Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth
Primary Purpose
Colorectal Neoplasms, Liver Neoplasms
Status
Unknown status
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
immediate surgery (resection of primary colorectal tumor)
neo-adjuvant treatment with bevacizumab
neoadjuvant treatment with capecitabine and oxaliplatin
neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Neoplasms focused on measuring colorectal cancer, liver metastases, angiogenesis, metabolism
Eligibility 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.
Sites / Locations
- The Netherlands Cancer Institute/ Antoni van Leeuwenhoek HospitalRecruiting
- Radboud University Nijmegen Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Experimental
Experimental
Experimental
Arm Label
A
B
C
D
Arm Description
immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Outcomes
Primary Outcome Measures
Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index
Difference in response of liver metastases between control group and experimental groups determined by FDG-PET
Secondary Outcome Measures
Toxicity of neo-adjuvant treatment
Complications of surgery
Full Information
NCT ID
NCT00659022
First Posted
April 3, 2008
Last Updated
September 9, 2011
Sponsor
Radboud University Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT00659022
Brief Title
Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth
Official Title
Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
February 2009
Overall Recruitment Status
Unknown status
Study Start Date
July 2008 (undefined)
Primary Completion Date
March 2014 (Anticipated)
Study Completion Date
April 2014 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
Radboud University Medical Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Neoplasms, Liver Neoplasms
Keywords
colorectal cancer, liver metastases, angiogenesis, metabolism
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Active Comparator
Arm Description
immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
Arm Title
B
Arm Type
Experimental
Arm Description
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
Arm Title
C
Arm Type
Experimental
Arm Description
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
Arm Title
D
Arm Type
Experimental
Arm Description
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Intervention Type
Procedure
Intervention Name(s)
immediate surgery (resection of primary colorectal tumor)
Intervention Description
no neo-adjuvant treatment, immediate surgery
Intervention Type
Drug
Intervention Name(s)
neo-adjuvant treatment with bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
Intervention Type
Drug
Intervention Name(s)
neoadjuvant treatment with capecitabine and oxaliplatin
Other Intervention Name(s)
Xeloda, Eloxatin
Intervention Description
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
Intervention Type
Drug
Intervention Name(s)
neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin
Other Intervention Name(s)
Avastin, Xeloda, Eloxatin
Intervention Description
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Primary Outcome Measure Information:
Title
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
Title
Difference in response of liver metastases between control group and experimental groups determined by FDG-PET
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Toxicity of neo-adjuvant treatment
Time Frame
12 weeks
Title
Complications of surgery
Time Frame
4 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Patricia Bottenberg, Ma ANP
Phone
+31-20-5122639
Email
p.bottenberg@nki.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Theo Ruers, PhD
Phone
+31-20-5122538
Email
t.ruers@nki.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Theo Ruers, PhD
Organizational Affiliation
The Netherlands Cancer Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kees Punt, PhD
Organizational Affiliation
Radboud University Nijmegen Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Wim Oyen, PhD
Organizational Affiliation
Radboud University Nijmegen Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Theo Ruers, PhD
Phone
+31-20-5122538
Email
t.ruers@nki.nl
Facility Name
Radboud University Nijmegen Medical Center
City
Nijmegen
ZIP/Postal Code
6500 HB
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kees Punt, PhD
Phone
+31-24-3610353
Email
C.Punt@onco.umcn.nl
12. IPD Sharing Statement
Citations:
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7287231
Citation
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Results Reference
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PubMed Identifier
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Citation
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Citation
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Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth
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