Bevacizumab and Cetuximab in Combination With FOLFOX6 in Patients With Metastatic Colorectal Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT00193219
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 36
• Locations: 10
• Arm: 1
• Duration (Months): 60
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This trial will evaluate the combination of modified infusional 5-fluorouracil/ leucovorin, oxaliplatin (FOLFOX6), bevacizumab, and cetuximab in patients with metastatic colorectal cancer. FOLFOX6 has proven to be a safe and effective regimen in first line treatment of advanced colorectal cancer. The role of epidermal growth factor (EGFR) inhibitors in an earlier treatment setting in combination with optimal chemotherapy regimens is an important emerging question.

Condition or Disease	Intervention/Treatment	Phase
Colon Cancer	Drug: Bevacizumab; Drug: Cetuximab; Drug: 5-fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin	Phase 2

Detailed Description

All patients received cetuximab: 400 mg/m2 (first cycle only) administered intravenously (IV) on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8. Day 1 cetuximab was immediately followed by bevacizumab 5 mg/kg IV, oxaliplatin 85 mg/m2 IV, and 5-fluorouracil 400 mg/m2 IV bolus, followed by 2400 mg/m2 administered as a continuous infusion over 46 hours via a pump (outpatient) and leucovorin 350 mg IV (modified FOLFOX6). Cycles were 14 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Modified FOLFOX6 (Infusional 5-Fluorouracil/Leucovorin, Oxaliplatin) and Bevacizumab With or Without Cetuximab in Patients With Metastatic Colorectal Cancer
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Intervention Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV

Drug: Bevacizumab; 5 mg/kg IV; Other Names: Avastin ; Drug: Cetuximab; 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8; Other Names: Erbitux ; Drug: 5-fluorouracil; 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient); Other Names: 5-FU Adrucil ; Drug: Leucovorin; 350 mg IV; Other Names: Folinic Acid ; Drug: Oxaliplatin; 85 mg/m2 IV; Other Names: Eloxatin

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR), the Percentage of Patients Who Experience an Objective Benefit From Treatment [18 months]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Progression Free Survival (PFS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Worsening of Their Disease [18 months]

   Progression Free Survival (PFS) is defined as the interval between the start date of treatment and the date of occurrence of progressive disease or death.

2. Overall Survival (OS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death [36 months]

   Measured from the date of first treatment until the date of death from any cause

3. Number of Patients With Adverse Events as a Measure of Safety With FOLFOX6 Combined With Bevacizumab and Cetuximab [18 months]

   The toxicity assessments were made according to the common terminology criteria for adverse events (CTCAE version 3.0) of the National Cancer Institute. Number of participants with Grade 1 to 5 adverse events are reported here.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

To be included in the study, you must meet the following criteria:

• Metastatic colorectal cancer confirmed by a biopsy sample

• 18 years of age or older

• Evidence of disease progression at time of study entry

• At least one prior adjuvant chemotherapy regimen

• No prior therapy for metastatic disease

• Measurable disease

• Able to perform activities of daily living with minimal assistance

• Adequate bone marrow, kidney, and liver function

• Tumor tissue available for assessment of EGFR

• Signed informed consent

Exclusion Criteria:

You cannot participate in the study if any of the following apply to you:

