Colorectal CancerPhase 3NCT00394992
Adjuvant Xeloda Plus Eloxatin +/- Avastin After Radical Resection of Liver Metastasis of Colorectal Cancer
A Phase 3 study testing oxaliplatin+capecitabine and Oxaliplatin+capecitabine+bevacizumab in people with Colorectal Cancer and Liver Metastases, run by Dutch Colorectal Cancer Group at 1 site in Netherlands.
Trial summary
The primary aim of this study is to investigate whether the addition of the new anti-cancer drug bevacizumab (Avastin) to the combination of the chemotherapeutic agents capecitabine (Xeloda) and oxaliplatin (Eloxatin) reduces (slows down) the recurrence of metastatic disease after a radical resection of liver… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Cancer, Liver Metastases
- What is being tested?
- oxaliplatin+capecitabine and Oxaliplatin+capecitabine+bevacizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 79 participants
- Where
- 1 siteNetherlands
- Study dates
- Dec 2006to Aug 2013
- Phase
- Phase 3
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed written informed consent obtained prior to any study-specific procedures.
- Age ≥ 18 years.
- Liver metastases radically resected (R0 resection).
- Study medication started ≥4 and ≤ 8 weeks post liver surgery.
- Histologically confirmed liver metastasis of colorectal cancer after surgery.
- ECOG performance status 0 or 1.
Show all 9Show fewer
- Adequate hematology: ANC ≥1.5 x 109/L, platelets ≥100 x 109/L, Hb ≥5.5 mmol/L, INR ≤ 1.5, APTT < 1.5 X UNL.
- Adequate biochemistry: total bilirubin ≤1.5 UNL, ASAT and ALAT ≤2.5 x UNL, alkaline phosphatase ≤2.5 x UNL, serum creatinine ≤1.5 UNL.
- Urine dipstick <2+ for protein.
Who cannot join
- Extrahepatic metastatic disease.
- Prior adjuvant chemotherapy given <6 months prior to detection of the liver metastases.
- Prior non colorectal malignancies.
- Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation.
- Major surgical procedure <4 weeks prior to start of study treatment.
- Females with a positive pregnancy test (within 14 days before treatment start) .
Show all 20Show fewer
- Lactating women.
- Fertile women (<2 years after last menstruation) and women of childbearing potential not willing to use effective means of contraception.
- History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.
- Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents (≤6 months prior to randomization), myocardial infarction (≤1 year prior to randomization), uncontrolled hypertension while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication.
- Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
- Known peripheral neuropathy, including oxaliplatin induced neuropathy > grade Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible.
- Organ allografts requiring immunosuppressive therapy.
- Serious, non-healing wound, ulcer, or bone fracture.
- Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
- Chronic, daily treatment with high-dose asprin (> 325 mg/day) or nonsteroidal anti-inflammatory medications (those known to inhibit platelet function at doses used to treat chronic inflammatory diseases). Patients can be rendered eligible by changing the treatment to COX II inhibitors.
- Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids).
- Serious intercurrent infections (uncontrolled or requiring treatment).
- Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
- Patients with known allergy to Chinese hamster Ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other component of the study drugs.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Randomized Phase III Study Post Radical Resection of Liver Metastasis of Colorectal Cancer: Bevacizumab in Combination With XELOX as Adjuvant Chemotherapy vs XELOX Alone
The primary aim of this study is to investigate whether the addition of the new anti-cancer drug bevacizumab (Avastin) to the combination of the chemotherapeutic agents capecitabine (Xeloda) and oxaliplatin (Eloxatin) reduces (slows down) the recurrence of metastatic disease after a radical resection of liver metastases in patients with colorectal cancer.
Read the detailed description
The primary therapy of colorectal cancer is surgical resection, but more than half of all colorectal cancer patients eventually die of metastatic disease. Although the introduction of new anticancer agents with efficacy in metastatic colorectal cancer, e.g.: oxaliplatin and irinotecan, and the targeted agents cetuximab and bevacizumab has changed therapeutic nihilism, chemotherapy alone has failed to cure these patients.
