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

• Sponsor: Vanderbilt-Ingram Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00466505
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 17
• Location: 1
• Arm: 1
• Duration (Months): 42.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: cetuximab; Drug: celecoxib; Genetic: proteomic profiling; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: mass spectrometry	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Cetuximab in Combination With Celecoxib in Colorectal Cancer
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Therapeutic Intervention

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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. One Year Survival Rate [1 year from on-study date]

   Percent of patients who remain alive one year from on-study date

4. 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.

5. 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

6. 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

7. 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

8. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt-Ingram Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jordan D. Berlin, MD, Vanderbilt-Ingram Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jordan Berlin, MD, Jordan Berlin, MD, Vanderbilt-Ingram Cancer Center
• ClinicalTrials.gov Identifier: NCT00466505
• Other Study ID Numbers: VICC GI 0410; P30CA068485; VU-VICC-GI-0410; VU-IRB-040227
• First Posted: Apr 27, 2007
• Last Update Posted: Dec 19, 2012
• Last Verified: Dec 1, 2012

• Keywords provided by Jordan Berlin, MD, Jordan Berlin, MD, Vanderbilt-Ingram Cancer Center: recurrent colon cancer; stage IV colon cancer; recurrent rectal cancer; stage IV rectal cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Celecoxib; Cetuximab

Study Results

Participant Flow

Recruitment Details	Study recruitment period was May 2005 through January 2007.
Pre-assignment Detail	A total of 18 people signed consent to participate in this study. One was determined ineligible, for a total of 17 patients on study.

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Period Title: Overall Study
STARTED	17
COMPLETED	0
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Overall Participants	17
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 70.6%
>=65 years	5 29.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (1)
Sex: Female, Male (Count of Participants)
Female	7 41.2%
Male	10 58.8%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Median (Full Range) [Days]	55

2. Secondary Outcome

Title	Patient Response to Treatment
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Partial Response	2 11.8%
Progressive Disease	7 41.2%
Stable Disease	4 23.5%
Unknown	4 23.5%

3. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Median (Inter-Quartile Range) [Months]	8.54

4. Secondary Outcome

Title	One Year Survival Rate
Description	Percent of patients who remain alive one year from on-study date
Time Frame	1 year from on-study date

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Number (95% Confidence Interval) [Percentage of participants]	17.6 103.5%

5. Secondary Outcome

Title	Number of Patients With Each Worst-grade Toxicity Response
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
No. of patients with worst-grade toxicity of 1	0
No. of patients with worst-grade toxicity of 2	0
No. of patients with worst-grade toxicity of 3	1
No. of patients with worst-grade toxicity of 4	1
No. of patients with worst-grade toxicity of 5	0

6. Secondary Outcome

Title	Urinary PGE-M : Treatment Cycle 1
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Stable or PR (n=6)	30.42 (17.15)
Progressive Disease (n=11)	21.94 (17.13)

7. Secondary Outcome

Title	Serum TGF-alpha: Treatment Cycle 1
Description	Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 1
Time Frame	on-study week 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Stable or PR (n=5)	26.38 (17.15)
Progressive Disease (n=10)	25.90 (10.93)

8. Secondary Outcome

Title	Urinary PGE-M : Treatment Cycle 2
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Stable or PR (n=6)	28.42 (25.73)
Progressive Disease (n=4)	29.76 (41.34)

9. Secondary Outcome

Title	Serum TGF-alpha: Treatment Cycle 2
Description	Measurement in ng/mL of tumor growth factor-alpha (TGF-alpha) in serum samples during treatment cycle 2
Time Frame	on-study week 9

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
Measure Participants	17
Stable or PR (n=6)	48.02 (16.94)
Progressive Disease (n=4)	49.95 (27.27)

Adverse Events

Arm/Group Title	Therapeutic Intervention
Arm/Group Description
All Cause Mortality
	Therapeutic Intervention
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Therapeutic Intervention
	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)
Nervous system disorders
neurology, brain mets	1/17 (5.9%)	1
Renal and urinary disorders
Hemorrhage, bladder	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Therapeutic Intervention
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
AST, SGOT	3/17 (17.6%)	3
leukocytes	1/17 (5.9%)	1
Eye disorders
cataract	1/17 (5.9%)	1
eye irritation	2/17 (11.8%)	3
blurred vision	2/17 (11.8%)	2
Gastrointestinal disorders
constipation	4/17 (23.5%)	4
diarrhea	7/17 (41.2%)	8
dyspepsi	3/17 (17.6%)	3
hemorrhage, rectum	3/17 (17.6%)	3
hemorrhoids	1/17 (5.9%)	1
anal incontinence	1/17 (5.9%)	1
reflux	2/17 (11.8%)	2
pain, abdominal	8/17 (47.1%)	8
pain, rectum	2/17 (11.8%)	2
vomiting	1/17 (5.9%)	1
flatulence	1/17 (5.9%)	1
General disorders
allergic reaction	3/17 (17.6%)	3
edema	2/17 (11.8%)	3
fatigue	12/17 (70.6%)	13
fever	2/17 (11.8%)	2
Infections and infestations
infection	3/17 (17.6%)	3
infection with normal ANC	1/17 (5.9%)	1
Investigations
alkaline phosphatase	4/17 (23.5%)	5
hemoglobin	7/17 (41.2%)	11
platelets	2/17 (11.8%)	2
Metabolism and nutrition disorders
hypoalbuminemia	2/17 (11.8%)	2
ALT, SGPT	2/17 (11.8%)	2
hyperbilirubinemia	3/17 (17.6%)	3
hypocalcemia	3/17 (17.6%)	4
hypomagnesiumia	6/17 (35.3%)	6
hypercholesterolemia	1/17 (5.9%)	1
hyperglycemia	4/17 (23.5%)	5
hypokalemia	5/17 (29.4%)	5
hyponatremia	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
muscle weakness	2/17 (11.8%)	2
pain, back	3/17 (17.6%)	3
pain, extremity	1/17 (5.9%)	1
pain, muscle	1/17 (5.9%)	1
pain, rib cage	2/17 (11.8%)	2
Nervous system disorders
dizziness	2/17 (11.8%)	2
restless leg	2/17 (11.8%)	2
peripheral neuropathy	5/17 (29.4%)	5
pain, head	1/17 (5.9%)	1
tremor	1/17 (5.9%)	1
Psychiatric disorders
anorexia	4/17 (23.5%)	4
insomnia	4/17 (23.5%)	4
agitation	2/17 (11.8%)	2
depression	2/17 (11.8%)	2
Renal and urinary disorders
hemorrhage, bladder	4/17 (23.5%)	4
urinary frequency	2/17 (11.8%)	2
urinary retention	2/17 (11.8%)	2
Reproductive system and breast disorders
vaginal discharge	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
cough	4/17 (23.5%)	4
dyspnea	3/17 (17.6%)	4
hemorrhage, pulmonary	1/17 (5.9%)	1
hiccoughs	1/17 (5.9%)	1
hoarseness	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
dermatologic general	7/17 (41.2%)	8
nail changes	2/17 (11.8%)	3
balanitis	2/17 (11.8%)	2
pruritus, itching	5/17 (29.4%)	5
rash, desquamation	15/17 (88.2%)	20
hand, foot rash	1/17 (5.9%)	1
Vascular disorders
hot flashes	1/17 (5.9%)	1
hypotension	1/17 (5.9%)	1
diaphoresis, sweating	2/17 (11.8%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.