Colorectal NeoplasmsPhase 2NCT00659022
Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth
A Phase 2 study testing immediate surgery (resection of primary colorectal tumor), neo-adjuvant treatment with bevacizumab and neoadjuvant treatment with capecitabine and oxaliplatin in people with Colorectal Neoplasms and Liver Neoplasms, run by Radboud University Medical Center at 2 sites in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Colorectal Neoplasms, Liver Neoplasms
- What is being tested?
- immediate surgery (resection of primary colorectal tumor), neo-adjuvant treatment with bevacizumab and neoadjuvant treatment with capecitabine and oxaliplatin
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 2 sitesNetherlands
- Study dates
- Jul 2008to Apr 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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.
Trial locations and contacts
2 sites in 1 country.
Netherlands2 sites, 2 recruiting
- Recruiting
The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital
Amsterdam, 1066 CX
Theo Ruers, PhD, +31-20-5122538, t.ruers@nki.nl
- Recruiting
Radboud University Nijmegen Medical Center
Nijmegen, 6500 HB
Kees Punt, PhD, +31-24-3610353, C.Punt@onco.umcn.nl
About this study
Official title: Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy
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.
Read more
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
- Conditions
- Colorectal Neoplasms, Liver Neoplasms
- Being tested
- 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
- Keywords
- colorectal cancer, liver metastases, angiogenesis, metabolism
- Medical subject headings
- Colorectal Neoplasms, Liver Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
immediate surgery (resection of primary colorectal tumor)Procedure or surgery
no neo-adjuvant treatment, immediate surgery
neo-adjuvant treatment with bevacizumabDrug
Also called Avastin
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with capecitabine and oxaliplatinDrug
Also called Xeloda, Eloxatin
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatinDrug
Also called Avastin, Xeloda, Eloxatin
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
| Study group | Role | What they receive |
|---|---|---|
| A | Active comparator | immediate surgery of the primary colorectal tumor, no neoadjuvant therapy Receives: Procedure: immediate surgery (resection of primary colorectal tumor) |
| B | Experimental | neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary Receives: Drug: neo-adjuvant treatment with bevacizumab |
| C | Experimental | neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary Receives: Drug: neoadjuvant treatment with capecitabine and oxaliplatin |
| D | Experimental | neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary Receives: Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index
Measured: 12 weeks
Difference in response of liver metastases between control group and experimental groups determined by FDG-PET
Measured: 12 weeks
Secondary outcomes (2)
Toxicity of neo-adjuvant treatment
Measured: 12 weeks
Complications of surgery
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2008 (estimated)
- Study startJul 2008
- Primary completionMar 2014 (estimated)
- Study completionApr 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Colorectal NeoplasmsStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Investigators
- Theo Ruers, PhD, Principal investigator, The Netherlands Cancer InstituteKees Punt, PhD, Principal investigator, Radboud University Nijmegen Medical CenterWim Oyen, PhD, Principal investigator, Radboud University Nijmegen Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00659022
- Sponsor's protocol ID
- SILENT
- Status last verified
- Feb 2009
- First submitted
- 3 Apr 2008
- Last updated
- 12 Sep 2011
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Gorelik E, Segal S, Feldman M. On the mechanism of tumor "concomitant immunity". Int J Cancer. 1981 Jun 15;27(6):847-56. doi: 10.1002/ijc.2910270618. No abstract available.
PubMed 7287231O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315-28. doi: 10.1016/0092-8674(94)90200-3.
PubMed 7525077O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277-85. doi: 10.1016/s0092-8674(00)81848-6.
PubMed 9008168Peeters CF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T, Ruers TJ. Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer. 2004 Nov 20;112(4):554-9. doi: 10.1002/ijc.20374.
PubMed 15382035Yang AD, Bauer TW, Camp ER, Somcio R, Liu W, Fan F, Ellis LM. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer. 2005 Apr 15;103(8):1561-70. doi: 10.1002/cncr.20942.
