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

This study is not yet open for participant recruitment.
Verified September 2012 by European Organisation for Research and Treatment of Cancer - EORTC
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier:
NCT01646554
First received: July 16, 2012
Last updated: September 20, 2012
Last verified: September 2012
  Purpose

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


Condition Intervention Phase
Colorectal Cancer Metastatic
Liver Metastases
KRAS Mutated Colorectal Cancer
Drug: Modified FOLFOX6
Biological: Aflibercept
Procedure: Surgery
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by European Organisation for Research and Treatment of Cancer - EORTC:

Primary Outcome Measures:
  • Progression free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Increase in progression free survival rate at 1 year in the experimental arm (mFOLFOX6 + aflibercept) compared to mFOLFOX6 alone arm.


Secondary Outcome Measures:
  • Pathological response rate [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm.

  • Resection rate [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Compare the percentage of patients with total resection with these three treatments.

  • Overall survival [ Time Frame: 8 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 240
Study Start Date: December 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

Drug: Modified FOLFOX6
Other Name: 5-FU, folinic acid, oxaliplatin
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.

Drug: Modified FOLFOX6
Other Name: 5-FU, folinic acid, oxaliplatin
Biological: Aflibercept
Targeted therapy
Procedure: Surgery

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01646554

Contacts
Contact: Michel Praet, PhD +32 2 774 16 72 michel.praet@eortc.be
Contact: Carlo GM Messina, MD, MPhil +32 2 774 15 18 carlo.messina@eortc.be

Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Sanofi
Investigators
Study Chair: Bernard Nordlinger, Pr. C.H.U. AMBROISE PARE AP-HP, Boulogne-Billancourt, France
  More Information

No publications provided

Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT01646554     History of Changes
Other Study ID Numbers: EORTC-1207, 2012-002317-18
Study First Received: July 16, 2012
Last Updated: September 20, 2012
Health Authority: Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Germany: Paul-Ehrlich-Institut
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
Liver metastases
Colorectal Cancer
KRAS mutated
FOLFOX
Aflibercept
Randomized
Phase II-III
Perioperative treatment
Adjuvant
Neo-adjuvant
Surgery
Progression Free Survival

Additional relevant MeSH terms:
Colorectal Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Neoplasms
Liver Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Liver Diseases
Leucovorin
Folic Acid
Levoleucovorin
Oxaliplatin
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Antidotes
Protective Agents
Hematinics

ClinicalTrials.gov processed this record on April 15, 2014