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Colorectal Cancer MetastaticPhase 2/3BOS3NCT01646554

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

A Phase 2/3 study testing Modified FOLFOX6, Aflibercept and Surgery in people with Colorectal Cancer Metastatic and Liver Metastases, run by European Organisation for Research and Treatment of Cancer - EORTC.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Modified FOLFOX6, Aflibercept and Surgery
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Dec 2012to Dec 2016
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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
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  • 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

About this study

Official title: 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.

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.

Read more

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

Being tested
Modified FOLFOX6, Aflibercept, Surgery
Keywords
Liver metastases, Colorectal Cancer, KRAS mutated, FOLFOX, Aflibercept, Randomized, Phase II-III, Perioperative treatment, Adjuvant, Neo-adjuvant, Surgery, Progression Free Survival
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Modified FOLFOX6Drug

    Also called 5-FU, folinic acid, oxaliplatin

  • AfliberceptBiological

    Targeted therapy

  • SurgeryProcedure or surgery

Study groups in NCT01646554
Study groupRoleWhat they receive
Arm A: modified FOLFOX6 and SurgeryActive comparator6 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
Receives: Drug: Modified FOLFOX6; Procedure: Surgery
Arm B: modified FOLFOX6 + Aflibercept and SurgeryExperimental6 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.
Receives: Drug: Modified FOLFOX6; Biological: Aflibercept; Procedure: Surgery

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression free survival

    Increase in progression free survival rate at 1 year in the experimental arm (mFOLFOX6 + aflibercept) compared to mFOLFOX6 alone arm.

    Measured: 1 year

Secondary outcomes (4)

  1. Pathological response rate

    Increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm.

    Measured: 4 years

  2. Resection rate

    Compare the percentage of patients with total resection with these three treatments.

    Measured: 4 years

  3. Overall survival

    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.

    Measured: 8 years

  4. Safety

    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.

    Measured: 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Jul 2012 (estimated)
  2. Study startDec 2012
  3. Primary completionDec 2015 (estimated)
  4. Study completionDec 2016 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01646554
Sponsor's protocol ID
EORTC-1207
Other IDs
2012-002317-18
Acronym
BOS3
Status last verified
May 2017
First submitted
16 Jul 2012
Last updated
9 May 2017
Results posted
No

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Modified FOLFOX6, Aflibercept and Surgery in people with Colorectal Cancer Metastatic and Liver Metastases, run by European Organisation for Research and Treatment of Cancer - EORTC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 9 May 2017. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression free survival (time frame: 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01646554.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2017.

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