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Combination Chemotherapy Plus Bevacizumab With or Without Oxaliplatin in Treating Older Patients With Metastatic Colorectal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Cancer and Leukemia Group B
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT01279681
First received: January 18, 2011
Last updated: August 11, 2016
Last verified: August 2016

January 18, 2011
August 11, 2016
January 2011
September 2014   (final data collection date for primary outcome measure)
PFS using RECIST version 1.1 [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
Progression-free survival, defined as the time (in days) from the date of randomization to the date of documented disease progression or death, whichever occurs first [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01279681 on ClinicalTrials.gov Archive Site
  • Overall survival [ Time Frame: assessed up to 5 years ] [ Designated as safety issue: No ]
    Efficacy interim analyses will be conducted.
  • Response rate, defined as the proportion of patients in each arm who have an objective status of complete response or partial response, confirmed by a second assessment measured at least 6 weeks from the initial assessment, using RECIST version 1.1 [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Response rates will be tabulated by arm and compared using two-sided chi-squared tests at level 0.05.
  • Incidence of adverse events per the Cancer Therapy Evaluation Program (CTEP) Active Version of the NCI CTCAE version 4.0 grading [ Time Frame: Up to 42 days after treatment discontinuation ] [ Designated as safety issue: Yes ]
    Adverse events will be tabulated by arm and compared using two-sided chi-squared tests at level 0.05.
  • Overall survival, defined as the time (in days) from randomization to death [ Designated as safety issue: No ]
  • Response rate, defined as the proportion of patients in each arm who have an objective status of complete response or partial response, confirmed by a second assessment measured at least 6 weeks from the initial assessment [ Designated as safety issue: No ]
  • Adverse events as per the CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading [ Designated as safety issue: Yes ]
  • Change in geriatric/frailty using the North Central Cancer Treatment Group (NCCTG) Brief Frailty Inventory and the Rockwood Frailty Index physician and patient-reported items [ Time Frame: Baseline to 42 days after termination of study treatment ] [ Designated as safety issue: No ]
    The various measures of geriatric/frailty (Canadian Geriatric Society [CGSA], Rockwood, and NCCTG measures) will be compared head to head using Bland-Altman methods to assess the differences between clinician and patient reported frailty and the relative information obtained from the various assessments. This will be the first head to head comparison of its type to assess geriatric/frailty measures.
  • Change in QOL using the Fatigue/Uniscale Assessment, Linear Analog Self-Assessment (LASA), and the European Quality of Live Five Dimensions questionnaire (EQ-5D) [ Time Frame: Baseline to up to 42 days after termination of study treatment ] [ Designated as safety issue: No ]
    A cut-point of 5 or lower on the overall QoL question will be defined to be the primary cut-off for analysis as that has been demonstrated to represent clinically deficient QoL.
  • Proportion of patients reporting satisfaction using the Was It Worth IT (WIWI) questionnaire [ Time Frame: Baseline to up to 42 days after termination of study treatment ] [ Designated as safety issue: No ]
    WIWI will be summarized descriptively to identify the number of patients who were satisfied with each treatment and indications for improvements therein. Proportion of patients' satisfaction will be compared between treatments by a Fisher's exact test. The impact of the clinical trial on patient QOL will be summarized via means and standard deviations and compared between treatment arms via a Wilcoxon rank sum test.
  • Overall incidence of grade >= 3 toxicity in elderly patients [ Time Frame: Up to 42 days after discontinuation of treatment ] [ Designated as safety issue: Yes ]
    A logistic regression model will be used to determine the odd ratios for the occurrence of grade 3 + toxicity with a 95% confidence interval, and the overall association will be assessed by a likelihood ratio test with a two-sided alpha level of 0.05. As a secondary analysis, a multivariate logistic model will be applied including covariates for treatment arm and the stratification factors: age, PS and metastatic sites.
  • Prognostic single-nucleotide polymorphisms (SNPs) for grade 3+ hypertension [ Time Frame: Up to 42 days after treatment discontinuation ] [ Designated as safety issue: No ]
    Logistic regression models and conditional inference trees (or more generally conditional random forests) will be used to construct multi-variable models based on the SNPs identified as interesting.
Not Provided
 
