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

This study has been terminated.
(Low or poor accrual)
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: January 28, 2016
Last verified: January 2016
  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.


Enrollment: 44
Study Start Date: June 2013
Estimated Study Completion Date: December 2016
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: 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   (Adult, Senior)
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

Locations
Austria
Allgemeines Krankenhaus der Stadt Wien
Vienna, Austria, A-1090
Belgium
Hopital Universitaire Brugmann
Brussels, Belgium
Universitair Ziekenhuis Gent
Gent, Belgium
AZ Groeninge Kortrijk - Campus Kennedylaan
Kortrijk, Belgium
AZ Turnhout - Campus Sint Elisabeth
Turnhout, Belgium
Centre Hospitalier Peltzer-La Tourelle
Verviers, Belgium
France
Institut Sainte Catherine
Avignon, France
Institut Bergonie
Bordeaux, France
CHU Ambroise Pare
Boulogne Billancourt, France, F-92104
Assistance Publique - Hôpitaux de Paris - Hopital De Bicetre AP-HP
Le Kremlin Bicetre, France
Centre Hospitalier Saint Joseph Saint Luc
Lyon, France
Centre Leon Berard
Lyon, France
Hopital Prive Jean Mermoz
Lyon, France
Centre Antoine Lacassagne
Nice, France
Hopital Europeen Georges Pompidou
Paris, France, 75015
Groupe Hospitalier Diaconesses Croix Saint-Simon - Site Reuilly
Paris, France
CHU de Lyon - Centre Hospitalier Lyon Sud
Pierre-Benite (lyon), France
CHU de Reims - Hôpital Robert Debré
Reims, France
Hopital Charles Nicolle
Rouen, France
CHU Saint-Etienne - CHU de Saint-Etienne - Hopital Nord
Saint Priest en Jarez, France
Centre Hospitalier Privé Saint-Grégoire
Saint-Gregoire, France
CHU d'Amiens - CHU Amiens - Hopital Sud
Salouel, France
Netherlands
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
Amsterdam, Netherlands
Spain
Hospital General Vall D'Hebron
Barcelona, Spain
Switzerland
Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie
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

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: January 28, 2016
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:
Colorectal Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Liver Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Liver Diseases
Bevacizumab
Oxaliplatin
Leucovorin
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors
Antidotes
Protective Agents

ClinicalTrials.gov processed this record on August 25, 2016