy Korhaz	Szekesfehervar
Italy	Azienda Ospedaliero- Universitaria di Bologna - Policlinico S.Orsola-Malpighi	Bologna
Italy	Fondazione del Piemonte per I'Oncologia IRCC	Candiolo
Italy	IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro	Genova
Italy	Istituto Clinico Humanitas	Rozzano (MI)
Netherlands	Amphia Ziekenhuis	Breda
Spain	Centro Oncologico de Galicia	Galicia
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	Corporacio Sanitaria Parc Tauli	Sabadell	Cataluna
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Hospital Mutua de Terrassa	Terrassa	Cataluna
Spain	Hospital Universitario Miguel Servet	Zaragoza	Aragon
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Center	Glasgow
United Kingdom	University College Hospital	London
United Kingdom	Maidstone Hospital	Maidstone
United Kingdom	Christie Hospital	Manchester
United Kingdom	Peterborough and Stamford Hospitals NHS Foundation Trust	Peterborough
United States	University of Michigan Health	Ann Arbor	Michigan
United States	Oncology Hematology of Lehigh Valley	Bethlehem	Pennsylvania
United States	Alamance Regional Medical Center	Burlington	North Carolina
United States	Tri Country Hematology / Oncology	Canton	Ohio
United States	Northwestern University	Chicago	Illinois
United States	University of Florida, Davis Cancer Center (VA)	Gainesville	Florida
United States	Banner MD Anderson Cancer Research Center	Gilbert	Arizona
United States	Mountain Blue Cancer Care Center	Golden	Colorado
United States	Kaiser Foundation Hospitals	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	University of Hawaii	Honolulu	Hawaii
United States	Genesis Cancer Center	Hot Springs	Arizona
United States	Investigative Clinical Research of Indiana, LLC	Indianapolis	Indiana
United States	University of California San Diego-Morris Cancer Center	La Jolla	California
United States	Horizon Oncology Research, Inc.	Lafayette	Indiana
United States	Signal Point Clinical Research Center, LLC	Middletown	Ohio
United States	NYU Cancer Institute	New York	New York
United States	Northern Utah Associates	Ogden	Utah
United States	UC Irvine Medical Center, Division of Hematology/Oncology	Orange	California
United States	Illinios Cancer Care	Peoria	Illinois
United States	Oregon Health and Science University	Portland	Oregon
United States	Desert Hematology Oncology Medical Group, Inc.	Rancho Mirage	California
United States	Associates of Oncology Hematology, P.C.	Rockville	Maryland
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Arizona Clinical Research Center	Tucson	Arizona
United States	Cancer Care Associates	Tulsa	Oklahoma
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AVEO Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czech Republic,  Finland,  Hungary,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Investigator-assessed Progression-Free Survival (PFS)	The time from the date of randomization until objective tumor progression or death due to any cause. Objective tumor progression was determined through radiological imaging and based on the requirements of the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1): Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.; Participants who did not progress or had not died at the time of the analysis were censored at the date of last tumor assessment where non-progression was documented.	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.	No
Secondary	Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)	The time from the date of randomization until the date of radiological disease progression assessed by the IRR or until death due to any cause, even in the absence of radiological progression.	3 years	No
Secondary	Overall Survival (OS)	Overall survival (OS) is defined as the time from the date of randomization until the documented date of death. Participants still alive at the time of analysis were censored on the last day the participant was known to be alive.	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.	No
Secondary	Objective Response Rate (ORR)	Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) confirmed a minimum of four weeks apart based on RECIST 1.1 criteria.; CR: Disappearance of all target and non-target lesions and no new lesions.; PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and no progression of non-target lesions and no new lesions, or, disappearance of all target lesions and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits and no new lesions.	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.	No
Secondary	Duration of Response (DoR)	Duration of response (DoR) is defined as the time from the date of the first documented response of CR or PR (whichever is first recorded) to documented progression or death. If a participant did not progress or had not died at the time of analysis, the duration of response was censored at the date of last tumor assessment. Duration of response is only defined for participants whose best overall response was CR or PR.	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.	No
Secondary	Time to Treatment Failure (TTF)	Time to Treatment Failure (TTF) is defined as the time from randomization to last dose date of tivozanib/bevacizumab. If a participant discontinued treatment for any reason, the participant was considered as an event. Participants remaining on treatment at the time of analysis were censored at date of last dose.	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.	No
Secondary	Health Related Quality of Life (HRQoL)	Time to deterioration in HRQoL measured by Colorectal cancer (CRC) subscale of the Functional Assessment of cancer Therapy Colorectal (FACT-C) scale, change in score from baseline using the European Quality of Life - 5 Dimensions (EQ-5D) and Fact Colorectal Symptom Index (FCSI) were not evaluated due to study closure.	3 years	No
Secondary	Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)	An abnormality identified during a medical test is defined as an AE if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study medication or was clinically significant in the investigator's opinion.; An AE was serious if it resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required or prolonged inpatient hospitalization or other medically important event.; AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute Common Terminology Criteria for Grading Adverse Events (NCI-CTCAE) Version 4.03 per the following: 1=mild; 2= moderate; 3= severe; 4= life threatening; 5=death.; Treatment-related AEs were defined as events where the relationship to study drug was marked as probably or possibly, or was missing.	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.	No
Secondary	Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum lactate dehydrogenase status.	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.	No
Secondary	Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum vascular endothelial growth factor-A (VEGF-A) level. VEGF-A protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.	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.	No
Secondary	Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C level. VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.	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.	No
Secondary	Progression-free Survival Events by Serum VEGF-C / VEGF-A Ratio	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C/VEGF-A ratio. VEGF-A and VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the ratio is expressed relative to the observed median.	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.	No
Secondary	Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-2 level. sVEGFR-2 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-3 level. sVEGFR-3 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum interleukin-8 level. IL-8 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Serum Neuropilin Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum neuropilin level. Neuropilin protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-A RNA level.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Tumor VEGF-C RNA Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C RNA level.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Tumor VEGF-C / VEGF-A RNA Ratio	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C/VEGF-A RNA ratio.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Tumor VEGF-D RNA Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-D RNA level.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.	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.	No
Secondary	Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor PIGF RNA level.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.	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.	No