Erbitux (Cetuximab) Given Alone to Patients With EGFR-Negative Metastatic Colon or Rectal Cancer That is Refractory to Chemotherapy

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00083720
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 87
• Locations: 27
• Arm: 1
• Duration (Months): 42
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a phase II, multicenter, open-label study of cetuximab in patients with epidermal growth factor receptor (EGFR) negative, metastatic colorectal carcinoma who have progressed after receiving at least one standard chemotherapeutic regimen that included a fluoropyrimidine. Target enrollment is 80 evaluable patients.

Patients with EGFR-negative metastatic colorectal carcinoma who have progressed after receiving at least one standard chemotherapeutic regimen that included a fluoropyrimidine, will receive an initial dose of cetuximab, 400 mg/m2 , intravenously (i.v.) over 120 minutes, followed by weekly treatment with cetuximab, 250 mg/m2 i.v. over 60 minutes. Patients who experience unacceptable toxicity or who have progressive disease (PD) will not receive further cetuximab therapy.

Patients will be evaluated for a tumor response at a minimum of every 6 weeks while on cetuximab therapy. Patients with stable disease (SD), partial response (PR), or a complete response (CR) may continue to receive weekly cetuximab therapy, unless they are dose-delayed or discontinued because of toxicity. Patients who have a PR or CR must have a confirmatory tumor assessment no less than 4 weeks after the initial evaluation demonstrating a response. To evaluate the objective response rate, a single-stage design will be used in this study.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms; Metastases; Neoplasm	Biological: cetuximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Multicenter Study of Erbitux (Cetuximab) in Patients With Refractory, EGFR-Negative Metastatic Colorectal Carcinoma
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: cetuximab Initial dose of 400 mg/m2 intravenously (i.v.) over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes	Biological: cetuximab; Initial dose of 400 mg/m2 intravenously (i.v.) over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes; Other Names: Erbitux™

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an Overall Resonse [Tumor evaluations were performed at a minimum every 6 weeks while on cetuximab therapy until progressive disease (PD) or recurrence. Patients with a PR or CR had a confirmatory tumor assessment no less than 4 weeks after the initial evaluation.]

   Determine the response rate (complete response [CR] and partial response [PR]) in patients with epidermal growth factor receptor (EGFR)-negative metastatic colorectal carcinoma treated with cetuximab, as classified by the investigator according to the World Health Organization (WHO) criteria. The calculation was the total number of patients with CR or PR divided by the total number of patients treated.

2. Number of Participants With Adverse Events [An adverse event (AE) was included in the safety analysis if its onset date occurred anytime during cetuximab treatment or up to 30 days after the last dose of cetuximab.]

   Reported adverse events (AEs) per patient were coded according to the corresponding preferred term and system organ class in the Medical Dictionary for Regulatory Activities dictionary. The National Cancer Insititute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0 was used to grade all AEs. The collection of AEs began at the time the patient received the first cetuximab dose and continued during the study until 30 days after the last dose of cetuximab. All patients who were enrolled and treated with cetuximab were assessed for safety (mITT population, as treated).

3. Number of Participants With Serious Adverse Events [A serious adverse event (SAE) was included in the safety analysis if its onset date occurred anytime during cetuximab treatment or up to 30 days after the last dose of cetuximab.]

   Reported SAEs per patient were coded according to the corresponding preferred term and system organ class in the Medical Dictionary for Regulatory Activities. The NCI-CTCAE Version 3.0 was used to grade all SAEs. An SAE was any untoward medical occurrence that resulted in death, persistent/significant disability/incapacity, was life threatening, required inpatient hospitalization or caused prolongation of existing hospitalization,congenital anomaly/birth defect, or any important medical event.

Secondary Outcome Measures

1. Percentage of Participants With Disease Control (CR, PR, or SD) [Tumor evaluations were performed at a minimum of every 6 weeks while on cetuximab therapy. Patients with a PR or CR had a confirmatory tumor assessment no less than 4 weeks after the initial evaluation demonstrating a response.]

   This is the total number of patients with a best overall response of CR, PR, and stable disease (SD) divided by the total number of patients treated.

2. Duration of Response [The duration of response was measured from the date of response to the first date of PD (range 2 to 7 months).]

   In patients with a best overall response of CR or PR, the duration of response is measured from the date criteria are first met for CR or PR, until the first date that Progressive Disease (PD) is objectively documented or death occurs. Duration of response of living patients with no evidence of PD was censored on the date of their last tumor assessment.

3. Time to Progression [Patients with PD after receiving at least one standard chemotherapeutic regimen that included a fluoropyrimidine (range: 1-3 months).]

   This measure was defined as the time from the first day of treatment until the date of PD. Deaths without objective progression were censored. Patients who did not progress were censored at their last day of tumor assessment.

4. Overall Survival [Survival information was collected every 3 months after completion of therapy and/or follow-up up to 24 months.]

   This measure is defined as the time from the first day of therapy to the date of death. Survival of living patients or those lost to follow-up were censored on the last date the patients were known to be alive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provided signed written informed consent.

• Histologically- or pathologically- confirmed metastatic colorectal carcinoma;

• Documented PD after treatment with at least one standard chemotherapy regimen for metastatic colorectal carcinoma;

• The chemotherapy regimen on which the patient progressed, must have included a fluoropyrimidine;

• Bidimensionally measurable disease;

• Immunohistochemical evidence of an absence of EGFR expression, (ie, EGFR-negative). Patients who do not have tumor tissue available for EGFR testing will undergo biopsy of accessible tumor. A reference laboratory designated by ImClone will perform the EGFR assay.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1 at study entry;

• Adequate recovery from recent surgery, chemotherapy, and radiation therapy. At least 30 days must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or medical device, or prior radiation therapy;

• Accessible for treatment and follow-up. Patients enrolled in this trial must be treated at the participating center.

• Men and women, 18 years of age and older

Exclusion Criteria:

• Women of child bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the study.

• Women who are pregnant or breastfeeding.

• Women with a positive pregnancy test on enrollment or prior to cetuximab administration.

• Sexually active fertile men not using effective birth control.

• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;

• A serious uncontrolled medical disorder that would impair the ability of the patient to receive protocol therapy;

• A history of uncontrolled angina, arrhythmias or congestive heart failure;

• Symptomatic or uncontrolled metastases to the central nervous system. Patients receiving a glucocorticoid for central nervous system (CNS) metastases will be excluded, but those receiving anticonvulsants will be eligible.

• Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. Patients with a previous malignancy but without evidence of disease for greater than or equal to 5 years will be allowed to enter the trial;

• Inadequate hematologic function defined by an absolute neutrophil count (ANC) less than 1,500/mm3 , a platelet count less than 100,000/mm3 , or a hemoglobin level less than 9 g/dL.

• Inadequate hepatic function, defined by a total bilirubin level greater than or equal to 1.5 times the upper limit of normal (ULN) and aspartate transaminase (AST) or alanine transaminase (ALT) levels greater than or equal to 5.0 times the ULN.

• Inadequate renal function defined by a serum creatinine level greater than 1.5 times the ULN.

• Prior cetuximab or other therapy, which specifically and directly targets the EGF pathway.

• Prior hypersensitivity reaction to chimerized or murine monoclonal antibody therapy.

• Any chemotherapy not indicated in the study protocol, radiation therapy, hormonal therapy (except for physiological replacement), or any other investigational agent.

• Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious disease) illness.

• Employees of the investigator or study center with direct involvement in this study or other studies under the direction of the investigator or study center, as well as family members of the employees.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Campbell	California	United States	95008
2	ImClone Investigational Site	Los Angeles	California	United States	90033
3	ImClone Investigational Site	Soquel	California	United States	95073
4	ImClone Investigational Site	Jacksonville	Florida	United States	32256
5	ImClone Investigational Site	Orlando	Florida	United States	32804
6	ImClone Investigational Site	Ormond Beach	Florida	United States	32174
7	ImClone Investigational Site	Gurnee	Illinois	United States	60031
8	ImClone Investigational Site	Evansville	Indiana	United States	47714
9	ImClone Investigational Site	Indianapolis	Indiana	United States	46202
10	ImClone Investigational Site	Lexington	Kentucky	United States	40503
11	ImClone Investigational Site	Louisville	Kentucky	United States	40202
12	ImClone Investigational Site	Metairie	Louisiana	United States	70006
13	ImClone Investigational Site	Boston	Massachusetts	United States	02114
14	ImClone Investigational Site	Ann Arbor	Michigan	United States	48106-0995
15	ImClone Investigational Site	Kalamazoo	Michigan	United States	49048
16	ImClone Investigational Site	St. Louis	Missouri	United States	63110
17	ImClone Investigational Site	Armonk	New York	United States	10504
18	ImClone Investigational Site	East Setauket	New York	United States	11733
19	ImClone Investigational Site	Durham	North Carolina	United States	27710
20	ImClone Investigational Site	Sellingsgrove	Pennsylvania	United States	17870
21	ImClone Investigational Site	Arlington	Texas	United States	76012
22	ImClone Investigational Site	Bryan	Texas	United States	77802
23	ImClone Investigational Site	Temple	Texas	United States	76508
24	ImClone Investigational Site	Oshawa	Ontario	Canada	L1G 2B9
25	ImClone Investigational Site	Ottawa	Ontario	Canada	K1H 1C4
26	ImClone Investigational Site	Toronto	Ontario	Canada	M4N 3M5
27	ImClone Investigational Site	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• Eli Lilly and Company
• Bristol-Myers Squibb

Investigators

• Study Chair: E-mail: ClinicalTrials@ ImClone.com, Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00083720
• Other Study ID Numbers: CP02-0451
• First Posted: Jun 2, 2004
• Last Update Posted: May 25, 2011
• Last Verified: May 1, 2011

• Keywords provided by , ,: EGFR-undetectable; Metastatic Colorectal Cancer
• Additional relevant MeSH terms: Neoplasms; Colorectal Neoplasms; Cetuximab

Study Results

Participant Flow

Recruitment Details	A total of 87 patients were enrolled between 22 Oct 2004 and 20 Aug 2007 at nine sites in the USA and four sites in Canada.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Period Title: Overall Study
STARTED	85
COMPLETED	85
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Overall Participants	85
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	42 49.4%
>=65 years	43 50.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.2 (11.41)
Sex: Female, Male (Count of Participants)
Female	26 30.6%
Male	59 69.4%
Region of Enrollment (participants) [Number]
United States	20 23.5%
Canada	65 76.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an Overall Resonse
Description	Determine the response rate (complete response [CR] and partial response [PR]) in patients with epidermal growth factor receptor (EGFR)-negative metastatic colorectal carcinoma treated with cetuximab, as classified by the investigator according to the World Health Organization (WHO) criteria. The calculation was the total number of patients with CR or PR divided by the total number of patients treated.
Time Frame	Tumor evaluations were performed at a minimum every 6 weeks while on cetuximab therapy until progressive disease (PD) or recurrence. Patients with a PR or CR had a confirmatory tumor assessment no less than 4 weeks after the initial evaluation.

Outcome Measure Data

Analysis Population Description

The overall response rate was calculated for the modified Intent to Treat (mITT) population.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	85
Mean (95% Confidence Interval) [percentage of participants]	8.2 9.6%

2. Secondary Outcome

Title	Percentage of Participants With Disease Control (CR, PR, or SD)
Description	This is the total number of patients with a best overall response of CR, PR, and stable disease (SD) divided by the total number of patients treated.
Time Frame	Tumor evaluations were performed at a minimum of every 6 weeks while on cetuximab therapy. Patients with a PR or CR had a confirmatory tumor assessment no less than 4 weeks after the initial evaluation demonstrating a response.

Outcome Measure Data

Analysis Population Description

Disease control rate was the total number of patients with best overall response of CR, PR and SD divided by the total number of patients treated.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	85
Mean (95% Confidence Interval) [Percentage of participants]	49.4 58.1%

3. Secondary Outcome

Title	Duration of Response
Description	In patients with a best overall response of CR or PR, the duration of response is measured from the date criteria are first met for CR or PR, until the first date that Progressive Disease (PD) is objectively documented or death occurs. Duration of response of living patients with no evidence of PD was censored on the date of their last tumor assessment.
Time Frame	The duration of response was measured from the date of response to the first date of PD (range 2 to 7 months).

Outcome Measure Data

Analysis Population Description

The duration of response was calculated for the subgroup of the mITT population who demonstrated a response.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	7
Median (95% Confidence Interval) [Months]	5.1

4. Secondary Outcome

Title	Time to Progression
Description	This measure was defined as the time from the first day of treatment until the date of PD. Deaths without objective progression were censored. Patients who did not progress were censored at their last day of tumor assessment.
Time Frame	Patients with PD after receiving at least one standard chemotherapeutic regimen that included a fluoropyrimidine (range: 1-3 months).

Outcome Measure Data

Analysis Population Description

This measure was calculated for the mITT population.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	85
Median (95% Confidence Interval) [Months]	2.5

5. Secondary Outcome

Title	Overall Survival
Description	This measure is defined as the time from the first day of therapy to the date of death. Survival of living patients or those lost to follow-up were censored on the last date the patients were known to be alive.
Time Frame	Survival information was collected every 3 months after completion of therapy and/or follow-up up to 24 months.

Outcome Measure Data

Analysis Population Description

Overall survival was calculated from the time of the first day of therapy to the date of death for the mITT population.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	85
Median (95% Confidence Interval) [Months]	10.0

6. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Reported adverse events (AEs) per patient were coded according to the corresponding preferred term and system organ class in the Medical Dictionary for Regulatory Activities dictionary. The National Cancer Insititute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0 was used to grade all AEs. The collection of AEs began at the time the patient received the first cetuximab dose and continued during the study until 30 days after the last dose of cetuximab. All patients who were enrolled and treated with cetuximab were assessed for safety (mITT population, as treated).
Time Frame	An adverse event (AE) was included in the safety analysis if its onset date occurred anytime during cetuximab treatment or up to 30 days after the last dose of cetuximab.

