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Efficacy of FOLFOX Versus FOLFOX Plus Aflibercept in K-ras Mutant Patients With Resectable Liver Metastases (BOS3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01646554
Recruitment Status : Withdrawn
First Posted : July 20, 2012
Last Update Posted : May 9, 2017
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Tracking Information
First Submitted Date  ICMJE July 16, 2012
First Posted Date  ICMJE July 20, 2012
Last Update Posted Date May 9, 2017
Study Start Date  ICMJE December 2012
Estimated Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2012)
Progression free survival [ Time Frame: 1 year ]
Increase in progression free survival rate at 1 year in the experimental arm (mFOLFOX6 + aflibercept) compared to mFOLFOX6 alone arm.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2012)
  • Pathological response rate [ Time Frame: 4 years ]
    Increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm.
  • Resection rate [ Time Frame: 4 years ]
    Compare the percentage of patients with total resection with these three treatments.
  • Overall survival [ Time Frame: 8 years ]
    Overall survival is defined as the time interval between the date of randomization and the date of death. Patients who are still alive when last traced will be censored at the date of last follow-up.
  • Safety [ Time Frame: 4 years ]
    All adverse events will be recorded; the investigator will assess whether those events are drug related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all adverse events.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of FOLFOX Versus FOLFOX Plus Aflibercept in K-ras Mutant Patients With Resectable Liver Metastases
Official Title  ICMJE BOS3: Randomized Phase II/III Trial Evaluating the Efficacy of FOLFOX Alone Versus FOLFOX Plus Aflibercept in K-ras Mutant as Perioperative Treatment in Patients With Resectable Liver Metastases From Colorectal Cancer.
Brief Summary

Patients presenting with multiple innumerable liver metastases will probably never come to resection, however, for all others, including patients with numerous multiple metastases or large metastases, resection should be considered after limited chemotherapy.

There is consensus for a backbone chemotherapy consisting of fluoropyrimidine + oxaliplatin. FOLFOX was used in the previous EORTC study and is again recommended.

The addition of targeted agents to standard chemotherapy in the perioperative strategy for mCRC might increase the ORR and R0 resectability, without significant increase in toxicity, therefore translating to a better outcome.

BOS2 (EORTC 40091) was designed to test this hypothesis in patients with a KRAS wold-type profile.

It was decided in parallel to design an open label, randomized, multi-center, 2-arm phase II-III study this time aimed at enrolling KRAS mutated patients.

Arm A: (standard) mFOLFOX6 + Surgery Arm B: (experimental) mFOLFOX6 + Aflibercept + Surgery

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Colorectal Cancer Metastatic
  • Liver Metastases
  • KRAS Mutated Colorectal Cancer
Intervention  ICMJE
  • Drug: Modified FOLFOX6
    Other Name: 5-FU, folinic acid, oxaliplatin
  • Biological: Aflibercept
    Targeted therapy
  • Procedure: Surgery
Study Arms  ICMJE
  • Active Comparator: Arm A: modified FOLFOX6 and Surgery

    6 cycles before and 6 cycles after surgery consisting in:

    Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion

    Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion

    Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes

    Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h.

    On day 1 of a 14 day cycle

    Interventions:
    • Drug: Modified FOLFOX6
    • Procedure: Surgery
  • Experimental: Arm B: modified FOLFOX6 + Aflibercept and Surgery

    6 cycles before and 6 cycles after surgery consisting in:

    Hour 0: Aflibercept 4 mg/kg intravenous infusion 1-h

    Hour 1: Oxaliplatin 85 mg/m2 2-h infusion

    Hour 1: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion

    Hour 3: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes

    Hour 3: 5-FU 2400 mg/m² given as a continuous infusion over 46h.

    Day 1 of a 14 day cycle

    Aflibercept should be given in all cycles, except cycle 6 of pre-operative treatment.

    Interventions:
    • Drug: Modified FOLFOX6
    • Biological: Aflibercept
    • Procedure: Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: February 19, 2015)
0
Original Estimated Enrollment  ICMJE
 (submitted: July 18, 2012)
240
Estimated Study Completion Date  ICMJE December 2016
Estimated Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically proven CRC with 1 to 8 metachronous or synchronous liver metastases considered to be completely resectable
  • Primary tumor (or liver metastasis) of CRC must be KRAS status "mutant"
  • Patients must have undergone complete resection (R0) of the primary tumor at least 4 weeks before randomization. Or for patients with synchronous metastases the primary tumor can be resected (R0) at the same time as the liver metastases if: the patient has a non-obstructive primary tumor and is able to receive preoperative chemotherapy (3-4 months) before surgery1.
  • Measurable hepatic disease by RECIST version 1.1
  • Patients must be 18 years old or older
  • A World Health Organization (WHO) performance status of 0 or 1
  • Previous adjuvant chemotherapy for primary CRC is allowed if completed at least 12 months before inclusion in this study
  • All the following tests should be done within 4 weeks prior to randomization:
  • Hematological status: neutrophils (ANC) = 1.5x10 9/L; platelets = 100x10 9/L; haemoglobin = 9g/dL
  • Serum creatinine = 1.5 times the upper limit of normal (ULN)
  • Proteinuria < 2+ (dipstick urinalysis) or =1g/24hour.
  • Liver function: serum bilirubin = 1.5 x upper normal limit (ULN), alkaline phosphatase < 5xULN
  • Magnesium ≥ lower limit of normal (LLN)
  • Patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry are acceptable. This will not apply for Renal Function, including Creatinine.
  • Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 14 days prior to the first dose of study treatment.
  • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
  • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  • Patient should be willing and able to comply with protocol requirements
  • Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

  • Evidence of extra-hepatic metastasis (of CRC)
  • Previous chemotherapy for metastatic disease or surgical treatment (e.g. surgical resection or radiofrequency ablation) for liver metastasis. Radiotherapy alone is allowed if given pre or post protocol treatment
  • Previous exposure to VEGF/VEGFR targeting therapy within the last 12 months
  • Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization
  • Gilbert's syndrome
  • History of myocardial infarction and/or stroke within 6 months prior to randomization
  • Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy
  • History or evidence upon physical examination of CNS metastasis
  • Bowel obstruction
  • Uncontrolled hypercalcemia
  • Pre-existing permanent neuropathy (NCI grade = 2)
  • Known allergy to any excipient to study drugs
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01646554
Other Study ID Numbers  ICMJE EORTC-1207
2012-002317-18 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party European Organisation for Research and Treatment of Cancer - EORTC
Study Sponsor  ICMJE European Organisation for Research and Treatment of Cancer - EORTC
Collaborators  ICMJE Sanofi
Investigators  ICMJE
Study Chair: Bernard Nordlinger, Pr. C.H.U. AMBROISE PARE AP-HP, Boulogne-Billancourt, France
PRS Account European Organisation for Research and Treatment of Cancer - EORTC
Verification Date May 2017

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