Combination Chemotherapy Plus Bevacizumab With or Without Oxaliplatin in Treating Older Patients With Metastatic Colorectal Cancer
Randomized Phase III Trial of mFOLFOX7 or XELOX Plus Bevacizumab Versus 5-Fluorouracil/Leucovorin or Capecitabine Plus Bevacizumab as First-line Treatment in Elderly Patients With Metastatic Colorectal Cancer
This randomized phase III trial studies how well combination chemotherapy plus bevacizumab with or without oxaliplatin works in treating older patients with colorectal cancer that has spread to other places in the body. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of cancer by blocking blood flow to the tumor. It is not yet known whether combination chemotherapy plus bevacizumab is more effective with or without oxaliplatin in treating colorectal cancer.

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) of elderly patients with metastatic colorectal carcinoma who are randomized to receive fluoropyrimidine (fluorouracil)-based therapy plus bevacizumab, with or without oxaliplatin.

SECONDARY OBJECTIVES:

I. In a prospectively planned pooled analysis with a similar trial to be conducted by the Japanese Clinical Oncology Group (JCOG), evaluate and compare the overall survival (OS) of elderly patients with metastatic colorectal carcinoma who are randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.

II. To assess and compare response rates and adverse events of elderly patients with metastatic colorectal carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients are assigned to 1 of 2 treatment groups based on physician decision for fluoropyrimidine.

ARM A1: Patients receive fluorouracil intravenously (IV) over 46-48 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV over 10-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM A2: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients are assigned to 1 of 2 treatment groups based on physician decision for fluoropyrimidine.

Arm B1: Patients receive mFOLFOX7 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients also receive bevacizumab IV over 10-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Arm B2: Patients receive XELOX comprising oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Cognitive/Functional Effects
  • Colorectal Cancer
  • Neurotoxicity
  • Biological: bevacizumab
    Given IV
  • Drug: capecitabine
    Given PO
  • Drug: fluorouracil
    Given IV
  • Drug: leucovorin calcium
    Given IV
  • Drug: oxaliplatin
    Given IV
  • Experimental: Arm A1 (fluorouracil, leucovorin calcium, and bevacizumab)
    Patients receive fluorouracil IV over 46-48 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV over 10-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: bevacizumab
    • Drug: fluorouracil
    • Drug: leucovorin calcium
  • Experimental: Arm A2 (bevacizumab and capecitabine)
    Patients receive capecitabine PO BID on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: bevacizumab
    • Drug: capecitabine
  • Active Comparator: Arm B1 (fluorouracil, leucovorin, bevacizumab, oxaliplatin)
    Patients receive mFOLFOX7 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients also receive bevacizumab IV over 10-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: bevacizumab
    • Drug: fluorouracil
    • Drug: leucovorin calcium
    • Drug: oxaliplatin
  • Experimental: Arm B2 (bevacizumab, capecitabine, oxaliplatin)
    Patients receive XELOX comprising oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: bevacizumab
    • Drug: capecitabine
    • Drug: oxaliplatin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
380
Not Provided
September 2014   (final data collection date for primary outcome measure)

Inclusion Criteria

  • Patients must have metastatic colorectal cancer that has been histologically or cytologically confirmed; Note: histologic confirmation can be obtained from the primary tumor with appropriate imaging studies confirming metastatic spread
  • Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Peripheral platelet count (PLT) >= 100,000/mm^3
  • Hemoglobin (HgB) > 9.0 g/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement)
  • Alkaline phosphatase =< 3 x ULN (=< 5 x ULN for patients with liver involvement)
  • Creatinine =< 1.5 x ULN
  • International normalized ratio (INR) < 1.5 x ULN unless patients are receiving anti-coagulation therapy; patients receiving prophylactic anti-coagulation therapy with an agent such as warfarin or heparin are allowed to participate if INR =< 3.0
  • Urine protein creatinine (UPC) ratio < 1 or urine dipstick < 2+

