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

This study is not yet open for participant recruitment.
Verified December 2012 by National Cancer Institute (NCI)
Sponsor:
Collaborators:
Cancer and Leukemia Group B
Information provided by:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01279681
First received: January 18, 2011
Last updated: January 2, 2013
Last verified: December 2012

January 18, 2011
January 2, 2013
January 2011
August 2013   (final data collection date for primary outcome measure)
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 ]
Same as current
Complete list of historical versions of study NCT01279681 on ClinicalTrials.gov Archive Site
  • 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 ]
Same as current
Not Provided
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

RATIONALE: 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, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. 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.

PURPOSE: This randomized phase III clinical trial is studying how well combination chemotherapy plus bevacizumab with or without oxaliplatin works in treating older patients with metastatic colorectal cancer.

OBJECTIVES:

Primary

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

Secondary

  • 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.
  • 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.

Tertiary (correlative)

  • To evaluate the quality of life (QoL) in elderly patients with metastatic colorectal carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.
  • To determine whether a geriatric/frailty assessment predicts overall ≥ grade 3 toxicity to chemotherapy and is associated with PFS, OS, overall QoL, hospitalization, dose modification (delay or reduction), or discontinuation of chemotherapy due to toxicity, morbidity, or mortality in elderly patients with metastatic colorectal cancer randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.
  • Determine whether a geriatric/frailty assessment tool can identify a subgroup of elderly patients who benefit from oxaliplatin-based chemotherapy as first-line treatment of metastatic colorectal carcinoma.
  • To analyze relevant pharmacogenetic markers in tissue and blood that may predict toxicity and/or tumor response in elderly patients with metastatic colorectal carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.
  • To evaluate the association of tissue-based biomarkers (e.g., KRAS and BRAF status) and outcome in elderly patients with metastatic colorectal carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.
  • To analyze pharmacokinetics and circulating biomarkers prior to and during therapy and to assess these alterations with outcome in elderly patients with metastatic colorectal carcinoma randomized to receive fluoropyrimidine-based therapy plus bevacizumab, with or without oxaliplatin.

OUTLINE: This is a multicenter study. Patients are stratified according to age (≥ 85 years vs 80-84 years vs 75-79 years vs 70-74 years), ECOG performance status (0-1 vs 2), and number of metastatic sites (1 vs > 1). 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 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 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 twice daily 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.

Patients may undergo blood and tissue sample collection at baseline and additional blood sample collection during and after study for correlative biomarker, pharmacogenetic, and pharmacological research studies.

Patients undergo neurotoxicity, quality of life, and geriatric/frailty assessments at baseline and periodically during and after study treatment.

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

Interventional
Phase 3
Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
  • Cognitive/Functional Effects
  • Colorectal Cancer
  • Neurotoxicity
  • Biological: bevacizumab
    Given IV
  • Drug: capecitabine
    Given orally
  • Drug: fluorouracil
    Given IV
  • Drug: leucovorin calcium
    Given IV
  • Drug: oxaliplatin
    Given IV
  • Experimental: Arm A1
    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
    Patients receive capecitabine orally (PO) twice daily 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
    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
    Patients receive XELOX comprising oxaliplatin IV over 2 hours on day 1 and capecitabine PO twice daily 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.
 
Not yet recruiting
380
Not Provided
August 2013   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Patients must have metastatic colorectal cancer that has been histologically or cytologically confirmed

    • Histologic confirmation can be obtained from the primary tumor with appropriate imaging studies confirming metastatic spread
  • No known central nervous system or brain metastasis that are either symptomatic or untreated

    • If a patient has a resection of the metastasis and is no longer symptomatic, the patient is eligible for the study
    • Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis

PATIENT CHARACTERISTICS:

  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2
  • Life expectancy ≥ 3 months
  • 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
  • No 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 be enrolled if measured creatinine clearance ≥ 60 mL/minute.
  • 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
  • UPC ratio < 1 or urine dipstick < 2+

    • NOTE: Urine protein must be screened by urine analysis for urine protein creatinine (UPC) ratio or by dipstick. For UPC ratio ≥ 1.0 or urine dipstick ≥ 2+, 24-hour urine protein must be obtained and the level should be < 1,000 mg.
  • No men of childbearing potential who are unwilling to employ adequate contraception during and for 6 months after the last dose of bevacizumab
  • Ability to complete questionnaire(s) by themselves or with assistance
  • Willing to provide mandatory blood samples for correlative research purposes
  • No co-morbid systemic illnesses or other severe concurrent disease that, 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
  • No immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be HIV positive with CD4 < 100 cells/uL
  • No uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness/social situations that would limit compliance with study requirements
  • No other active malignancy ≤ 3 years prior to randomization EXCEPT for nonmelanotic skin cancer or carcinoma-in-situ of the cervix
  • No New York Heart Association (NYHA) classification III or IV congestive heart failure
  • No inadequately controlled hypertension (systolic blood pressure of > 150 mm Hg or diastolic blood pressure > 100 mm Hg on anti-hypertensive medications)
  • No significant traumatic injury ≤ 28 days prior to randomization
  • No active or recent hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤ 30 days prior to randomization
  • No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 6 months prior to randomization
  • No serious non-healing wound, active ulcer, or untreated bone fracture

    • NOTE: Patients with fractures secondary to metastatic disease are eligible after appropriate radiotherapy.
  • No history of hypertensive crisis or hypertensive encephalopathy
  • No patient that 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
    • Congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • No significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis ≤ 6 months prior to randomization
  • No evidence or history of bleeding diathesis (greater than normal risk of bleeding), coagulopathy (in the absence of therapeutic anticoagulation), or hemorrhage/bleeding event > grade 3 ≤ 4 weeks prior to randomization
  • No known hypersensitivity to any of the components of 5-fluorouracil/leucovorin, capecitabine, oxaliplatin, or bevacizumab
  • No clinically significant peripheral neuropathy at the time of randomization (defined in the NCI Common Terminology Criteria for Adverse Events [CTCAE] v4.0 as ≥ grade 2 neurosensory or neuromotor toxicity)

PRIOR CONCURRENT THERAPY:

  • No 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.
  • No progressive disease ≤ 12 months of completing oxaliplatin-containing adjuvant therapy
  • No prior radiation to > 30% of the bone marrow at any time
  • No major surgical procedures or open biopsy ≤ 28 days prior to randomization or anticipation of need for elective or planned major surgical procedure during the course of the study
  • No core biopsy or other minor surgical procedures ≤ 7 days prior to randomization

    • NOTE: Placement of a vascular access device is allowed.
  • If there is a history of prior malignancy, patients must not be receiving other specific treatment (other than hormonal therapy) for this prior cancer
  • Not receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Patients receiving full-dose anticoagulants are eligible provided the patient has been on a stable dose, for at least 2 weeks, of low molecular weight heparin or warfarin and has an INR range 2-3
  • No aspirin doses > 325 mg daily
Both
70 Years and older
No
Not Provided
Not Provided
 
NCT01279681
CDR0000692257, NCCTG-N0949
Not Provided
Axel Grothey, Mayo Clinic Cancer Center
North Central Cancer Treatment Group
  • National Cancer Institute (NCI)
  • Cancer and Leukemia Group B
Principal Investigator: Axel Grothey, MD Mayo Clinic
Investigator: Nadine J. McCleary, MD, MPH Dana-Farber Cancer Institute
National Cancer Institute (NCI)
December 2012

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