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A randomized, open-label, multicenter phase II study of bevacizumab, infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (A-FOLFOXIRI) compared with bevacizumab, infusional fluorouracil, leucovorin, and irinotecan/oxaliplatin (A-FOLFIRI/FOLFOX) as first-line treatment for metastatic right-sided colon cancer

Status Approved

  • First Submitted Date

    2018/08/22

  • Registered Date

    2018/10/19

  • Last Updated Date

    2020/08/03

CRIS Required

WHO ICTRP (International Clinical Trial Registry Platform) Required

  • 1. Background

    Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
    CRIS
    Registration Number
    KCT0003278
    Unique Protocol ID 4-2018-0460
    Public/Brief Title A study of bevacizumab, infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (A-FOLFOXIRI) compared with bevacizumab, infusional fluorouracil, leucovorin, and irinotecan/oxaliplatin (A-FOLFIRI/FOLFOX) as first-line treatment for metastatic right-sided colon cancer
    Scientific Title A randomized, open-label, multicenter phase II study of bevacizumab, infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (A-FOLFOXIRI) compared with bevacizumab, infusional fluorouracil, leucovorin, and irinotecan/oxaliplatin (A-FOLFIRI/FOLFOX) as first-line treatment for metastatic right-sided colon cancer
    Acronym
    MFDS Regulated Study Yes
    IND/IDE Protocol No
    Registered at Other Registry No
    Healthcare Benefit Approval Status Submitted approval
  • 2. Institutional Review Board / Ethics Committee

    Institutional Review Board Information
    Board Approval Status Submitted approval
    Board Approval Number 4-2018-0460
    Approval Date 2018-06-29
    Institutional Review Board Name Yonsei University Health System, Severance Hospital, Institutional Review Board
    Institutional Review Board Address 50-1, Yonsei-ro, Seodaemun-gu, Seoul
    Institutional Review Board Telephone 02-2228-0435
    Data Monitoring Committee Yes
    Independent Data-Monitoring Committee
  • 3. Contact Details

    Contact Details Information - Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Contact Person for Updating Information의 Name, Title, Email, Telephone, Cellular Phone, Affiliation, Address
    Contact Person for Principal Investigator / Scientific Queries
    Name Joong Bae Ahn
    Title M.D.,Ph.D
    Telephone +82-2-2228-4320
    Affiliation Yonsei University Health System, Severance Hospital
    Address 50-1 Yonsei-ro, Seodaemun-gu, Seoul
    Contact Person for Public Queries
    Name Hyon Jung Park
    Title RN, CCRC
    Telephone +82-2-2228-8054
    Affiliation Yonsei University Health System, Severance Hospital
    Address 50-1 Yonsei-ro, Seodaemun-gu, Seoul
    Contact Person for Updating Information
    Name Hyon Jung Park
    Title RN. CCRC
    Telephone +82-2-2228-8054
    Affiliation Yonsei University Health System, Severance Hospital
    Address 50-1 Yonsei-ro, Seodaemun-gu, Seoul
  • 4. Status

    Status Information - Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt
    Study Site Single
    Overall Recruitment Status Recruiting
    Date of First Enrollment 2019-01-02 Actual
    Target Number of Participant 120
    Primary Completion Date
    Study Completion Date
    Recruitment Status by Participating Study Site 1
    Name of Study Yonsei University Health System, Severance Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2019-01-02 ,
  • 5. Source of Monetary / Material Support

    Source of Monetary / Material Support Information - Organization Name, Organization Type, Project ID
    1. Source of Monetary/Material Support
    Organization Name Boryung Pharm
    Organization Type Pharmaceutical Company
    Project ID
  • 6. Sponsor Organization

    Sponsor Organization Information - Organization Name, Organization Type
    1. Sponsor Organization
    Organization Name Yonsei University Health System, Severance Hospital
    Organization Type Medical Institute
  • 7. Study Summary

    Study Summary Information
    Lay Summary
    RATIONALE: Recently, the importance of prognosis according to the location of the primary tumor in colorectal cancer has been raised. In the CALGB / SWOG 80405 study published in 2016, the addition of bevacizumab or cetuximab to the first line FOLFIRI / FOLFOX in KRAS (codon 12, 13) wild type metastatic colorectal cancer (mCRC) patients did not show a significant difference between overall survival (OS) and progression free survival (PFS) in both groups. Alan P. Venook et al. published a follow-up subgroup analysis on the effect of primary tumor location at 2016 ASCO. In the treatment group with cetuximab, the difference in treatment effect was significant according to the primary tumor location. The right colon cancer showed a poor prognosis for cetuximab treatment. (PFS: 7.8 vs 12.4 months, HR 1.56, p <0.0001 / OS: 16.7 vs 36.0months, HR 1.87, P <0.0001). 
    
    Therefore, we propose a phase II trial for the efficacy evaluation of bevacizumab-FOLFOXIRI and bevacizumab-FOLFIRI or FOLFOX treatment in patients with poor prognosis of unresectable right-sided colorectal cancer.
  • 8. Study Design

    Study Design Information - Study Type, Study Purpose, Phase, Intervention Model, Blinding/Masking, Blinded Subject, Allocation, Intervention Type, Intervention Description, Number of Arms, Arm Label, Target Number of Participant, Arm Type, Arm Description
    Study Type Interventional Study
    Study Purpose
    Treatment
    Phase Phase2
    Intervention Model Parallel  
    Blinding/Masking Open
    Allocation RCT
    Intervention Type Drug  
    Intervention Description
    Patients are stratified according to ECOG performance status (0 vs 1-2), prior adjuvant chemotherapy (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.
    
    Arm I (A-FOLFOXIRI): Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.
    
    Arm II (A-FOLFOX/FOLFIRI): Patients receive irinotecan hydrochloride IV over 1 hour (or oxaliplatin IV over 2 hours), leucovorin calcium IV over 2 hours, flurorourcal IV bolus, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.
    
    In both arms, treatment repeats every 2 weeks for up to 12 courses. After the 12 cycle treatment finished, investigator decides whether to keep the study drug. Treatment continues in the absence of disease progression, withdrawal consent, or unacceptable toxicity. If treatment with oxaliplatin or irinotecan is difficult due to side effects, treatment with bevacizumab, fluorouracil, and leucovorin calcium continues in the absence of disease progression, withdrawal consent, or unacceptable toxicity.
    Number of Arms 2
    Arm 1

    Arm Label

    A-FOLFOX/A-FOLFIRI

    Target Number of Participant

    60

    Arm Type

    Active comparator

    Arm Description

    Patients receive irinotecan hydrochloride IV over 1 hour (or oxaliplatin IV over 2 hours), leucovorin calcium IV over 2 hours, flurorourcal IV bolus, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.
    Arm 2

    Arm Label

    A-FOLFOXIRI

    Target Number of Participant

    60

    Arm Type

    Experimental

    Arm Description

    Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.
  • 9. Subject Eligibility

    Subject Eligibility Information
    Condition(s)/Problem(s) * (C00-D48)Neoplasms 
       (C18.2)Malignant neoplasm of ascending colon 