Outcome Measure Data

Analysis Population Description

Patients who were enrolled and treated with any quantity of cetuximab constitute the mITT population. Since this trial was a single arm trial, the mITT population used for the efficacy analyses was also used for the safety analyses.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	85
Number [Participants]	85 100%

7. Primary Outcome

Title	Number of Participants With Serious Adverse Events
Description	Reported SAEs per patient were coded according to the corresponding preferred term and system organ class in the Medical Dictionary for Regulatory Activities. The NCI-CTCAE Version 3.0 was used to grade all SAEs. An SAE was any untoward medical occurrence that resulted in death, persistent/significant disability/incapacity, was life threatening, required inpatient hospitalization or caused prolongation of existing hospitalization,congenital anomaly/birth defect, or any important medical event.
Time Frame	A serious adverse event (SAE) was included in the safety analysis if its onset date occurred anytime during cetuximab treatment or up to 30 days after the last dose of cetuximab.

Outcome Measure Data

Analysis Population Description

Patients who were enrolled and treated with any quantity of cetuximab constitute the mITT population. Since this trial was a single arm trial, the mITT population used for the efficacy analyses was also used for the safety analyses.

Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
Measure Participants	85
Number [Participants]	19 22.4%

Adverse Events

Time Frame	Adverse events were collected from the time that the patient received the initial cetuximab infusion and continued during the study until 30 days after the last dose of cetuximab.
Adverse Event Reporting Description	The NCI-CTCAE V3.0 toxicity criteria was used to grading the severity of all AEs.
Arm/Group Title	Cetuximab
Arm/Group Description	Initial dose of 400 mg/m2 i.v. over 120 minutes, followed by 250 mg/m2 weekly i.v. over 60 minutes
All Cause Mortality
	Cetuximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Cetuximab
	Affected / at Risk (%)	# Events
Total	19/85 (22.4%)
Gastrointestinal disorders
Diarrhea	1/85 (1.2%)	1
Gastrointestinal haemorrhage	1/85 (1.2%)	2
Intestinal obstruction	1/85 (1.2%)	1
Small intestinal obstruction	1/85 (1.2%)	1
General disorders
Disease progression	3/85 (3.5%)	3
Death	1/85 (1.2%)	1
Infusion related reaction	1/85 (1.2%)	1
Pyrexia	1/85 (1.2%)	1
Immune system disorders
Anaphylactic reaction	1/85 (1.2%)	1
Hypersensitivity	1/85 (1.2%)	1
Serum sickness	1/85 (1.2%)	1
Infections and infestations
Catheter site infection	1/85 (1.2%)	1
Cellulitis	1/85 (1.2%)	1
Sepsis	1/85 (1.2%)	1
Staphylococcal infection	1/85 (1.2%)	1
Investigations
Blood magnesium decreased	1/85 (1.2%)	1
Metabolism and nutrition disorders
Gout	1/85 (1.2%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/85 (1.2%)	1
Psychiatric disorders
Dissociation	1/85 (1.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/85 (3.5%)	4
Hypoxia	1/85 (1.2%)	1
Lung infiltration	1/85 (1.2%)	1
Respiratory failure	1/85 (1.2%)	1
Other (Not Including Serious) Adverse Events
	Cetuximab
	Affected / at Risk (%)	# Events
Total	84/85 (98.8%)
Gastrointestinal disorders
Abdominal pain	8/85 (9.4%)	8
Constipation	8/85 (9.4%)	11
Diarrhea	12/85 (14.1%)	17
Nausea	13/85 (15.3%)	14
Stomatitis	9/85 (10.6%)	10
Vomiting	8/85 (9.4%)	11
General disorders
Chills	6/85 (7.1%)	8
Fatigue	27/85 (31.8%)	33
Oedema peripheral	6/85 (7.1%)	6
Pyrexia	6/85 (7.1%)	6
Metabolism and nutrition disorders
Anorexia	20/85 (23.5%)	21
Hypomagnesaemia	10/85 (11.8%)	14
Musculoskeletal and connective tissue disorders
Back pain	6/85 (7.1%)	7
Nervous system disorders
Headache	25/85 (29.4%)	28
Respiratory, thoracic and mediastinal disorders
Cough	5/85 (5.9%)	6
Dyspnea	6/85 (7.1%)	7
Epistaxis	5/85 (5.9%)	6
Skin and subcutaneous tissue disorders
Dermatitis acneiform	73/85 (85.9%)	102
Dry skin	15/85 (17.6%)	16
Nail disorder	9/85 (10.6%)	12
Pruritus	6/85 (7.1%)	7
Skin disorder	6/85 (7.1%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigators may not independently publish/disclose any study data, findings or conclusions except as part of an overall multi-center publication. After final publication, or if a draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to review for sponsor confidential information which may be redacted at sponsor request. Publication may be delayed up to 90 days to seek patent protection.