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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00043004
• Other study ID #: EORTC-40004
• Secondary ID: EORTC-40004ALM-C
• Status: Terminated
• Phase: Phase 2
• First received: August 5, 2002
• Last updated: September 20, 2012
• Start date: May 2002

Study information

• Verified date: September 2012
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 119
• Est. primary completion date: June 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Metastatic Cancer
• Neoplasm Metastasis

Intervention

Biological:
• bevacizumab

Drug:
• FOLFOX regimen

• fluorouracil

• leucovorin calcium

• oxaliplatin

Procedure:
• conventional surgery

• radiofrequency ablation

Locations

Country	Name	City	State
Austria	Allgemeines Krankenhaus - Universitatskliniken	Vienna
Belgium	Ziekenhuis Netwerk Antwerpen Middelheim	Antwerp
Belgium	Institut Jules Bordet	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	Universitair Ziekenhuis Gent	Ghent
Belgium	Clinique Universitaire De Mont-Godinne	Mont-Godinne Yvoir
Egypt	National Cancer Institute - Cairo	Cairo
France	Centre Hospitalier Regional et Universitaire d'Angers	Angers
France	Centre Hospitalier Universitaire Ambroise Pare - Boulogne	Boulogne Billancourt
France	Hopital Universitaire Hautepierre	Strasbourg
France	Centre Alexis Vautrin	Vandoeuvre-les-Nancy
Germany	Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch	Berlin
Germany	Kliniken Essen - Mitte	Essen
Germany	Klinikum der J.W. Goethe Universitaet	Frankfurt
Germany	Staedtische Kliniken Frankfurt am Main - Hoechst	Frankfurt
Germany	Klinikum der Universitaet Regensburg	Regensburg
Hungary	National Institute of Oncology	Budapest
Italy	Azienda Ospedaliera S. Camillo-Forlanini	Rome
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam
Netherlands	Amphia Ziekenhuis - locatie Langendijk	Breda
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Atrium Medical Centre - Heerlen	Heerlen
Netherlands	Medisch Centrum Leeuwarden - Zuid	Leeuwarden
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
Netherlands	Universitair Medisch Centrum St. Radboud - Nijmegen	Nijmegen
Netherlands	University Medical Center Utrecht	Utrecht
Netherlands	Maxima Medisch Centrum - Veldhoven	Veldhoven
Sweden	Sahlgrenska University Hospital at Gothenburg University	Gothenburg (Goteborg)
Sweden	Karolinska University Hospital - Huddinge	Stockholm
Sweden	Uppsala University Hospital	Uppsala
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Birmingham	England
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	England
United Kingdom	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales
United Kingdom	Leicester General Hospital	Leicester	England
United Kingdom	Royal Liverpool University Hospital	Liverpool	England
United Kingdom	Cancer Research UK and University College London Cancer Trials Centre	London	England
United Kingdom	University College of London Hospitals	London	England
United Kingdom	Manchester Royal Infirmary	Manchester	England
United Kingdom	Clatterbridge Centre for Oncology NHS Trust	Merseyside	England
United Kingdom	Churchill Hospital	Oxford	England
United Kingdom	Glan Clywd District General Hospital	Rhyl, Denbighshire	Wales
United Kingdom	Royal South Hants Hospital	Southampton	England

Sponsors (3)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Arbeitsgruppe Lebermetastasen und Tumoren, Institute of Cancer Research, United Kingdom

Countries where clinical trial is conducted

Austria,  Belgium,  Egypt,  France,  Germany,  Hungary,  Italy,  Netherlands,  Sweden,  United Kingdom, 

References & Publications (1)

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).

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival rate as measured by Kaplan Meier method at 30 months			No
Secondary	Overall survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter			No
Secondary	Progression-free survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter			No
Secondary	Toxicity as measured by CTC version 2.0 every 3 months for 30 months then every 6 months thereafter			Yes
Secondary	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			No
Secondary	Response to treatment (arm II) as measured by RECIST criteria from start of treatment until disease progression			No