PubMed 15754332Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004 Oct;4(10):806-13. doi: 10.1038/nrc1456.
PubMed 15510161Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004 Jun 1;64(11):3731-6. doi: 10.1158/0008-5472.CAN-04-0074.
PubMed 15172975Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005 Jan 7;307(5706):58-62. doi: 10.1126/science.1104819.
PubMed 15637262
Study at a glance
From the registry record, last updated by the sponsor on 12 Sep 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy
- ClinicalTrials.gov ID
- NCT00659022
- Acronym / sponsor ID
- SILENT
- Conditions
- Colorectal Neoplasms, Liver Neoplasms
- Keywords
- colorectal cancer, liver metastases, angiogenesis, metabolism
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Jul 2008
- Primary completion
- Mar 2014 (estimated)
- Study completion
- Apr 2014 (estimated)
- First posted
- 16 Apr 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| A | Active comparator | Procedure: immediate surgery (resection of primary colorectal tumor)immediate surgery of the primary colorectal tumor, no neoadjuvant therapy |
| B | Experimental | Drug: neo-adjuvant treatment with bevacizumabneoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary |
| C | Experimental | Drug: neoadjuvant treatment with capecitabine and oxaliplatinneoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary |
| D | Experimental | Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatinneoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (18 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| immediate surgery (resection of primary colorectal tumor)no neo-adjuvant treatment, immediate surgery | Procedure or surgery | A |
| neo-adjuvant treatment with bevacizumabAlso: Avastinneoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary | Drug | B |
| neoadjuvant treatment with capecitabine and oxaliplatinAlso: Xeloda, Eloxatinneoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary | Drug | C |
| neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatinAlso: Avastin, Xeloda, Eloxatinneoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary | Drug | D |
Primary outcome
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
Difference in response of liver metastases between control group and experimental groups determined by FDG-PET
Time frame: 12 weeks
2 secondary outcomes
Toxicity of neo-adjuvant treatment
Time frame: 12 weeks
Complications of surgery
Time frame: 4 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Sep 2011.
- Background: PubMed 7287231Gorelik E, Segal S, Feldman M. On the mechanism of tumor "concomitant immunity". Int J Cancer. 1981 Jun 15;27(6):847-56. doi: 10.1002/ijc.2910270618. No abstract available.
- Background: PubMed 7525077O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315-28. doi: 10.1016/0092-8674(94)90200-3.
- Background: PubMed 9008168O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277-85. doi: 10.1016/s0092-8674(00)81848-6.
- Background: PubMed 15382035Peeters CF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T, Ruers TJ. Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer. 2004 Nov 20;112(4):554-9. doi: 10.1002/ijc.20374.
- Background: PubMed 15754332Yang AD, Bauer TW, Camp ER, Somcio R, Liu W, Fan F, Ellis LM. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer. 2005 Apr 15;103(8):1561-70. doi: 10.1002/cncr.20942.
- Background: PubMed 15510161Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004 Oct;4(10):806-13. doi: 10.1038/nrc1456.
- Background: PubMed 15172975Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004 Jun 1;64(11):3731-6. doi: 10.1158/0008-5472.CAN-04-0074.
- Background: PubMed 15637262Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005 Jan 7;307(5706):58-62. doi: 10.1126/science.1104819.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Theo Ruers, PhD principal investigator
The Netherlands Cancer Institute
Kees Punt, PhD principal investigator
Radboud University Nijmegen Medical Center
Wim Oyen, PhD principal investigator
Radboud University Nijmegen Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing immediate surgery (resection of primary colorectal tumor), neo-adjuvant treatment with bevacizumab and neoadjuvant treatment with capecitabine and oxaliplatin in people with Colorectal Neoplasms and Liver Neoplasms, run by Radboud University Medical Center at 2 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 12 Sep 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Patricia Bottenberg, Ma ANP (+31-20-5122639, p.bottenberg@nki.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00659022, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2011.