Cetuximab & Celecoxib for Metastatic Colorectal Cancer or Colorectal Cancer That Cannot Be Removed by Surgery

• Patient Response to Treatment [ Time Frame: On study date to off study date in this study with median 9.76 months ] [ Designated as safety issue: No ]
  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.
• Overall Survival [ Time Frame: On study date to off study date in this study with median 9.76 months ] [ Designated as safety issue: No ]
  Median survival time in months, from on-study date to date of death
• One Year Survival Rate [ Time Frame: 1 year from on-study date ] [ Designated as safety issue: No ]
  Percent of patients who remain alive one year from on-study date
• Number of Patients With Each Worst-grade Toxicity Response [ Time Frame: On study date to off study date in this study with median 9.76 months ] [ Designated as safety issue: Yes ]
  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.
• Urinary PGE-M : Treatment Cycle 1 [ Time Frame: on-study week 5 ] [ Designated as safety issue: No ]
  Measurement in ng/mL of a stable metabolite of prostaglandin E2 (PGE-M) in urine during treatment cycle 1
• Serum TGF-alpha: Treatment Cycle 1 [ Time Frame: on-study week 5 ] [ Designated as safety issue: No ]
  Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 1
• Urinary PGE-M : Treatment Cycle 2 [ Time Frame: on-study week 9 ] [ Designated as safety issue: No ]
  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 [ Time Frame: on-study week 9 ] [ Designated as safety issue: No ]
  Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 2

• Response rate
• Overall survival
• Toxicity
• Correlation of molecular changes seen in biopsy, serum, and/or urine specimens with pharmacodynamic effects (response, survival, PFS, and toxicity)
• Urinary PGE-M
• Serum TGF-alpha and amphiregulin
• Tissue PGE-2 and EGFR pathway as measured by immunohistochemistry

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.

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.

• Biological: cetuximab
  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.
  Other Name: Erbitux, IMC-C225
• Drug: celecoxib
  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.
  Other Name: celebrex
• Genetic: proteomic 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.
• Other: immunohistochemistry staining method
  phospho-EGFR levels using western blots of tissue extracts and immunohistochemistry on frozen and (if no other option available, paraffinembedded tissue sections).
• Other: laboratory biomarker analysis
  Serum samples obtained as above will be analyzed by proteomic analysis in order to determine biomarkers of treatment response and toxicity prediction.
• Other: mass 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.

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.