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Chemotherapy and Bevacizumab With or Without Radiofrequency Ablation in Treating Unresectable Liver Metastases in Patients With Colorectal Cancer

Primary Purpose

Colorectal Cancer, Metastatic Cancer

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
bevacizumab
FOLFOX regimen
fluorouracil
leucovorin calcium
oxaliplatin
conventional surgery
radiofrequency ablation
Sponsored by
European Organisation for Research and Treatment of Cancer - EORTC
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring liver metastases, stage IV colon cancer, stage IV rectal cancer

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Unresectable liver metastases secondary to colorectal adenocarcinoma, including: Metastases that cannot be radically resected due to size, location, or number of deposits Metastases invading right and left branches of hepatic artery or portal vein Metastases extended to the 3 main hepatic veins No detectable extra-hepatic disease Fewer than 10 metastatic deposits on liver Total metastatic involvement of liver no more than 50% Adequate treatment of all metastatic lesions deemed possible either by radiofrequency interstitial ablation (RFA) alone or by a combination of resection of resectable lesions and RFA of the remaining unresectable lesions Maximum diameter of 4 cm for lesions to be treated with RFA No maximum diameter of lesions to be resected as long as negative resection margins are obtainable If synchronous liver metastases, must have undergone prior resection of primary tumor PATIENT CHARACTERISTICS: Age 18 to 80 Performance status WHO 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count greater than 1,500/mm^3 Platelet count greater than 100,000/mm^3 No bleeding disorder or coagulopathy or need for full-dose anticoagulation Hepatic Bilirubin less than 3 times upper limit of normal (ULN) Alkaline phosphatase less than 3 times ULN Renal Creatinine less than 2 times ULN Protein < 0.5 g/24 hr urine collection if proteinuria positive by dipstick Cardiovascular No uncontrolled congestive heart failure No uncontrolled angina pectoris No uncontrolled hypertension No uncontrolled arrhythmia No myocardial infarction within the past 12 months No cerebrovascular accident or transient ischemic attack within the past 6 months Other Not pregnant or nursing Fertile patients must use effective contraception No greater than grade 1 peripheral neuropathy No significant neurologic or psychiatric disorder No active infection No contraindication to the use of fluorouracil, leucovorin calcium, oxaliplatin, or bevacizumab No other malignancy within the past 10 years except nonmelanoma skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy except for metastatic disease confined to the liver Prior fluorouracil, leucovorin calcium, and oxaliplatin allowed if administered for at least 3 courses (2 weeks each) but no longer than 3 months with at least stabilization of disease achieved Prior adjuvant chemotherapy for primary cancer allowed except for patients who received oxaliplatin and have been diagnosed with metastatic disease within 12 months after completion of adjuvant treatment Endocrine therapy Not specified Radiotherapy Not specified Surgery More than 28 days since major surgery or open biopsy past 28 days More than 28 days since significant traumatic injury Other No other concurrent investigational treatment No other concurrent anticancer therapy

Sites / Locations

  • Allgemeines Krankenhaus - Universitatskliniken
  • Ziekenhuis Netwerk Antwerpen Middelheim
  • Institut Jules Bordet
  • Universitair Ziekenhuis Antwerpen
  • Universitair Ziekenhuis Gent
  • Clinique Universitaire De Mont-Godinne
  • National Cancer Institute - Cairo
  • Centre Hospitalier Regional et Universitaire d'Angers
  • Centre Hospitalier Universitaire Ambroise Pare - Boulogne
  • Hopital Universitaire Hautepierre
  • Centre Alexis Vautrin
  • Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch
  • Kliniken Essen - Mitte
  • Klinikum der J.W. Goethe Universitaet
  • Staedtische Kliniken Frankfurt am Main - Hoechst
  • Klinikum der Universitaet Regensburg
  • National Institute of Oncology
  • Azienda Ospedaliera S. Camillo-Forlanini
  • Jeroen Bosch Ziekenhuis
  • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
  • Amphia Ziekenhuis - locatie Langendijk
  • Medisch Spectrum Twente
  • Atrium Medical Centre - Heerlen
  • Medisch Centrum Leeuwarden - Zuid
  • Academisch Ziekenhuis Maastricht
  • Universitair Medisch Centrum St. Radboud - Nijmegen
  • University Medical Center Utrecht
  • Maxima Medisch Centrum - Veldhoven
  • Sahlgrenska University Hospital at Gothenburg University
  • Karolinska University Hospital - Huddinge
  • Uppsala University Hospital
  • Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
  • Bristol Haematology and Oncology Centre
  • Leicester General Hospital
  • Royal Liverpool University Hospital
  • Cancer Research UK and University College London Cancer Trials Centre
  • University College of London Hospitals
  • Manchester Royal Infirmary
  • Clatterbridge Centre for Oncology NHS Trust
  • Churchill Hospital
  • Royal South Hants Hospital
  • Velindre Cancer Center at Velindre Hospital
  • Glan Clywd District General Hospital

