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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. completion date
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


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
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