    * NOTE: Urine protein must be screened by urine analysis for urine protein creatinine (UPC) ratio or by dip stick; for UPC ratio >= 1.0 or urine dipstick >= 2+, 24-hour urine protein must be obtained and the level should be < 1000 mg

  • Life expectancy >= 3 months
  • Ability to complete questionnaire(s) by themselves or with assistance
  • Provide informed written consent
  • Willing to provide mandatory blood samples for correlative research purposes

Exclusion Criteria

  • Men of child bearing potential who are unwilling to employ adequate contraception
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of the safety and adverse events of the prescribed regimens
  • Immunocompromised patients (other than that related to the use of corticoid steroids) including patients known to be human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 < 100 cells/uL
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, patients must not be receiving other specific treatment (other than hormonal therapy) for this prior cancer
  • Prior chemotherapy, radiation therapy, immunotherapy, or biological therapy for recurrent or metastatic colorectal cancer

    * NOTE: prior chemotherapy or radiotherapy is permitted if they had been administered as adjuvant or neoadjuvant therapy and a complete surgical resection of the original colorectal cancer had been achieved

  • Progressive disease =< 12 months of completing oxaliplatin-containing adjuvant therapy
  • Prior radiation to > 30% of the bone marrow at any time
  • Calculated creatinine clearance < 60 mL/minute

    * NOTE: If calculated creatinine clearance does not meet eligibility requirement, a 24-hour urine can be collected for a creatinine clearance, and the patient can been rolled if measured creatinine clearance >= 60 mL/minute

  • Known central nervous system or brain metastasis that are either symptomatic or untreated; Note: if a patient has a resection of the metastasis and is no longer symptomatic, the patient is eligible for the study; Note: patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis
  • New York Heart Association (NYHA) classification III or IV congestive heart failure
  • Inadequately controlled hypertension (systolic blood pressure of > 150 mm Hg or diastolic blood pressure > 100 mm Hg on anti-hypertensive medications)
  • Major surgical procedures, open biopsy or significant traumatic injury =< 28 days prior to randomization or anticipation of need for elective or planned major surgical procedure during the course of the study
  • Core biopsy or other minor surgical procedures =< 7 days prior to randomization

    * NOTE: Placement of a vascular access device is allowed

  • Active or recent hemoptysis (>= ½ teaspoon of bright red blood per episode) =< 30 days prior to randomization
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess =< 6 months prior to randomization
  • Serious non-healing wound, active ulcer, or untreated bone fracture

    * NOTE: patients with fractures secondary to metastatic disease are eligible after appropriate radiotherapy

  • History of hypertensive crisis or hypertensive encephalopathy
  • Patient has experienced any arterial thromboembolic events including, but not limited to myocardial infarction, stroke, transient ischemic attack (TIA), cerebrovascular accident, unstable angina =< 6 months prior to randomization or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis =< 6 months prior to randomization
  • Evidence or history of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation) any hemorrhage/bleeding event > grade 3 =< 4 weeks prior to randomization; patients with full-dose anticoagulants are eligible provided the patient has been on a stable dose, at least 2 weeks, of low molecular weight heparin or warfarin and has an INR range 2-3; aspirin doses > 325 mg daily are not allowed
  • Known hypersensitivity to any of the components of 5-fluorouracil/leucovorin, capecitabine, oxaliplatin, or bevacizumab
  • Clinically significant peripheral neuropathy at the time of randomization (defined in the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0 as >= grade 2 neurosensory or neuromotor toxicity)
Both
70 Years and older   (Senior)
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
United States
 
NCT01279681
N0949, NCCTG-N0949, CDR0000692257, NCI-2011-02622
Yes
Not Provided
Not Provided
Alliance for Clinical Trials in Oncology
Alliance for Clinical Trials in Oncology
  • National Cancer Institute (NCI)
  • Cancer and Leukemia Group B
Study Chair: Axel Grothey, MD Mayo Clinic
Alliance for Clinical Trials in Oncology
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP