Colorectal Cancer
Conditions
Keywords
recurrent colon cancer, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer
Brief summary
RATIONALE: Monoclonal antibodies, such as cetuximab, 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. Cetuximab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cetuximab together with celecoxib may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cetuximab together with celecoxib works in treating patients with metastatic colorectal cancer or colorectal cancer that cannot be removed by surgery.
Detailed description
OBJECTIVES: Primary * Determine the time to progression in patients with unresectable or metastatic colorectal cancer treated with cetuximab and celecoxib. Secondary * Determine the response rate, median survival, and 1-year survival rate of patients treated with this regimen. * Determine the toxicity profile of this regimen in these patients. * Determine the feasibility of testing urinary PGE-M in patients treated with this regimen. * Determine the feasibility of testing serum transforming growth factor-α and amphiregulin in patients treated with this regimen. * Determine the effects of this regimen on the EGFR pathway in tumor cells (i.e., phosphorylated EGFr, phosphorylated AKT, activated mitogen-activated protein kinase). * Determine the effects of this regimen on the cyclooxygenase-2 pathway in tumor cells by measuring PGE-2 levels. OUTLINE: Patients receive cetuximab IV over 1-2 hours once weekly and oral celecoxib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Serum and urine samples are collected at baseline, after week 1, and every other course thereafter for evaluation of PGE-2 by mass spectrometry, cyclooxygenase-2 activity, and phospho-EGFR levels by western blot analysis and immunohistochemistry. Samples are also analyzed for TGF-α and amphiregulin proteomics. PROJECTED ACCRUAL: A total of 54 patients will be accrued for this study.
Interventions
BIOLOGICALcetuximab
400 mg/m2 iv week 1, then 250 mg/m2 weekly thereafter, starting on day 1 and continuing until progressive disease, excessive toxicity or removal from study for other reasons listed in the protocol.
DRUGcelecoxib
200 mg po BID starting on day 1 and continuing until progressive disease, excessive toxicity or removal from study for other reasons listed in the protocol.
GENETICproteomic profiling
Serum samples obtained as above will be analyzed by proteomic analysis in order to determine biomarkers of treatment response and toxicity prediction. We will use LC-MS-MS or MALDITOF mass spectrometry.
OTHERimmunohistochemistry staining method
phospho-EGFR levels using western blots of tissue extracts and immunohistochemistry on frozen and (if no other option available, paraffinembedded tissue sections).
OTHERlaboratory biomarker analysis
Serum samples obtained as above will be analyzed by proteomic analysis in order to determine biomarkers of treatment response and toxicity prediction.
OTHERmass spectrometry
We will use LC-MS-MS or MALDITOF mass spectrometry. Before any tissues are received, the drug of interest is evaluated via MALDI mass spectrometry on a MDS/Sciex QStar QqTOF mass spectrometer.
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed colorectal cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> or equal to 20 mm with conventional techniques or as \> or equal 10 mm with spiral CT scan. * Patients must have progressed after at least 1 chemotherapy regimen for advanced disease. No prior therapy which specifically and directly targets the EGFR pathway. * Age 18 years or older * ECOG performance status ≤ 2. * Life expectancy of greater than 3 months. * Normal organ and marrow functions as defined below: * absolute neutrophil count ≤ 1,500/μl * platelets ≤ 100,000/μl * total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) \> or equal to 2.5 times institutional upper limit of normal or \> or equal to 5.0 times normal if liver metastases are present * creatinine within normal institutional limits OR * creatinine clearance \> or equal to 60 mL/min/1.73 m2 for patients creatinine levels above institutional normal * The effects of cetuximab and/or celecoxib on the developing human fetus at the recommended therapeutic doses are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Ability to understand and the willingness to provide written informed consent.
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. * Patients may not be receiving any other investigational agents. * Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Prior severe infusion reaction to a monoclonal antibody * Serum calcium \>12.0 mg/dl. * Patients must be off all other selective or non-selective COX-2 inhibitors for at least 2 weeks prior to study entry (with the exception of 81 mg of daily aspirin). * No major surgery within 4 weeks. No minor surgery (laparoscopy, thoracoscopy, port placement) within 1 week. * Patients must be \> 4 weeks from prior pelvic radiation and recovered from side effects. * Patients must be \> 1 week from prior palliative radiation and have recovered from all side effects. * Prior treatment with EGFR targeting therapies. * Significant traumatic injury occurring within 28 days prior to treatment. * Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because cetuximab is an epidermal growth factor inhibitor with the potential for teratogenic or abortifacient effects based on the data suggesting that EGFR expression is important for normal organ development. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cetuximab, breastfeeding should be discontinued if the mother is treated with cetuximab. * Patients with known HIV disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | On study date to off study date in this study with median 9.76 months | Number of days from study enrollment to evidence of progressive disease radiographically, with progression defined under RECIST criteria as at least 20% increase in sum of longest diameter of target lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | On study date to off study date in this study with median 9.76 months | Median survival time in months, from on-study date to date of death |
| One Year Survival Rate | 1 year from on-study date | Percent of patients who remain alive one year from on-study date |
| Number of Patients With Each Worst-grade Toxicity Response | On study date to off study date in this study with median 9.76 months | Number of patients with worst-grade toxicity response of each grade (grade 1 to 5) following NCI Common Toxicity Criteria, with grade 1=mild adverse event; 2=moderate adverse event; 3=severe and undesirable adverse event; 4=life-threatening or disabling adverse event; 5=death. |
| Patient Response to Treatment | On study date to off study date in this study with median 9.76 months | Number of patients in each response category according to RECIST criteria: Progressive disease (PD): \>=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): \>=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. |
| Serum TGF-alpha: Treatment Cycle 1 | on-study week 5 | Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 1 |
| Urinary PGE-M : Treatment Cycle 2 | on-study week 9 | Measurement in ng/mL of a stable metabolite of prostaglandin E2 (PGE-M) in urine during treatment cycle 2 |
| Serum TGF-alpha: Treatment Cycle 2 | on-study week 9 | Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 2 |
| Urinary PGE-M : Treatment Cycle 1 | on-study week 5 | Measurement in ng/mL of a stable metabolite of prostaglandin E2 (PGE-M) in urine during treatment cycle 1 |
Countries
United States
Participant flow
Recruitment details
Study recruitment period was May 2005 through January 2007.
Pre-assignment details
A total of 18 people signed consent to participate in this study. One was determined ineligible, for a total of 17 patients on study.
Participants by arm
| Arm | Count |
|---|---|
| Therapeutic Intervention | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | disease progression | 13 |
Baseline characteristics
| Characteristic | Therapeutic Intervention |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age Continuous | 60 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 2 / 17 |
Outcome results
Primary
Progression-free Survival (PFS)
Number of days from study enrollment to evidence of progressive disease radiographically, with progression defined under RECIST criteria as at least 20% increase in sum of longest diameter of target lesions
Time frame: On study date to off study date in this study with median 9.76 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Therapeutic Intervention | Progression-free Survival (PFS) | 55 Days |
Secondary
Number of Patients With Each Worst-grade Toxicity Response
Number of patients with worst-grade toxicity response of each grade (grade 1 to 5) following NCI Common Toxicity Criteria, with grade 1=mild adverse event; 2=moderate adverse event; 3=severe and undesirable adverse event; 4=life-threatening or disabling adverse event; 5=death.
Time frame: On study date to off study date in this study with median 9.76 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Therapeutic Intervention | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 1 | 0 patients |
| Therapeutic Intervention | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 2 | 0 patients |
| Therapeutic Intervention | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 3 | 1 patients |
| Therapeutic Intervention | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 4 | 1 patients |
| Therapeutic Intervention | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 5 | 0 patients |
Secondary
One Year Survival Rate
Percent of patients who remain alive one year from on-study date
Time frame: 1 year from on-study date
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Therapeutic Intervention | One Year Survival Rate | 17.6 Percentage of participants |
Secondary
Overall Survival
Median survival time in months, from on-study date to date of death
Time frame: On study date to off study date in this study with median 9.76 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Therapeutic Intervention | Overall Survival | 8.54 Months |
Secondary
Patient Response to Treatment
Number of patients in each response category according to RECIST criteria: Progressive disease (PD): \>=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): \>=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD.
Time frame: On study date to off study date in this study with median 9.76 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Therapeutic Intervention | Patient Response to Treatment | Partial Response | 2 participants |
| Therapeutic Intervention | Patient Response to Treatment | Progressive Disease | 7 participants |
| Therapeutic Intervention | Patient Response to Treatment | Stable Disease | 4 participants |
| Therapeutic Intervention | Patient Response to Treatment | Unknown | 4 participants |
Secondary
Serum TGF-alpha: Treatment Cycle 1
Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 1
Time frame: on-study week 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapeutic Intervention | Serum TGF-alpha: Treatment Cycle 1 | Stable or PR (n=5) | 26.38 ng/mL | Standard Deviation 17.15 |
| Therapeutic Intervention | Serum TGF-alpha: Treatment Cycle 1 | Progressive Disease (n=10) | 25.90 ng/mL | Standard Deviation 10.93 |
Secondary
Serum TGF-alpha: Treatment Cycle 2
Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 2
Time frame: on-study week 9
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapeutic Intervention | Serum TGF-alpha: Treatment Cycle 2 | Stable or PR (n=6) | 48.02 ng/mL | Standard Deviation 16.94 |
| Therapeutic Intervention | Serum TGF-alpha: Treatment Cycle 2 | Progressive Disease (n=4) | 49.95 ng/mL | Standard Deviation 27.27 |
Secondary
Urinary PGE-M : Treatment Cycle 1
Measurement in ng/mL of a stable metabolite of prostaglandin E2 (PGE-M) in urine during treatment cycle 1
Time frame: on-study week 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapeutic Intervention | Urinary PGE-M : Treatment Cycle 1 | Stable or PR (n=6) | 30.42 ng/mL | Standard Deviation 17.15 |
| Therapeutic Intervention | Urinary PGE-M : Treatment Cycle 1 | Progressive Disease (n=11) | 21.94 ng/mL | Standard Deviation 17.13 |
Secondary
Urinary PGE-M : Treatment Cycle 2
Measurement in ng/mL of a stable metabolite of prostaglandin E2 (PGE-M) in urine during treatment cycle 2
Time frame: on-study week 9
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapeutic Intervention | Urinary PGE-M : Treatment Cycle 2 | Stable or PR (n=6) | 28.42 ng/mL | Standard Deviation 25.73 |
| Therapeutic Intervention | Urinary PGE-M : Treatment Cycle 2 | Progressive Disease (n=4) | 29.76 ng/mL | Standard Deviation 41.34 |