    Colonic Neoplasms
    Rare Disease No
    Inclusion Criteria

    Gender

    Both

    Age

    19Year~No Limit

    Description

    1) Histologically proven diagnosis of unresectable recurrent or advanced stage IV right-sided colon cancer
    (The definition of the right colon cancer is confirmed by the colonoscopy result, the surgical report, or the image reading paper including CT, MRI, and PET CT. (cecum~splenic flexure))
    2) Not previously treated with chemotherapy for metastatic disease
    3) At least one measurable lesion according to Response evaluation criteria in solid tumors criteria 
    4) Age over 19 years old 
    5) Eastern Cooperative Oncology Group (ECOG) Performance Status 0~2 
    6) Life expectancy of at least 3 months
    7) Adequate major organ functions
    8) Absolute neutrophil count ≥ 1.5 x 109/L
    9) Platelet ≥ 100 x 109/L
    10) hemoglobin ≥ 9.0 g/dL (can be corrected by blood transfusion) 
    11) Total bilirubin ≤ upper normal limit(UNL) * 1.5
    12) Aspartate transaminase, Alanine transaminase≤ UNL * 3 (in case of liver metastasis,  Aspartate transaminase, Alanine transaminase≤ UNL * 5), alkaline phosphatase ≤ UNL *3 (in case of liver metastasis,  ALP ≤ UNL * 5
    13) adequate renal function : corrected creatinine clearance by Cockcroft and Gault formula ≥ 30mL/min 
    14) Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate 1 g of protein/24 hr.
    15) Written informed consent.
    Exclusion Criteria
    1) Previously treated with chemotherapy for metastatic disease 
    2) Within 6 months after adjuvant chemotherapy
    3) Major surgical procedure within 28
    days prior to study treatment start, or patients who have not fully recovered from major surgery
    4) Radiotherapy to target lesion within 4 weeks before the study (A 2-week washout is permitted for palliative radiation.) 
    5) Has known uncontrolled active CNS metastases and/or carcinomatous meningitis 
    6) Peripheral neuropathy Common Terminology Criteria for Adverse Events v4.03 ≥ grade 2 
    7) Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 
    Note: Participants with basal cell carcinoma of skin, squamous cell carcinoma of the skin, low grade thyroid cancer or carcinoma in situ (eg, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 
    8) Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic systemic treatment and is allowed. 
    9) Uncontrolled hyeprtension or clinically active cardiovascular disease: for example, cerebrovascular accident or transient isschemic attack, unstable angina, myocaridal infarction within 24 weeks prior to randomization. Have symptomatic congestive heart failure (CHF; New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia. 
    10) Have significant bleeding disorders, or evidence of bleeding diathesis or coagulopathy
    11) have had a significant bleeding episode from the gastrointestinal (GI) tract or lung 
    12) Have a history of GI perforation and/or fistula, or intraabominal abscess within 24 weeks prior to randomization.
    13) Have a history of Hereditary nonpolyposis colorectal cancer syndrome or polyposis 
    14) Have experienced any arterial thromboembolic event or ongoing treatment with anticoagulants for therapeutic purpose within 24 weeks prior to randomization. 
    15) Has a known history of human immunodeficiency virus (HIV) infection
    16) Are pregnant or breast feeding. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to first dose of study treatment. For women of childbearing potential and men, agreement to remain abstinent or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 30 days after the last dose of study drugs. Postmenopausal women is defined that : 
     - must have been amenorrheic for at least 12 months, > 50 years old or 
     - Age ≤ 50 years old and amenorrheic for 12 or more months in the abscence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range  (>40 mIU/mL) 
     - prior bilateral oophorectomy 
    17) Patients who are hypesenstivie reaction to experimental drugs 
    18) Patients who are hypersensitive to CHO(Chinese Hamster Ovary) cell products or other recombinant or humanized antibodies
    19) In case of contraindication of experimental drugs
    20) Have any condition (eg, psychological, geographical, or medical) that does not permit compliance with the study and follow-up procedures or suggest that the patient is, in the investigator’s opinion, not an appropriate candidate for the study.
    Healthy Volunteers No
  • 10. Outcome Measure(s)

    Outcome Measure(s) Information - Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint
    Type of Primary Outcome /Safety/Efficacy
    Primary Outcome(s) 1
    Outcome
    6-months progression-free survival rate
    Timepoint
    6 months
    Secondary Outcome(s) 1
    Outcome
    adverse event
    Timepoint
    every 2 weeks
  • 11. Study Results and Publication

    Study Results and Publication Information - Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary
    Result Registered No
  • 12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

    Sharing of Study Data Information - Sharing Statement, Time of Sharing, Way of Sharing
    Sharing Statement No
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