• Treatment with a previous regimen for metastatic disease

• Prior treatment with any EGFR inhibitor or anti-angiogenic agents

• Brain or nervous system metastases

• History of severe thromboembolic event

• Clinical evidence or history of bleeding or coagulopathy

• History of stroke or heart attack within six months

• Poorly controlled hypertension

• Non-healing wound, ulcer, or bone fracture

• History of abdominal fistula, perforation, or abscess within six months

• Other uncontrolled or significant disease or medical condition

Please note: There are additional inclusion/exclusion criteria. The study center will determine if you meet all of the criteria. If you do not qualify for the trial, study personnel will explain the reasons. If you do qualify, study personnel will explain the trial in detail and answer any questions you may have. You can then decide if you wish to participate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oncology Hematology Associates of SW Indiana	Evansville	Indiana	United States	47714
2	Consultants in Blood Disorders and Cancer	Louisville	Kentucky	United States	40207
3	Mercy Hospital	Portland	Maine	United States	04101
4	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
5	Jackson Oncology Associates	Jackson	Mississippi	United States	39202
6	St. Louis Cancer Care	Chesterfield	Missouri	United States	63017
7	Methodist Cancer Center	Omaha	Nebraska	United States	68114
8	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
9	Chattanooga Oncology and Hematology Associates	Chattanooga	Tennessee	United States	37404
10	Tennessee Oncology	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Bristol-Myers Squibb

Investigators

• Principal Investigator: David R. Spigel, MD, SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

• Spigel DR, Greco FA, Waterhouse D, Shipley D, Lane CM, Vazquez ER, Clark BL, Infante JR, Bendell JC, Burris HA 3rd, Hainsworth JD. Phase II trial of FOLFOX6, bevacizumab, and cetuximab in the first-line treatment of metastatic colorectal cancer. Clin Adv Hematol Oncol. 2010 Jul;8(7):480-5, 498.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT00193219
• Other Study ID Numbers: SCRI GI 64
• First Posted: Sep 19, 2005
• Last Update Posted: Jan 11, 2022
• Last Verified: Dec 1, 2021

• Keywords provided by SCRI Development Innovations, LLC: Colon Cancer
• Additional relevant MeSH terms: Colonic Neoplasms; Leucovorin; Bevacizumab; Cetuximab; Fluorouracil; Oxaliplatin

Study Results

Participant Flow

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV
Period Title: Overall Study
STARTED	36
COMPLETED	6
NOT COMPLETED	30

Baseline Characteristics

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV
Overall Participants	36
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55
Sex: Female, Male (Count of Participants)
Female	16 44.4%
Male	20 55.6%
Region of Enrollment (participants) [Number]
United States	36 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR), the Percentage of Patients Who Experience an Objective Benefit From Treatment
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

This study was originally designed as a randomized study with patients receiving FOLFOX and bevacizumab with or without cetuximab. Following an amendment, all patients received cetuximab, FOLFOX and bevacizumab. The 5 patients randomized prior to the amendment that did not receive cetuximab are excluded from the analysis.

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV
Measure Participants	31
Number (95% Confidence Interval) [percentage of patients]	55

2. Secondary Outcome

Title	Progression Free Survival (PFS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Worsening of Their Disease
Description	Progression Free Survival (PFS) is defined as the interval between the start date of treatment and the date of occurrence of progressive disease or death.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

This study was originally designed as a randomized study with patients receiving FOLFOX and bevacizumab with or without cetuximab. Following an amendment, all patients received cetuximab, FOLFOX and bevacizumab. The 5 patients randomized prior to the amendment that did not receive cetuximab are excluded from the analysis.

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV
Measure Participants	31
Median (95% Confidence Interval) [months]	9

3. Secondary Outcome

Title	Overall Survival (OS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death
Description	Measured from the date of first treatment until the date of death from any cause
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

This study was originally designed as a randomized study with patients receiving FOLFOX and bevacizumab with or without cetuximab. Following an amendment, all patients received cetuximab, FOLFOX and bevacizumab. The 5 patients randomized prior to the amendment that did not receive cetuximab are excluded from the analysis.

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV
Measure Participants	31
Median (95% Confidence Interval) [months]	25.7

4. Secondary Outcome

Title	Number of Patients With Adverse Events as a Measure of Safety With FOLFOX6 Combined With Bevacizumab and Cetuximab
Description	The toxicity assessments were made according to the common terminology criteria for adverse events (CTCAE version 3.0) of the National Cancer Institute. Number of participants with Grade 1 to 5 adverse events are reported here.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

This study was originally designed as a randomized study with patients receiving FOLFOX and bevacizumab with or without cetuximab. Following an amendment, all patients received cetuximab, FOLFOX and bevacizumab. The 5 patients randomized prior to the amendment that did not receive cetuximab are excluded from the analysis.

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV
Measure Participants	31
Count of Participants [Participants]	31 86.1%

Adverse Events

Arm/Group Title	Bevacizumab/Cetuximab/FOLFOX		Bevacizumab/FOLFOX
Arm/Group Description	Bevacizumab 5 mg/kg IV Cetuximab 400 mg/m2 (first cycle only) IV on day 1 and 250 mg/m2 IV on day 8 with all subsequent cycles 250 mg/m2 IV on days 1 and 8 5-Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient) Leucovorin 350 mg IV Oxaliplatin 85 mg/m2 IV		Bevacizumab 5 mg/kg IV; Fluorouracil 400 mg/m2 bolus IV bolus followed by 2400 mg/m2 administered as continuous IV infusion over 46 hours via pump (outpatient); Leucovorin 350 mg IV; Oxaliplatin 85 mg/m2 IV
All Cause Mortality
	Bevacizumab/Cetuximab/FOLFOX		Bevacizumab/FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab/Cetuximab/FOLFOX		Bevacizumab/FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/31 (45.2%)		2/5 (40%)
Ear and labyrinth disorders
Hearing loss	0/31 (0%)	0	1/5 (20%)	1
Eye disorders
Blurred Vision	1/31 (3.2%)	1	0/5 (0%)	0
Gastrointestinal disorders
Pain - Gastrointestinal	2/31 (6.5%)	2	0/5 (0%)	0
Hemorrhage	1/31 (3.2%)	1	0/5 (0%)	0
Dehydration	1/31 (3.2%)	1	0/5 (0%)	0
Pain - Abdominal	1/31 (3.2%)	1	0/5 (0%)	0
Diarrhea	1/31 (3.2%)	1	0/5 (0%)	0
Acute Appendicitis	1/31 (3.2%)	1	0/5 (0%)	0
General disorders
Multi Organ Failure	1/31 (3.2%)	1	0/5 (0%)	0
Immune system disorders
Allergic Reaction	2/31 (6.5%)	2	0/5 (0%)	0
Infections and infestations
Sepsis	1/31 (3.2%)	1	0/5 (0%)	0
Febrile Neutropenia	1/31 (3.2%)	1	0/5 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Progressive Disease	3/31 (9.7%)	3	0/5 (0%)	0
Nervous system disorders
Mental Status	1/31 (3.2%)	1	0/5 (0%)	0
Psychiatric disorders
Dementia	1/31 (3.2%)	1	0/5 (0%)	0
Renal and urinary disorders
Pain - Renal/Genitourinary	1/31 (3.2%)	1	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
ARDS	1/31 (3.2%)	1	0/5 (0%)	0
Pulmonary infiltrates	0/31 (0%)	0	1/5 (20%)	1
Surgical and medical procedures
Chemoport Malfunction	1/31 (3.2%)	1	0/5 (0%)	0
Vascular disorders
Thrombosis/Thrombus/Embolism	4/31 (12.9%)	4	0/5 (0%)	0
Venous Occlusion	1/31 (3.2%)	1	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Bevacizumab/Cetuximab/FOLFOX		Bevacizumab/FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/31 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Anemia	19/31 (61.3%)	105	3/5 (60%)	45
Deep Vein Thrombosis	3/31 (9.7%)	21	0/5 (0%)	0
Edema	8/31 (25.8%)	21	0/5 (0%)	0
leukopenia	19/31 (61.3%)	76	0/5 (0%)	0
Neutropenia	25/31 (80.6%)	92	4/5 (80%)	34
thrombocytopenia	19/31 (61.3%)	78	0/5 (0%)	0
