Colorectal CancerPhase 2NCT00602329
MRI in Predicting Response in Patients Receiving Combination Chemotherapy and Bevacizumab For Advanced or Metastatic Colorectal Cancer
A Phase 2 study testing bevacizumab, fluorouracil and leucovorin calcium in people with Colorectal Cancer, run by Abramson Cancer Center at Penn Medicine at 1 site in United States.
Trial summary
RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Colorectal Cancer
- What is being tested?
- bevacizumab, fluorouracil and leucovorin calcium
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2006to Oct 2009
- 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 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
DISEASE CHARACTERISTICS:
- Histologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum
- Patients receiving bevacizumab must have tumor tissue available for immunohistochemical analysis
- Formalin-fixed, paraffin-embedded tissue from previous biopsy or surgical resection is sufficient
- Measurable disease, defined by RECIST as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques (i.e., CT or MRI)
- CEA elevation alone is insufficient for study entry
- No known brain metastases
PATIENT CHARACTERISTICS:
Criteria for all patients
- ECOG performance status 0-1
- Life expectancy > 3 months
- Granulocytes ≥ 1,500/mL
- Platelet Count ≥ 100,000/mL
- Creatinine ≤ 1.5 times upper limit of normal (ULN)
- Bilirubin ≤ 1.5 times ULN
- AST ≤ 5 times ULN
- Urine protein:creatinine ratio ≤ 1.0 at screening
- Patients with other prior malignancies are eligible, provided they have been treated with curative intent and have no evidence of recurrence
- Not pregnant or nursing
- Negative pregnancy test
- No contraindications to MRI, including any of the following:
- Hypersensitivity to gadolinium
- Metallic device, including pacemaker, non-MRI compatible aneurysm clip, other non-MRI-compatible mechanical and/or electrical device, or metallic fragments
- Severe claustrophobia
Additional criteria for patients receiving bevacizumab:
- No significant traumatic injury within the past 28 days
- No serious nonhealing wounds, ulcers, or bone fractures
- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
- No myocardial infarction, unstable angina, or cerebrovascular accident within the past 6 months
- No clinically significant peripheral vascular disease
- No New York Heart Association class II-IV congestive heart failure
- Patients with pre-existing hypertension should be on a stable antihypertensive regimen with blood pressure ≤ 150/100 mm Hg at study entry
PRIOR CONCURRENT THERAPY:
Criteria for all patients
- Prior adjuvant treatment including oxaliplatin allowed
- No prior bevacizumab
- At least 14 days since prior radiotherapy and recovered
- More than 6 months since prior chemotherapy
- No other concurrent investigational agents
Additional criteria for patients receiving bevacizumab:
- At least 28 days since prior major surgical procedure or open biopsy
- At least 7 days since prior minor surgical procedure (e.g., fine-needle aspirations or core biopsies)
- No anticipation of need for a major surgical procedure during study treatment
- Concurrent oral or parenteral anticoagulation therapy allowed provided dose is stable
Trial locations and contacts
1 site in 1 country.
United States1 site
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104-4283
About this study
Official title: A Phase II Study Assessing Tumor Blood Flow as Measured by Dynamic Contrast Enhanced MRI in Patients With Metastatic Colorectal Cancer Receiving FOLFOX Alone Versus Patients Randomized to Receive FOLFOX Plus Bevacizumab at 5mg/kg or 10mg/kg.
RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may kill more tumor cells. Diagnostic procedures, such as MRI, may help doctors predict a patient's response to treatment and help plan the best treatment.
PURPOSE: This randomized phase II trial is studying how well MRI works in predicting response to combination chemotherapy given together with bevacizumab in treating patients with advanced or metastatic colorectal cancer.
Read the detailed description
OBJECTIVES:
Primary
- To determine the alteration of tumor blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced or metastatic colorectal cancer after 2 courses of combination chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin (FOLFOX) and bevacizumab at 5 mg/kg vs 10 mg/kg or FOLFOX alone.
Secondary
- To correlate tumor blood flow, as assessed by DCE-MRI, with time to progression in patients receiving bevacizumab at 5mg/kg vs 10mg/kg.
- To correlate vascular proliferation, as measured by DCE-MRI, with markers of endothelial cell proliferation (i.e., CD31, 34, 105; integrin αvß3; phospho-ERK; Ki67; PCNA; and smooth muscle actin).
- To obtain pilot data on whether assays that measure vascular endothelial cell mitogenic stimulation and mitogenic activity may predict response to therapy, time to progression, and overall survival of patients receiving bevacizumab at 5mg/kg vs 10mg/kg.
- To investigate the association of various markers of apoptosis in tumor cells (e.g., MIF, CREB, or HIF-1-alpha expression/polymorphism and others) and tumor vascularity, as assessed by DCE-MRI.
