Clinical trial NCT00466505: Cetuximab & Celecoxib for Metastatic Colorectal Cancer or Colorectal Cancer That Cannot Be Removed by Surgery
Official title: A Phase 2 Study of Cetuximab in Combination With Celecoxib in Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer
Lead sponsor: Vanderbilt-Ingram Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-04-27
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: On study date to off study date in this study with median 9.76 months
Secondary outcomes:
measure: Patient Response to Treatment
timeFrame: On study date to off study date in this study with median 9.76 months
measure: Overall Survival
timeFrame: On study date to off study date in this study with median 9.76 months
measure: One Year Survival Rate
timeFrame: 1 year from on-study date
measure: Number of Patients With Each Worst-grade Toxicity Response
timeFrame: On study date to off study date in this study with median 9.76 months
measure: Urinary PGE-M : Treatment Cycle 1
timeFrame: on-study week 5
measure: Serum TGF-alpha: Treatment Cycle 1
timeFrame: on-study week 5
measure: Urinary PGE-M : Treatment Cycle 2
timeFrame: on-study week 9
measure: Serum TGF-alpha: Treatment Cycle 2
timeFrame: on-study week 9
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: Vanderbilt-Ingram Cancer Center
name: Jordan D. Berlin, MD
role: PRINCIPAL_INVESTIGATOR
References: