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

Phase 2

Completed

• Conditions: Colorectal Cancer
• Interventions: Drug: Tivozanib; Drug: Bevacizumab; Drug: mFOLFOX6

• Registration Number: NCT01478594
• Lead Sponsor: AVEO Pharmaceuticals, Inc.

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.

Study Timeline

• Study First Submitted: 2011-11-21
• Study First Submitted QC: 2011-11-21
• Study First Posted: 2011-11-23
• Study Start: 2011-12
• Primary Completion: 2013-09
• Study Completion: 2015-01
• Results First Submitted: 2015-02-19
• Results First Submitted QC: 2015-04-02
• Results First Posted: 2015-04-03
• Status Verified: 2015-06
• Last Update Submitted: 2015-06-09
• Last Update Posted: 2015-07-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 265

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tivozanib + mFOLFOX6	Tivozanib	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.
Tivozanib + mFOLFOX6	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.
Bevacizumab + mFOLFOX6	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.
Bevacizumab + mFOLFOX6	Bevacizumab	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Progression-Free Survival (PFS) Based on Independent Radiological Review (IRR)	3 years	The time from the date of randomization until the date of radiological disease progression assessed by the IRR or until death due to any cause, even in the absence of radiological progression.
Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C level. VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-A RNA level.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
Progression-Free Survival Events by Tumor VEGF-C / 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.
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.
Safety as Assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events (AEs)	From first dose through 30 days after last dose of either tivozanib or bevacizumab, until the data cut-off date of 28 February 2014. The median duration of treatment was 168.0 days in the tivozanib (tiv) arm and 162.0 days in the bevacizumab (bev) arm.	An abnormality identified during a medical test is defined as an AE if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study medication or was clinically significant in the investigator's opinion.; An AE was serious if it resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required or prolonged inpatient hospitalization or other medically important event.; AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute Common Terminology Criteria for Grading Adverse Events (NCI-CTCAE) Version 4.03 per the following: 1=mild; 2= moderate; 3= severe; 4= life threatening; 5=death.; Treatment-related AEs were defined as events where the relationship to study drug was marked as probably or possibly, or was missing.
Progression-free Survival Events by 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.
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.
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.
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.
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.
Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-3 level. sVEGFR-3 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Progression-Free Survival Events by 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.
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.
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.
Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum lactate dehydrogenase status.
Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum vascular endothelial growth factor-A (VEGF-A) level. VEGF-A protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Progression-Free Survival Events by Serum Neuropilin Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum neuropilin level. Neuropilin protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
Progression-Free Survival Events by Tumor VEGF-C RNA Level	From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group.	The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C RNA level.; RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
Progression-Free Survival Events by Tumor 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.

Trial Locations

Locations (73)

Kaiser Foundation Hospitals; 🇺🇸 Honolulu, Hawaii, United States

Hopital Saint-Luc - Pavillon Principal; 🇨🇦 Montreal, Quebec, Canada

Associates of Oncology Hematology, P.C.; 🇺🇸 Rockville, Maryland, United States

Banner MD Anderson Cancer Research Center; 🇺🇸 Gilbert, Arizona, United States

Genesis Cancer Center; 🇺🇸 Hot Springs, Arizona, United States

Arizona Clinical Research Center; 🇺🇸 Tucson, Arizona, United States

UC Irvine Medical Center, Division of Hematology/Oncology; 🇺🇸 Orange, California, United States

Mountain Blue Cancer Care Center; 🇺🇸 Golden, Colorado, United States

University of Florida, Davis Cancer Center (VA); 🇺🇸 Gainesville, Florida, United States

Cleveland Clinic Florida; 🇺🇸 Weston, Florida, United States

Queen's Medical Center; 🇺🇸 Honolulu, Hawaii, United States

University of Hawaii; 🇺🇸 Honolulu, Hawaii, United States

Horizon Oncology Research, Inc.; 🇺🇸 Lafayette, Indiana, United States

University of Michigan Health; 🇺🇸 Ann Arbor, Michigan, United States

Alamance Regional Medical Center; 🇺🇸 Burlington, North Carolina, United States

Tri Country Hematology / Oncology; 🇺🇸 Canton, Ohio, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Northern Utah Associates; 🇺🇸 Ogden, Utah, United States

Cancer Care Associates; 🇺🇸 Tulsa, Oklahoma, United States

Oncology Hematology of Lehigh Valley; 🇺🇸 Bethlehem, Pennsylvania, United States

Seattle Cancer Care Alliance; 🇺🇸 Seattle, Washington, United States

Tweed Hospital; 🇦🇺 Tweed Heads, New South Wales, Australia

St George Hospital; 🇦🇺 Kogarah, New South Wales, Australia

Flinders Medical Centre; 🇦🇺 Bedford Park, South Australia, Australia

Royal Hobart Hospital; 🇦🇺 Hobart, Tasmania, Australia

Ballarat Health Services; 🇦🇺 Ballarat, Victoria, Australia

Klinikum Wels-Grieskirchen GmbH; 🇦🇹 Wels, Austria

Cabrini Hospital Malvern; 🇦🇺 Malvern, Victoria, Australia

Border Medical Oncology; 🇦🇺 Wodonga, Victoria, Australia

Medizinische Universitat Graz; 🇦🇹 Graz, Austria

Salzburger Landesklinken; 🇦🇹 Salzburg, Austria

Ziekenhuisnetwerk Antwerpen - AZ Middelheim; 🇧🇪 Antwerpen, Belgium

Imelda VZW; 🇧🇪 Bonheiden, Belgium

AZ Sint-Lucas Brugge; 🇧🇪 Brugge, Belgium

AZ Groeninge - Campus Sint-Niklaas; 🇧🇪 Kortrijk, Belgium

British Columbia Cancer Agency; 🇨🇦 Vancouver, British Columbia, Canada

QEII Health Science Centre; 🇨🇦 Halifax, Nova Scotia, Canada

Hopital De La Cite-De-La-Sante; 🇨🇦 Laval, Quebec, Canada

Masarykuv onkologicky ustav; 🇨🇿 Brno, Czech Republic

Chuq Centre Hospitalier Universitaire De Quebec; 🇨🇦 Quebec, Canada

Orszagos Onkologiai Intezet; 🇭🇺 Budapest, Hungary

Fakultni nemocnice Hradec Kralove; 🇨🇿 Hradec Kralove, Czech Republic

Turun yliopistollinen keskussairaala; 🇫🇮 Turku, Finland

Tampereen yliopistollinen sairaala; 🇫🇮 Tampere, Finland

Petz Aladar Megyei Oktato Korhaz; 🇭🇺 Gyor, Hungary

Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza; 🇭🇺 Gyula, Hungary

Fejer Megyei Szent Gyorgy Korhaz; 🇭🇺 Szekesfehervar, Hungary

Fondazione del Piemonte per I'Oncologia IRCC; 🇮🇹 Candiolo, Italy

Azienda Ospedaliero- Universitaria di Bologna - Policlinico S.Orsola-Malpighi; 🇮🇹 Bologna, Italy

IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro; 🇮🇹 Genova, Italy

Istituto Clinico Humanitas; 🇮🇹 Rozzano (MI), Italy

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

Hospital Universitario Miguel Servet; 🇪🇸 Zaragoza, Aragon, Spain

Hospital Universitario Marques de Valdecilla; 🇪🇸 Santander, Cantabria, Spain

Corporacio Sanitaria Parc Tauli; 🇪🇸 Sabadell, Cataluna, Spain

Centro Oncologico de Galicia; 🇪🇸 Galicia, Spain

Hospital Mutua de Terrassa; 🇪🇸 Terrassa, Cataluna, Spain

Centro Integral Oncologico Clara Campal; 🇪🇸 Madrid, Spain

Addenbrooke's Hospital; 🇬🇧 Cambridge, United Kingdom

University College Hospital; 🇬🇧 London, United Kingdom

Maidstone Hospital; 🇬🇧 Maidstone, United Kingdom

Western General Hospital; 🇬🇧 Edinburgh, United Kingdom

Beatson West of Scotland Cancer Center; 🇬🇧 Glasgow, United Kingdom

Christie Hospital; 🇬🇧 Manchester, United Kingdom

Peterborough and Stamford Hospitals NHS Foundation Trust; 🇬🇧 Peterborough, United Kingdom

University of California San Diego-Morris Cancer Center; 🇺🇸 La Jolla, California, United States

Desert Hematology Oncology Medical Group, Inc.; 🇺🇸 Rancho Mirage, California, United States

Illinios Cancer Care; 🇺🇸 Peoria, Illinois, United States

Investigative Clinical Research of Indiana, LLC; 🇺🇸 Indianapolis, Indiana, United States

NYU Cancer Institute; 🇺🇸 New York, New York, United States

Calvary Mater Newcastle; 🇦🇺 Waratah, New South Wales, Australia

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Signal Point Clinical Research Center, LLC; 🇺🇸 Middletown, Ohio, United States