- To correlate markers of apoptosis in tumor cells with response to therapy, time to progression, and overall survival.
- To determine serum levels of VEGF prior to the initiation of chemotherapy and then prior to courses 2 and 3 of chemotherapy as potential markers of antiangiogenic activity.
OUTLINE: Patients who are eligible to receive bevacizumab are randomized to 1 of 2 treatment arms. Patients who are ineligible to receive bevacizumab receive FOLFOX alone.
- Arm I: Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours (FOLFOX) beginning on day 1. Patients also receive bevacizumab at 5 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive FOLFOX as in arm I and bevacizumab at 10 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.
- FOLFOX alone (control): Patients receive FOLFOX as in arm I. All patients undergo dynamic contrast-enhanced MRI at baseline and between courses 2 and 3 (between days 17 and 29) to assess tumor blood flow.
Tumor tissue specimens are obtained from prior colonoscopic biopsy or surgical resection in patients receiving bevacizumab. Tissue specimens are examined by immunohistochemistry to evaluate tumor markers of angiogenesis and apoptosis (e.g., CD31, 34, 105, phospho-ERK, PCNA, Ki67, SMA, and integrin αvß3). Blood specimens are obtained at baseline and prior to courses 2 and 3 (days 15 and 29) to evaluate plasma levels of VEGF.
After completion of study therapy, patients are followed every 2 months for 1 year and then every 3 months thereafter.
- Conditions
- Colorectal Cancer
- Being tested
- bevacizumab, fluorouracil, leucovorin calcium, oxaliplatin
- Keywords
- recurrent colon cancer, recurrent rectal cancer, stage III colon cancer, stage III rectal cancer, stage IV colon cancer, stage IV rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum
- Medical subject headings
- Colorectal Neoplasms, Colonic Neoplasms, Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
bevacizumabBiological
Given IV
fluorouracilDrug
Given IV
Given IV
oxaliplatinDrug
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Arm I | Experimental | Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours (FOLFOX) beginning on day 1. Patients also receive bevacizumab at 5 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. Receives: Biological: bevacizumab; Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin |
| Arm II | Experimental | Patients receive FOLFOX as in arm I and bevacizumab at 10 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. Receives: Biological: bevacizumab; Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin |
| FOLFOX alone (control) | Active comparator | Patients receive FOLFOX as in arm I. Receives: Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Analysis of tumor blood flow, assessed by DCE-MRI as percentage change in Ktrans, after 2 courses of FOLFOX and bevacizumab or FOLFOX alone compared to baseline value
Measured: 2 cycles for all subjects
Secondary outcomes (3)
Analysis of tumor markers of angiogenesis and apoptosis, and the effect of treatment
Measured: 2 cycles for all subjects
Correlation of tumor blood flow with time to progression
Measured: 2 cycles
Correlation of markers of apoptosis in tumor cells with response to therapy, time to progression, and overall survival
Measured: 2 cycles for all subjects
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2008 (estimated)
- Study startFeb 2006
- Primary completionJul 2009
- Study completionOct 2009
Why it stopped: Due to Poor accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal CancerStudies of the same condition, open and under way.
- More trials run by Abramson Cancer Center at Penn MedicineThe 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
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Abramson Cancer Center at Penn Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Peter O'Dwyer, MD, Principal investigator, Abramson Cancer Center at Penn Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00602329
- Sponsor's protocol ID
- CDR0000580810
- Other IDs
- UPCC-09205, GENENTECH-UPCC-09205, UPCC-804021
- Status last verified
- Apr 2020
- First submitted
- 19 Jan 2008
- Last updated
- 28 Apr 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study Assessing Tumor Blood Flow as Measured by Dynamic Contrast Enhanced MRI in Patients With Metastatic Colorectal Cancer Receiving FOLFOX Alone Versus Patients Randomized to Receive FOLFOX Plus Bevacizumab at 5mg/kg or 10mg/kg.
- ClinicalTrials.gov ID
- NCT00602329
- Acronym / sponsor ID
- CDR0000580810
- Conditions
- Colorectal Cancer
- Keywords
- recurrent colon cancer, recurrent rectal cancer, stage III colon cancer, stage III rectal cancer, stage IV colon cancer, stage IV rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to Poor accrual
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Abramson Cancer Center at Penn MedicineUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Feb 2006
- Primary completion
- Jul 2009 (actual)
- Study completion
- Oct 2009 (actual)
- First posted
- 28 Jan 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.
RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may kill more tumor cells. Diagnostic procedures, such as MRI, may help doctors predict a patient's response to treatment and help plan the best treatment.
PURPOSE: This randomized phase II trial is studying how well MRI works in predicting response to combination chemotherapy given together with bevacizumab in treating patients with advanced or metastatic colorectal cancer.
Detailed description
OBJECTIVES:
Primary
- To determine the alteration of tumor blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced or metastatic colorectal cancer after 2 courses of combination chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin (FOLFOX) and bevacizumab at 5 mg/kg vs 10 mg/kg or FOLFOX alone.
Secondary
- To correlate tumor blood flow, as assessed by DCE-MRI, with time to progression in patients receiving bevacizumab at 5mg/kg vs 10mg/kg.
- To correlate vascular proliferation, as measured by DCE-MRI, with markers of endothelial cell proliferation (i.e., CD31, 34, 105; integrin αvß3; phospho-ERK; Ki67; PCNA; and smooth muscle actin).
- To obtain pilot data on whether assays that measure vascular endothelial cell mitogenic stimulation and mitogenic activity may predict response to therapy, time to progression, and overall survival of patients receiving bevacizumab at 5mg/kg vs 10mg/kg.
- To investigate the association of various markers of apoptosis in tumor cells (e.g., MIF, CREB, or HIF-1-alpha expression/polymorphism and others) and tumor vascularity, as assessed by DCE-MRI.
- To correlate markers of apoptosis in tumor cells with response to therapy, time to progression, and overall survival.
- To determine serum levels of VEGF prior to the initiation of chemotherapy and then prior to courses 2 and 3 of chemotherapy as potential markers of antiangiogenic activity.
OUTLINE: Patients who are eligible to receive bevacizumab are randomized to 1 of 2 treatment arms. Patients who are ineligible to receive bevacizumab receive FOLFOX alone.
- Arm I: Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours (FOLFOX) beginning on day 1. Patients also receive bevacizumab at 5 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive FOLFOX as in arm I and bevacizumab at 10 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.
- FOLFOX alone (control): Patients receive FOLFOX as in arm I. All patients undergo dynamic contrast-enhanced MRI at baseline and between courses 2 and 3 (between days 17 and 29) to assess tumor blood flow.
Tumor tissue specimens are obtained from prior colonoscopic biopsy or surgical resection in patients receiving bevacizumab. Tissue specimens are examined by immunohistochemistry to evaluate tumor markers of angiogenesis and apoptosis (e.g., CD31, 34, 105, phospho-ERK, PCNA, Ki67, SMA, and integrin αvß3). Blood specimens are obtained at baseline and prior to courses 2 and 3 (days 15 and 29) to evaluate plasma levels of VEGF.
After completion of study therapy, patients are followed every 2 months for 1 year and then every 3 months thereafter.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm I | Experimental | Biological: bevacizumab, Drug: fluorouracil, Drug: leucovorin calcium, Drug: oxaliplatinPatients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours (FOLFOX) beginning on day 1. Patients also receive bevacizumab at 5 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. |
| Arm II | Experimental | Biological: bevacizumab, Drug: fluorouracil, Drug: leucovorin calcium, Drug: oxaliplatinPatients receive FOLFOX as in arm I and bevacizumab at 10 mg/kg IV over 90 minutes on day 1. Treatment repeats every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. |
| FOLFOX alone (control) | Active comparator | Drug: fluorouracil, Drug: leucovorin calcium, Drug: oxaliplatinPatients receive FOLFOX as in arm I. |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
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 |
|---|---|---|
| bevacizumabGiven IV | Biological | Arm I, Arm II |
| fluorouracilGiven IV | Drug | Arm I, Arm II, FOLFOX alone (control) |
| leucovorin calciumGiven IV | Drug | Arm I, Arm II, FOLFOX alone (control) |
| oxaliplatinGiven IV | Drug | Arm I, Arm II, FOLFOX alone (control) |
Primary outcome
Analysis of tumor blood flow, assessed by DCE-MRI as percentage change in Ktrans, after 2 courses of FOLFOX and bevacizumab or FOLFOX alone compared to baseline value
Time frame: 2 cycles for all subjects
3 secondary outcomes
Analysis of tumor markers of angiogenesis and apoptosis, and the effect of treatment
Time frame: 2 cycles for all subjects
Correlation of tumor blood flow with time to progression
Time frame: 2 cycles
Correlation of markers of apoptosis in tumor cells with response to therapy, time to progression, and overall survival
Time frame: 2 cycles for all subjects
Results and safety
The study was stopped early (reason given: Due to Poor accrual). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2020.
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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.
Peter O'Dwyer, MD principal investigator
Abramson Cancer Center at Penn Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing bevacizumab, fluorouracil and leucovorin calcium in people with Colorectal Cancer, run by Abramson Cancer Center at Penn Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
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 28 Apr 2020. 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 United States. 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?
The study was stopped early (reason given: Due to Poor accrual). 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?
Analysis of tumor blood flow, assessed by DCE-MRI as percentage change in Ktrans, after 2 courses of FOLFOX and bevacizumab or FOLFOX alone compared to baseline value (time frame: 2 cycles for all subjects). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 28 Apr 2020.