Outcomes

Primary Outcome Measures

Survival rate as measured by Kaplan Meier method at 30 months

Secondary Outcome Measures

Overall survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
Progression-free survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
Toxicity as measured by CTC version 2.0 every 3 months for 30 months then every 6 months thereafter
Quality of life as measured by Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 at baseline, weeks 6, 12, 18, and 24, every 3 months for years 1-2 after start of treatment, then every 6 months thereafter
Response to treatment (arm II) as measured by RECIST criteria from start of treatment until disease progression

Full Information

First Posted
August 5, 2002
Last Updated
September 20, 2012
Sponsor
European Organisation for Research and Treatment of Cancer - EORTC
Collaborators
Arbeitsgruppe Lebermetastasen und Tumoren, Institute of Cancer Research, United Kingdom
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1. Study Identification

Unique Protocol Identification Number
NCT00043004
Brief Title
Chemotherapy and Bevacizumab With or Without Radiofrequency Ablation in Treating Unresectable Liver Metastases in Patients With Colorectal Cancer
Official Title
CLOCC Trial (Chemotherapy + Local Ablation Versus Chemotherapy) Randomized Phase II Study Of Local Treatment Of Liver Metastases By Radiofrequency Combined With Chemotherapy Versus Chemotherapy Alone In Patients With Unresectable Colorectal Liver Metastases
Study Type
Interventional

2. Study Status

Record Verification Date
September 2012
Overall Recruitment Status
Terminated
Why Stopped
low accrual
Study Start Date
May 2002 (undefined)
Primary Completion Date
June 2007 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
European Organisation for Research and Treatment of Cancer - EORTC
Collaborators
Arbeitsgruppe Lebermetastasen und Tumoren, Institute of Cancer Research, United Kingdom