It is estimated that 15-20 % of colorectal cancer patients present with synchronous liver metastases and approximately 50% of the patients with colorectal tumors will develop liver metastases at some point during the course of their disease. In almost one third of the cases, the liver was shown at autopsy to be the only site of cancer spread. This is in accordance with the 20% - 45 % five-year survival obtained with surgical resection of hepatic metastases.
Previous studies have not shown a clear benefit of adjuvant chemotherapy after metastasectomy of liver metastases. However, most of these studies have been performed with 5-fluorouracil with or without other older cytostatic drugs. Since new effective agents have been developed (e.g.: capecitabine, oxaliplatin and bevacizumab), adjuvant combination treatment with these agents might be more effective. These drugs have proven activity as first line palliative treatment of recurrent metastases. This raises the question if this new effective treatment is of value as an adjuvant treatment after metastasectomy.
As mentioned before, a two-arm EORTC study: neoadjuvant and adjuvant FOLFOX vs no chemotherapy in resectable liver metastases of colorectal cancer is almost completed (Nordlinger et al). It is expected that this study will show a 10% 3 year DFS benefit in favour of th treatment arm. Definitive data of this trial will be released at the end of 2006, and will most probably lead to adjuvant treatment post metastasectomy as a standard of care. In the HEPATCIA trial we anticipate on this by using adjuvant XELOX as the control arm.
As mentioned earlier, the 3-year disease free survival in patients post metastasectomy of liver metastases is approximately 25%. There is no data available on the effectivity of the XELOX regimen as adjuvant treatment after metastasectomy of colorectal cancer metastases. The EORTC study was designed to demonstrate a 10% improvement in 3y DFS. Assuming that this study is positive, 3 year DFS would be 35% in the control arm (XELOX post liver resection).
Since bevacizumab inhibits angiogenesis, which is required for growth of metastases, this drug may be valuable in the adjuvant setting. Several studies investigate the value of this drug in combination with fluoropyrimidines as an adjuvant regimen after resection of primary colorectal cancers. However, at this moment there is no mature data available of these studies. Therefore, we assume an increase in 3-year disease free survival of 10%, to 45% in the XELOX and bevacizumab treatment arm.
This study will therefore evaluate patients with resectable liver metastasis without extra-hepatic disease, investigating whether the capecitabine, oxaliplatin and bevacizumab regimen is superior to capecitabine and oxaliplatin alone applied as adjuvant treatment, in order to extent disease free and overall survival.
- Conditions
- Colorectal Cancer, Liver Metastases
- Being tested
- oxaliplatin+capecitabine, Oxaliplatin+capecitabine+bevacizumab
- Keywords
- Colorectal cancer, Liver metastasis, Radical resection, Adjuvant therapy, Bevacizumab, Capecitabine, Oxaliplatin, Hepatica
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
oxaliplatin+capecitabineDrug
postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w
Oxaliplatin+capecitabine+bevacizumabDrug
postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w
| Study group | Role | What they receive |
|---|---|---|
| 1 oxaliplatin+capecitabine | Active comparator | postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w Receives: Drug: oxaliplatin+capecitabine |
| 2 oxaliplatin+capecitabine+bevacizumab | Experimental | postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w Receives: Drug: Oxaliplatin+capecitabine+bevacizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
3-year disease free survival, defined as the percentage of disease free patients 3 year after randomisation.
Measured: study duration
Secondary outcomes (1)
Overall survival, defined as the percentage of patients alive 5 year after randomisation.
Measured: study duration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Nov 2006 (estimated)
- Study startDec 2006
- Primary completionAug 2013
- Study completionAug 2013
Why it stopped: Data from the C08 study and Avant study
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Colorectal CancerStudies of the same condition, open and under way.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 79 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dutch Colorectal Cancer Group
- Sponsor type
- University, hospital or other
- Collaborators
- Sanofi, Roche Pharma AG
- Responsible party
- Sponsor
- Investigators
- Richard van Hillegersberg, MD PhD, Principal investigator, Universitair Medisch Centrum Utrecht
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00394992
- Sponsor's protocol ID
- HEPATICA
- Status last verified
- Feb 2014
- First submitted
- 1 Nov 2006
- Last updated
- 4 Feb 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Snoeren N, Voest EE, Bergman AM, Dalesio O, Verheul HM, Tollenaar RA, van der Sijp JR, Schouten SB, Rinkes IH, van Hillegersberg R. A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment. BMC Cancer. 2010 Oct 11;10:545. doi: 10.1186/1471-2407-10-545.
PubMed 20937118
Study at a glance
From the registry record, last updated by the sponsor on 4 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Phase III Study Post Radical Resection of Liver Metastasis of Colorectal Cancer: Bevacizumab in Combination With XELOX as Adjuvant Chemotherapy vs XELOX Alone
- ClinicalTrials.gov ID
- NCT00394992
- Acronym / sponsor ID
- HEPATICA
- Conditions
- Colorectal Cancer, Liver Metastases
- Keywords
- Colorectal cancer, Liver metastasis, Radical resection, Adjuvant therapy, Bevacizumab, Capecitabine, Oxaliplatin, Hepatica
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Data from the C08 study and Avant study
- Enrolment
- 79 participants (actual)
- Lead sponsor
- Dutch Colorectal Cancer GroupUniversity, hospital or other
- Collaborators
- Sanofi, Roche Pharma AG
- Study start
- Dec 2006
- Primary completion
- Aug 2013 (actual)
- Study completion
- Aug 2013 (actual)
- First posted
- 2 Nov 2006 (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.
The primary aim of this study is to investigate whether the addition of the new anti-cancer drug bevacizumab (Avastin) to the combination of the chemotherapeutic agents capecitabine (Xeloda) and oxaliplatin (Eloxatin) reduces (slows down) the recurrence of metastatic disease after a radical resection of liver metastases in patients with colorectal cancer.
Detailed description
The primary therapy of colorectal cancer is surgical resection, but more than half of all colorectal cancer patients eventually die of metastatic disease. Although the introduction of new anticancer agents with efficacy in metastatic colorectal cancer, e.g.: oxaliplatin and irinotecan, and the targeted agents cetuximab and bevacizumab has changed therapeutic nihilism, chemotherapy alone has failed to cure these patients.
It is estimated that 15-20 % of colorectal cancer patients present with synchronous liver metastases and approximately 50% of the patients with colorectal tumors will develop liver metastases at some point during the course of their disease. In almost one third of the cases, the liver was shown at autopsy to be the only site of cancer spread. This is in accordance with the 20% - 45 % five-year survival obtained with surgical resection of hepatic metastases.
Previous studies have not shown a clear benefit of adjuvant chemotherapy after metastasectomy of liver metastases. However, most of these studies have been performed with 5-fluorouracil with or without other older cytostatic drugs. Since new effective agents have been developed (e.g.: capecitabine, oxaliplatin and bevacizumab), adjuvant combination treatment with these agents might be more effective. These drugs have proven activity as first line palliative treatment of recurrent metastases. This raises the question if this new effective treatment is of value as an adjuvant treatment after metastasectomy.
As mentioned before, a two-arm EORTC study: neoadjuvant and adjuvant FOLFOX vs no chemotherapy in resectable liver metastases of colorectal cancer is almost completed (Nordlinger et al). It is expected that this study will show a 10% 3 year DFS benefit in favour of th treatment arm. Definitive data of this trial will be released at the end of 2006, and will most probably lead to adjuvant treatment post metastasectomy as a standard of care. In the HEPATCIA trial we anticipate on this by using adjuvant XELOX as the control arm.
As mentioned earlier, the 3-year disease free survival in patients post metastasectomy of liver metastases is approximately 25%. There is no data available on the effectivity of the XELOX regimen as adjuvant treatment after metastasectomy of colorectal cancer metastases. The EORTC study was designed to demonstrate a 10% improvement in 3y DFS. Assuming that this study is positive, 3 year DFS would be 35% in the control arm (XELOX post liver resection).
Since bevacizumab inhibits angiogenesis, which is required for growth of metastases, this drug may be valuable in the adjuvant setting. Several studies investigate the value of this drug in combination with fluoropyrimidines as an adjuvant regimen after resection of primary colorectal cancers. However, at this moment there is no mature data available of these studies. Therefore, we assume an increase in 3-year disease free survival of 10%, to 45% in the XELOX and bevacizumab treatment arm.
This study will therefore evaluate patients with resectable liver metastasis without extra-hepatic disease, investigating whether the capecitabine, oxaliplatin and bevacizumab regimen is superior to capecitabine and oxaliplatin alone applied as adjuvant treatment, in order to extent disease free and overall survival.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 oxaliplatin+capecitabine | Active comparator | Drug: oxaliplatin+capecitabinepostoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w |
| 2 oxaliplatin+capecitabine+bevacizumab | Experimental | Drug: Oxaliplatin+capecitabine+bevacizumabpostoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Signed written informed consent obtained prior to any study-specific procedures.
- Age ≥ 18 years.
- Liver metastases radically resected (R0 resection).
- Study medication started ≥4 and ≤ 8 weeks post liver surgery.
- Histologically confirmed liver metastasis of colorectal cancer after surgery.
Key exclusion criteria (20 listed)
- Extrahepatic metastatic disease.
- Prior adjuvant chemotherapy given <6 months prior to detection of the liver metastases.
- Prior non colorectal malignancies.
- Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation.
- Major surgical procedure <4 weeks prior to start of study treatment.
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 |
|---|---|---|
| oxaliplatin+capecitabinepostoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w | Drug | 1 oxaliplatin+capecitabine |
| Oxaliplatin+capecitabine+bevacizumabpostoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w | Drug | 2 oxaliplatin+capecitabine+bevacizumab |
Primary outcome
3-year disease free survival, defined as the percentage of disease free patients 3 year after randomisation.
Time frame: study duration
1 secondary outcome
Overall survival, defined as the percentage of patients alive 5 year after randomisation.
Time frame: study duration
Results and safety
The study was stopped early (reason given: Data from the C08 study and Avant study). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Feb 2014.
- Derived from this study: PubMed 20937118Snoeren N, Voest EE, Bergman AM, Dalesio O, Verheul HM, Tollenaar RA, van der Sijp JR, Schouten SB, Rinkes IH, van Hillegersberg R. A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment. BMC Cancer. 2010 Oct 11;10:545. doi: 10.1186/1471-2407-10-545.
- Websites Dutch Colorectal Cancer GroupLink provided by the sponsor.
- University Medical Center UtrechtLink provided by the sponsor.
Related trials for Colorectal Cancer
Not yet recruitingPhase 1
Hepatic Artery Infusion of Carfilzomib in Participants With Liver Metastatic Disease Previously Treated With Hepatic Artery Infusion Pump Therapy
Colorectal Neoplasms, Neoplasms
Active, not recruiting
Streamlined Geriatric and Oncological Evaluation Based On IC Technology
Breast Cancer, Comorbidities and Coexisting Conditions
RecruitingObservational study
Pre- and On-treatment Multi-omics Profiling of Locally Advanced Rectal Cancer
Rectal Neoplasms
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 2
Tislelizumab in People With Colorectal Cancer
Colorectal Cancer
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.
Richard van Hillegersberg, MD PhD principal investigator
Universitair Medisch Centrum Utrecht
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing oxaliplatin+capecitabine and Oxaliplatin+capecitabine+bevacizumab in people with Colorectal Cancer and Liver Metastases, run by Dutch Colorectal Cancer Group at 1 site 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 20 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: stopped early, as of the sponsor's last update on 4 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Data from the C08 study and Avant study). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
3-year disease free survival, defined as the percentage of disease free patients 3 year after randomisation. (time frame: study duration). 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 NCT00394992, which also lists 1 linked publication.
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 4 Feb 2014.