Cardiac disorders
Hypertension	2/31 (6.5%)	4	1/5 (20%)	6
Eye disorders
Blurred Vision	2/31 (6.5%)	4	0/5 (0%)	0
Gastrointestinal disorders
Anorexia	22/31 (71%)	83	1/5 (20%)	4
Constipation	14/31 (45.2%)	52	2/5 (40%)	7
Cramps (abdominal)	2/31 (6.5%)	3	0/5 (0%)	0
Dehydration	3/31 (9.7%)	4	0/5 (0%)	0
Diarrhea	22/31 (71%)	112	3/5 (60%)	14
Hemorrhoids	4/31 (12.9%)	15	0/5 (0%)	0
Indigestion	2/31 (6.5%)	2	0/5 (0%)	0
Mucositis	13/31 (41.9%)	35	2/5 (40%)	12
Nausea	24/31 (77.4%)	75	2/5 (40%)	18
reflux	2/31 (6.5%)	7	0/5 (0%)	0
Taste Alteration	7/31 (22.6%)	19	0/5 (0%)	0
Vomiting	14/31 (45.2%)	28	2/5 (40%)	3
General disorders
Chills	4/31 (12.9%)	8	0/5 (0%)	0
Cold Sensitivity	8/31 (25.8%)	36	2/5 (40%)	4
Fatigue	30/31 (96.8%)	248	5/5 (100%)	37
Fever	6/31 (19.4%)	9	1/5 (20%)	1
Hypersensitivity Reaction	5/31 (16.1%)	5	1/5 (20%)	12
Insomnia	7/31 (22.6%)	13	2/5 (40%)	22
Night Sweats	0/31 (0%)	0	1/5 (20%)	3
Pain	20/31 (64.5%)	80	3/5 (60%)	16
Weakness	7/31 (22.6%)	34	0/5 (0%)	0
Hepatobiliary disorders
Elevated AST	2/31 (6.5%)	3	0/5 (0%)	0
Infections and infestations
Esophagitis	3/31 (9.7%)	5	0/5 (0%)	0
Febrile Neutropenia	3/31 (9.7%)	7	0/5 (0%)	0
Infection	3/31 (9.7%)	4	0/5 (0%)	0
Infection	2/31 (6.5%)	2	0/5 (0%)	0
sinus infection	2/31 (6.5%)	2	0/5 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	11/31 (35.5%)	36	0/5 (0%)	0
Hypoalbuminemia	2/31 (6.5%)	8	0/5 (0%)	0
Hypocalcemia	2/31 (6.5%)	3	0/5 (0%)	0
Hypokalemia	4/31 (12.9%)	6	0/5 (0%)	0
Hypomagnesemia	3/31 (9.7%)	10	0/5 (0%)	0
Proteinuria	12/31 (38.7%)	30	1/5 (20%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	7/31 (22.6%)	13	1/5 (20%)	1
Myalgia	3/31 (9.7%)	3	0/5 (0%)	0
Nervous system disorders
Altered Mental Status	2/31 (6.5%)	3	0/5 (0%)	0
Confusion	2/31 (6.5%)	3	0/5 (0%)	0
Dizziness	2/31 (6.5%)	2	0/5 (0%)	0
Motor Neuropathy	0/31 (0%)	0	1/5 (20%)	8
Sensory Neuropathy	20/31 (64.5%)	136	3/5 (60%)	36
Psychiatric disorders
Anxiety	3/31 (9.7%)	6	1/5 (20%)	1
Depression	4/31 (12.9%)	6	1/5 (20%)	2
Renal and urinary disorders
Dysuria	3/31 (9.7%)	5	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/31 (9.7%)	8	0/5 (0%)	0
Epistaxis	2/31 (6.5%)	3	2/5 (40%)	6
Flu Syndrome	0/31 (0%)	0	1/5 (20%)	3
Hiccoughs	0/31 (0%)	0	1/5 (20%)	1
Pulmonary embolism	5/31 (16.1%)	12	0/5 (0%)	0
Sinus Drainage	2/31 (6.5%)	2	0/5 (0%)	0
Sore Throat	4/31 (12.9%)	17	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	11/31 (35.5%)	54	1/5 (20%)	1
Fingertip Fissures	2/31 (6.5%)	12	0/5 (0%)	0
Nail Changes	4/31 (12.9%)	16	1/5 (20%)	1
palmar plantar erythrodysesthesia	5/31 (16.1%)	16	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.