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread by blocking blood flow. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiofrequency ablation uses high-frequency electric current to kill tumor cells. It is not yet known if chemotherapy is more effective with or without radiofrequency ablation in treating liver metastases. PURPOSE: This randomized phase II trial is studying combination chemotherapy, bevacizumab, and radiofrequency ablation to see how well they work compared to combination chemotherapy and bevacizumab alone in treating unresectable liver metastases in patients with colorectal cancer.
Detailed Description
OBJECTIVES: Primary Compare the 30-month overall survival rate of patients with unresectable liver metastases secondary to colorectal adenocarcinoma treated with chemotherapy and bevacizumab with or without radiofrequency interstitial ablation. Secondary Compare overall survival of patients treated with these regimens. Compare quality of life of patients treated with these regimens. Determine the health economics associated with this study. OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to treatment center, prior adjuvant chemotherapy for primary cancer (yes vs no), prior chemotherapy for liver metastases (yes vs no), and route of randomization (before surgery vs during surgery). Patients are randomized to 1 of 2 treatment arms. Arm I: Within 4 weeks of randomization, patients undergo radiofrequency interstitial ablation (RFA) with or without additional resection of resectable lesions. Within 8 weeks after RFA, patients receive chemotherapy and bevacizumab. Arm II: Within 4 weeks of randomization, patients receive chemotherapy and bevacizumab. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients in both arms receive one of the following chemotherapy and bevacizumab regimens to be determined by participating center: Regimen A: Patients receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5 and leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 24 hours on day 1 of weeks 1-6 and bevacizumab IV over 30-90 minutes on days 1 or 2, 15 or 16, and 29 or 30. Treatment repeats every 7 weeks for 4 courses. Regimen B: Patients receive oxaliplatin IV and leucovorin calcium IV over 2 hours on day 1 followed by fluorouracil IV continuously over 46 hours and bevacizumab IV over 30-90 minutes on day 1 or 3. Treatment repeats every 15 days for 12 courses. Regimen C: Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 22 hours on days 1 and 2 and bevacizumab IV over 30-90 minutes on day 1 or 3. Treatment repeats every 15 days for 12 courses. Quality of life is assessed at baseline, within 1 week after completion of RFA (arm I only), within 1 week before start of chemotherapy (arm I only), at weeks 6, 12, 18, and 24 during chemotherapy, every 3 months for 2 years after treatment, and then every 6 months thereafter. After completion of study treatment, patients are followed every 3 months for 2½ years and then every 6 months thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK PROJECTED ACCRUAL: A total of 152 patients (71 per treatment arm) will be accrued for this study within 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer, Metastatic Cancer
Keywords
liver metastases, stage IV colon cancer, stage IV rectal cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Masking
None (Open Label)
Allocation
Randomized
Enrollment
119 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
bevacizumab
Intervention Type
Drug
Intervention Name(s)
FOLFOX regimen
Intervention Type
Drug
Intervention Name(s)
fluorouracil
Intervention Type
Drug
Intervention Name(s)
leucovorin calcium
Intervention Type
Drug
Intervention Name(s)
oxaliplatin
Intervention Type
Procedure
Intervention Name(s)
conventional surgery
Intervention Type
Procedure
Intervention Name(s)
radiofrequency ablation
Primary Outcome Measure Information:
Title
Survival rate as measured by Kaplan Meier method at 30 months
Secondary Outcome Measure Information:
Title
Overall survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
Title
Progression-free survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
Title
Toxicity as measured by CTC version 2.0 every 3 months for 30 months then every 6 months thereafter
Title
Quality of life as measured by Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 at baseline, weeks 6, 12, 18, and 24, every 3 months for years 1-2 after start of treatment, then every 6 months thereafter
Title
Response to treatment (arm II) as measured by RECIST criteria from start of treatment until disease progression

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Unresectable liver metastases secondary to colorectal adenocarcinoma, including: Metastases that cannot be radically resected due to size, location, or number of deposits Metastases invading right and left branches of hepatic artery or portal vein Metastases extended to the 3 main hepatic veins No detectable extra-hepatic disease Fewer than 10 metastatic deposits on liver Total metastatic involvement of liver no more than 50% Adequate treatment of all metastatic lesions deemed possible either by radiofrequency interstitial ablation (RFA) alone or by a combination of resection of resectable lesions and RFA of the remaining unresectable lesions Maximum diameter of 4 cm for lesions to be treated with RFA No maximum diameter of lesions to be resected as long as negative resection margins are obtainable If synchronous liver metastases, must have undergone prior resection of primary tumor PATIENT CHARACTERISTICS: Age 18 to 80 Performance status WHO 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count greater than 1,500/mm^3 Platelet count greater than 100,000/mm^3 No bleeding disorder or coagulopathy or need for full-dose anticoagulation Hepatic Bilirubin less than 3 times upper limit of normal (ULN) Alkaline phosphatase less than 3 times ULN Renal Creatinine less than 2 times ULN Protein < 0.5 g/24 hr urine collection if proteinuria positive by dipstick Cardiovascular No uncontrolled congestive heart failure No uncontrolled angina pectoris No uncontrolled hypertension No uncontrolled arrhythmia No myocardial infarction within the past 12 months No cerebrovascular accident or transient ischemic attack within the past 6 months Other Not pregnant or nursing Fertile patients must use effective contraception No greater than grade 1 peripheral neuropathy No significant neurologic or psychiatric disorder No active infection No contraindication to the use of fluorouracil, leucovorin calcium, oxaliplatin, or bevacizumab No other malignancy within the past 10 years except nonmelanoma skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy except for metastatic disease confined to the liver Prior fluorouracil, leucovorin calcium, and oxaliplatin allowed if administered for at least 3 courses (2 weeks each) but no longer than 3 months with at least stabilization of disease achieved Prior adjuvant chemotherapy for primary cancer allowed except for patients who received oxaliplatin and have been diagnosed with metastatic disease within 12 months after completion of adjuvant treatment Endocrine therapy Not specified Radiotherapy Not specified Surgery More than 28 days since major surgery or open biopsy past 28 days More than 28 days since significant traumatic injury Other No other concurrent investigational treatment No other concurrent anticancer therapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Theo Ruers, MD
Organizational Affiliation
Universitair Medisch Centrum St. Radboud - Nijmegen
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Wolf O. Bechstein, MD
Organizational Affiliation
Arbeitsgruppe Lebermetastasen und Tumoren
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jonathan A. Ledermann, MD
Organizational Affiliation
Cancer Research UK
Official's Role
Study Chair
Facility Information:
Facility Name
Allgemeines Krankenhaus - Universitatskliniken
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
Ziekenhuis Netwerk Antwerpen Middelheim
City
Antwerp
ZIP/Postal Code
2020
Country
Belgium
Facility Name
Institut Jules Bordet
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
Facility Name
Universitair Ziekenhuis Antwerpen
City
Edegem
ZIP/Postal Code
B-2650
Country
Belgium
Facility Name
Universitair Ziekenhuis Gent
City
Ghent
ZIP/Postal Code
B-9000
Country
Belgium
Facility Name
Clinique Universitaire De Mont-Godinne
City
Mont-Godinne Yvoir
ZIP/Postal Code
5530
Country
Belgium
Facility Name
National Cancer Institute - Cairo
City
Cairo
Country
Egypt
Facility Name
Centre Hospitalier Regional et Universitaire d'Angers
City
Angers
ZIP/Postal Code
49033
Country
France
Facility Name
Centre Hospitalier Universitaire Ambroise Pare - Boulogne
City
Boulogne Billancourt
ZIP/Postal Code
F-92104
Country
France
Facility Name
Hopital Universitaire Hautepierre
City
Strasbourg
ZIP/Postal Code
67098
Country
France
Facility Name
Centre Alexis Vautrin
City
Vandoeuvre-les-Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch
City
Berlin
ZIP/Postal Code
D-13122
Country
Germany
Facility Name
Kliniken Essen - Mitte
City
