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Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

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ClinicalTrials.gov Identifier: NCT00659022
Recruitment Status : Unknown
Verified February 2009 by Radboud University.
Recruitment status was:  Recruiting
First Posted : April 16, 2008
Last Update Posted : September 12, 2011
Sponsor:
Information provided by:
Radboud University

Brief Summary:

Study Hypothesis

• As well as in animal models as in patients with colorectal cancer resection of the primary tumor resulted in increase in vascular density, metabolism and secondary tumor growth of the distant metastases. These data strongly suggest an inhibitory effect of the primary tumor on the outgrowth of its metastases.

In this study we investigate whether pre-operative treatment with the anti-angiogenic agent bevacizumab and/or chemotherapy before resection of the primary colorectal tumor shifts the balance between angiogenic and anti-angiogenic factors in favor of the anti-angiogenic factors and results in reduced growth of the liver metastases.

Eligibility

  • Histological proven colorectal cancer without signs of bowel obstruction or bleeding
  • Synchronous liver metastases
  • WHO performance status 0-1

Treatment

  • Arm A: immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
  • Arm B: neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
  • Arm C: neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
  • Arm D: neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary

Primary endpoint Difference in response of liver metastases to resection of the primary tumor between the experimental groups and the control group, as determined by histopathological scoring of vascular density, apoptotic and mitotic index and by measurement of the metabolic activity of liver metastases by FDG-PET and SUV measurements.

Secondary endpoints Toxicity of neo-adjuvant treatment Complications of surgery


Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Liver Neoplasms Procedure: immediate surgery (resection of primary colorectal tumor) Drug: neo-adjuvant treatment with bevacizumab Drug: neoadjuvant treatment with capecitabine and oxaliplatin Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy
Study Start Date : July 2008
Estimated Primary Completion Date : March 2014
Estimated Study Completion Date : April 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: A
immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
Procedure: immediate surgery (resection of primary colorectal tumor)
no neo-adjuvant treatment, immediate surgery

Experimental: B
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
Drug: neo-adjuvant treatment with bevacizumab
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
Other Name: Avastin

Experimental: C
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
Drug: neoadjuvant treatment with capecitabine and oxaliplatin
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
Other Names:
  • Xeloda
  • Eloxatin

Experimental: D
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Other Names:
  • Avastin
  • Xeloda
  • Eloxatin




Primary Outcome Measures :
  1. Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index [ Time Frame: 12 weeks ]
  2. Difference in response of liver metastases between control group and experimental groups determined by FDG-PET [ Time Frame: 12 weeks ]

Secondary Outcome Measures :
  1. Toxicity of neo-adjuvant treatment [ Time Frame: 12 weeks ]
  2. Complications of surgery [ Time Frame: 4 weeks ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with histological proven primary colorectal cancer and synchronous unresectable liver metastases with or without additional extrahepatic disease (primary tumor in situ). Unresectable liver metastases defined as too extensive hepatic involvement or extrahepatic disease.
  • Measurable liver metastases on CT scan (RECIST), positive signal of liver metastases on FDG-PET scan
  • Age: 18-80 years
  • WHO performance scale 0-1
  • ASA category I or II
  • Negative pregnancy test in women with childbearing potential
  • Life expectancy > 12 weeks
  • Laboratory values obtained ≤ 3 weeks prior to study entry, disease evaluation performed ≤ 3 weeks prior to study entry. Adequate bone marrow function (Hb > 6.5 mmol/L, absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L), renal function (serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated according to Cockroft and Gault), liver function (ASAT and ALAT ≤ 3 x upper normal limit, serum bilirubin ≤ 2 x upper normal limit)
  • Written informed consent

Exclusion Criteria:

  • Signs of bowel obstruction or bleeding from primary tumor
  • Prior chemotherapy treatment for advanced disease, prior treatment with anti-angiogenic drugs
  • Resectable liver metastases
  • Diabetes mellitus
  • Continuous use of immunosuppressive agents
  • Pregnancy or lactation
  • Contra-indications for systemic therapy with bevacizumab (Avastin)/ chemotherapy (Xelox)
  • Concurrent severe or uncontrolled disease (i.e. uncontrolled hypertension, congestive heart failure, myocardial infarction < 12 months, chronic active infection)
  • Sensory neuropathy > grade 1
  • Serious non-healing wound or ulcer
  • Patients (M/F) with reproductive potential not implementing adequate contraceptive measures
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to start of bevacizumab
  • Bleeding disorders or coagulopathy or need for full-dose anticoagulation
  • Signs or symptoms of brain metastases
  • Cerebrovascular accident or transient ischemic attack within the past 12 months
  • Impairment of gastrointestinal function or -disease that may significantly impair the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow tablets)
  • Presence of proteinuria at baseline as defined by: patients with > 1 g of protein/24 hr by a 24-hour urine collection.
  • Any concomitant disorder preventing the safe administration of study drugs or surgical procedure.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00659022


Contacts
Contact: Patricia Bottenberg, Ma ANP +31-20-5122639 p.bottenberg@nki.nl
Contact: Theo Ruers, PhD +31-20-5122538 t.ruers@nki.nl

Locations
Netherlands
The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Theo Ruers, PhD    +31-20-5122538    t.ruers@nki.nl   
Radboud University Nijmegen Medical Center Recruiting
Nijmegen, Netherlands, 6500 HB
Contact: Kees Punt, PhD    +31-24-3610353    C.Punt@onco.umcn.nl   
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Theo Ruers, PhD The Netherlands Cancer Institute
Principal Investigator: Kees Punt, PhD Radboud University Nijmegen Medical Center
Principal Investigator: Wim Oyen, PhD Radboud University Nijmegen Medical Center

Publications:

Responsible Party: T.J.M Ruers, PhD, The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital Amsterdam
ClinicalTrials.gov Identifier: NCT00659022     History of Changes
Other Study ID Numbers: SILENT
First Posted: April 16, 2008    Key Record Dates
Last Update Posted: September 12, 2011
Last Verified: February 2009

Keywords provided by Radboud University:
colorectal cancer
liver metastases
angiogenesis
metabolism

Additional relevant MeSH terms:
Neoplasms
Colorectal Neoplasms
Liver Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Liver Diseases
Bevacizumab
Oxaliplatin
Capecitabine
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action