Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab in Patients With Resectable Liver Metastases (BOS2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by European Organisation for Research and Treatment of Cancer - EORTC
Sponsor:
Collaborators:
Amgen
Roche Pharma AG
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier:
NCT01508000
First received: January 9, 2012
Last updated: July 30, 2014
Last verified: July 2014
  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.

It was therefore decided to design an open label, randomized, multi-center, 3-arm late phase II study.

Arm A: (standard) mFOLFOX6 + Surgery Arm B: (experimental) mFOLFOX6 + Bevacizumab + Surgery Arm C: (experimental) mFOLFOX6 + Panitumumab + Surgery


Condition Intervention Phase
Colorectal Cancer Metastatic
Liver Metastases
KRAS Wild Type Colorectal Cancer
Drug: FOLFOX6
Biological: Bevacizumab
Biological: Panitumumab
Procedure: Surgery
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial Evaluating the Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab as Perioperative Treatment in Patients With Resectable Liver Metastases From Wild Type KRAS/NRAS 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 each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) 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: 360
Study Start Date: June 2013
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: October 2016 (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: FOLFOX6
5-FU, folinic acid, oxaliplatin
Other Name: Chemotherapy
Procedure: Surgery
Experimental: Arm B: modified FOLFOX6 + Bevacizumab and Surgery

6 cycles before and 6 cycles after surgery consisting in:

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

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

Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion*.

Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes

Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h.

On day 1 of a 14 day cycle

Drug: FOLFOX6
5-FU, folinic acid, oxaliplatin
Other Name: Chemotherapy
Biological: Bevacizumab
Targeted therapy
Other Name: Avastin
Procedure: Surgery
Experimental: Arm C: modified FOLFOX6 + Panitumumab and Surgery

Experimental: Arm B: modified FOLFOX6 + Bevacizumab and Surgery

6 cycles before and 6 cycles after surgery consisting in:

Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) +/- 15 min. infusion*.

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: FOLFOX6
5-FU, folinic acid, oxaliplatin
Other Name: Chemotherapy
Biological: Panitumumab
Targeted therapy
Other Name: Vectibix
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 and NRAS status "wild type".
  • 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 surgery.
  • Measurable hepatic disease by RECIST version 1.1.
  • Patients must be 18 years old or older.
  • A WHO performance status of 0 or 1. Radiotherapy alone is allowed if given pre or post protocol treatment.
  • 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:
  • Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9 g/dL and white blood cell count (WBC) ≥ 3 x 109/L.
  • Serum creatinine ≤ 1.5 times the upper limit of normal (ULN) (to exclude severe renal impairment); no significant proteinuria (urine protein < 1g/24 hours urine collection) OR urine protein/creatinine ratio < 1.0 OR 1+ proteinuria on urine dipstick.
  • Absence of major hepatic insufficiency (bilirubin ≤ 1.5 x ULN and aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 5 x ULN).
  • 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.
  • 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.
  • Previous exposure to EGFR or VEGF/VEGFR targeting therapy within the last 12 months.
  • Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization.
  • Regular use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
  • Bleeding diathesis (e.g. hemoptysis of ≥ 1/2 teaspoon or 2.5mL), coagulopathy, or need for administration of full-dose anti-coagulant(s).
  • Clinically significant cardiovascular disease, including: uncontrolled hypertension, New York Heart Association (NYHA) class II-IV heart failure, myocardial infarction or unstable angina pectoris, cerebrovascular accident or transient ischemic attack within the past 12 months, peripheral vascular disease ≥ grade 2, serious cardiac arrhythmia requiring medication and other clinically significant cardiovascular disease.
  • Peripheral neuropathy > grade 1 (Common Terminology Criteria for Adverse Events, v4.0) serious wound complications, ulcers, or bone fractures.
  • Symptomatic diverticulitis or active or uncontrolled gastroduodenal ulceration.
  • History or evidence of interstitial lung disease (e.g. pneumonitis, pulmonary fibrosis)
  • Significant disease that, in the investigator's opinion, would exclude the patient from the study. Including known allergy or any other adverse reaction to any of the study drugs (including any of the excipients) or to any related compound, including hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies.
  • Presence 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.
  • Participation in another clinical study (except sub studies of this protocol) within the 30 days before randomization and during this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01508000

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

Locations
Austria
Allgemeines Krankenhaus der Stadt Wien Recruiting
Vienna, Austria, A-1090
Contact: Contact Person    43-1-4040-2726      
Belgium
Hopital Universitaire Brugmann Recruiting
Brussels, Belgium
Universitair Ziekenhuis Gent Recruiting
Gent, Belgium
AZ Groeninge Kortrijk - Campus Kennedylaan Recruiting
Kortrijk, Belgium
AZ Turnhout - Campus Sint Elisabeth Recruiting
Turnhout, Belgium
Centre Hospitalier Peltzer-La Tourelle Recruiting
Verviers, Belgium
France
Institut Sainte Catherine Recruiting
Avignon, France
Institut Bergonie Recruiting
Bordeaux, France
CHU Ambroise Pare Recruiting
Boulogne Billancourt, France, F-92104
Contact: Contact Person    33-149-095-000      
Assistance Publique - Hôpitaux de Paris - Hopital De Bicetre AP-HP Recruiting
Le Kremlin Bicetre, France
Centre Hospitalier Saint Joseph Saint Luc Recruiting
Lyon, France
Hopital Prive Jean Mermoz Recruiting
Lyon, France
Centre Leon Berard Recruiting
Lyon, France
Centre Antoine Lacassagne Recruiting
Nice, France
Groupe Hospitalier Diaconesses Croix Saint-Simon - Site Reuilly Recruiting
Paris, France
Hopital Europeen Georges Pompidou Recruiting
Paris, France, 75015
Contact: Contact Person    33-56-092-000      
CHU de Lyon - Centre Hospitalier Lyon Sud Recruiting
Pierre-Benite (lyon), France
CHU de Reims - Hôpital Robert Debré Recruiting
Reims, France
Hopital Charles Nicolle Recruiting
Rouen, France
CHU Saint-Etienne - CHU de Saint-Etienne - Hopital Nord Recruiting
Saint Priest en Jarez, France
Centre Hospitalier Privé Saint-Grégoire Recruiting
Saint-Gregoire, France
CHU d'Amiens - CHU Amiens - Hopital Sud Recruiting
Salouel, France
Netherlands
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis Recruiting
Amsterdam, Netherlands
Spain
Hospital General Vall D'Hebron Recruiting
Barcelona, Spain
Switzerland
Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie Recruiting
Geneve, Switzerland
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Amgen
Roche Pharma AG
Investigators
Study Chair: Bernard Nordlinger, Pr. C.H.U. AMBROISE PARE AP-HP, Boulogne-Billancourt, France
Study Chair: Stephane Benoist, Pr. HOPITAL DE BICETRE AP-HP, Le Kremlin Bicetre, France
  More Information

No publications provided

Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT01508000     History of Changes
Other Study ID Numbers: EORTC-40091, 2010-019238-29
Study First Received: January 9, 2012
Last Updated: July 30, 2014
Health Authority: Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Paul-Ehrlich-Institut
Norway: Norwegian Medicines Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
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 wild type
FOLFOX
Bevacizumab
Panitumumab
Randomized
Phase II
Perioperative treatment
Adjuvant
Neo-adjuvant
Surgery
Progression Free Survival

Additional relevant MeSH terms:
Rectal Diseases
Colorectal Neoplasms
Liver Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Liver Diseases
Neoplasms
Neoplasms by Site
Neoplastic Processes
Pathologic Processes
Antibodies, Monoclonal
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014