Essen
ZIP/Postal Code
D-45136
Country
Germany
Facility Name
Klinikum der J.W. Goethe Universitaet
City
Frankfurt
ZIP/Postal Code
D-60590
Country
Germany
Facility Name
Staedtische Kliniken Frankfurt am Main - Hoechst
City
Frankfurt
ZIP/Postal Code
D-65929
Country
Germany
Facility Name
Klinikum der Universitaet Regensburg
City
Regensburg
ZIP/Postal Code
D-93053
Country
Germany
Facility Name
National Institute of Oncology
City
Budapest
ZIP/Postal Code
1122
Country
Hungary
Facility Name
Azienda Ospedaliera S. Camillo-Forlanini
City
Rome
ZIP/Postal Code
00152
Country
Italy
Facility Name
Jeroen Bosch Ziekenhuis
City
's-Hertogenbosch
ZIP/Postal Code
5211 NL
Country
Netherlands
Facility Name
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Amphia Ziekenhuis - locatie Langendijk
City
Breda
ZIP/Postal Code
4800 RL
Country
Netherlands
Facility Name
Medisch Spectrum Twente
City
Enschede
ZIP/Postal Code
7500 KA
Country
Netherlands
Facility Name
Atrium Medical Centre - Heerlen
City
Heerlen
ZIP/Postal Code
6401 CX
Country
Netherlands
Facility Name
Medisch Centrum Leeuwarden - Zuid
City
Leeuwarden
ZIP/Postal Code
8934 AD
Country
Netherlands
Facility Name
Academisch Ziekenhuis Maastricht
City
Maastricht
ZIP/Postal Code
6202 AZ
Country
Netherlands
Facility Name
Universitair Medisch Centrum St. Radboud - Nijmegen
City
Nijmegen
ZIP/Postal Code
NL-6500 HB
Country
Netherlands
Facility Name
University Medical Center Utrecht
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
Maxima Medisch Centrum - Veldhoven
City
Veldhoven
ZIP/Postal Code
5500 MB
Country
Netherlands
Facility Name
Sahlgrenska University Hospital at Gothenburg University
City
Gothenburg (Goteborg)
ZIP/Postal Code
S-413 45
Country
Sweden
Facility Name
Karolinska University Hospital - Huddinge
City
Stockholm
ZIP/Postal Code
S - 141 86
Country
Sweden
Facility Name
Uppsala University Hospital
City
Uppsala
ZIP/Postal Code
SE 75185
Country
Sweden
Facility Name
Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
City
Birmingham
State/Province
England
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Facility Name
Bristol Haematology and Oncology Centre
City
Bristol
State/Province
England
ZIP/Postal Code
BS2 8ED
Country
United Kingdom
Facility Name
Leicester General Hospital
City
Leicester
State/Province
England
ZIP/Postal Code
LE5 4PW
Country
United Kingdom
Facility Name
Royal Liverpool University Hospital
City
Liverpool
State/Province
England
ZIP/Postal Code
L69 3GA
Country
United Kingdom
Facility Name
Cancer Research UK and University College London Cancer Trials Centre
City
London
State/Province
England
ZIP/Postal Code
NW1 2ND
Country
United Kingdom
Facility Name
University College of London Hospitals
City
London
State/Province
England
ZIP/Postal Code
WIT 3AA
Country
United Kingdom
Facility Name
Manchester Royal Infirmary
City
Manchester
State/Province
England
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Facility Name
Clatterbridge Centre for Oncology NHS Trust
City
Merseyside
State/Province
England
ZIP/Postal Code
CH63 4JY
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
State/Province
England
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom
Facility Name
Royal South Hants Hospital
City
Southampton
State/Province
England
ZIP/Postal Code
SO14 0YG
Country
United Kingdom
Facility Name
Velindre Cancer Center at Velindre Hospital
City
Cardiff
State/Province
Wales
ZIP/Postal Code
CF14 2TL
Country
United Kingdom
Facility Name
Glan Clywd District General Hospital
City
Rhyl, Denbighshire
State/Province
Wales
ZIP/Postal Code
LL 18 5UJ
Country
United Kingdom

12. IPD Sharing Statement

Citations:
Citation
Ruers T, van Coevorden F, Pierie J, et al.: Radiofrequency ablation (RFA) combined with chemotherapy for unresectable colorectal liver metastases (CRC LM): interim results of a randomised phase II study of the EORTC-NCRI CCSG-ALM Intergroup 40004 (CLOCC). [Abstract] J Clin Oncol 26 (Suppl 15): A-9535, 2008.
Results Reference
result
PubMed Identifier
22431703
Citation
Ruers T, Punt C, Van Coevorden F, Pierie JPEN, Borel-Rinkes I, Ledermann JA, Poston G, Bechstein W, Lentz MA, Mauer M, Van Cutsem E, Lutz MP, Nordlinger B; EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol. 2012 Oct;23(10):2619-2626. doi: 10.1093/annonc/mds053. Epub 2012 Mar 19.
Results Reference
derived

Learn more about this trial

Chemotherapy and Bevacizumab With or Without Radiofrequency Ablation in Treating Unresectable Liver Metastases in Patients With Colorectal Cancer

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