Cetuximab and Bevacizumab as First-Line Therapy Followed By Combination Chemotherapy and Bevacizumab With or Without Cetuximab as Second-Line Therapy in Treating Patients With Stage IV Colorectal Cancer - Full Text View

Sponsors and Collaborators:	North Central Cancer Treatment Group National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00571740

Purpose

RATIONALE: Monoclonal antibodies, such as cetuximab and bevacizumab, 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. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibodies together with combination chemotherapy may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying how well giving cetuximab together bevacizumab works as first-line therapy, followed by combination chemotherapy and bevacizumab with or without cetuximab as second-line therapy in treating patients with stage IV colorectal cancer.

Condition	Intervention	Phase
Colorectal Cancer	Drug: bevacizumab Drug: cetuximab Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin	Phase II

MedlinePlus related topics: Cancer Colorectal Cancer

Drug Information available for: Leucovorin Calcium Citrovorum factor Folinic acid calcium salt pentahydrate Leucovorin Bevacizumab Fluorouracil Oxaliplatin Calcium gluconate Cetuximab

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized
Official Title:	Randomized Phase II Trial of Cetuximab/Bevacizumab (CB) as Palliative First-Line Therapy in Patients With Advanced Colorectal Cancer Followed by FOLFOX+CB vs. FOLFOX+B

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Progression-free survival (PFS) rate at 6 months [ Designated as safety issue: No ]

Secondary Outcome Measures:

Tumor response rate associated with second-line therapy [ Designated as safety issue: No ]
Time to progression during second-line therapy [ Designated as safety issue: No ]
Duration of response [ Designated as safety issue: No ]
Quality of life [ Designated as safety issue: No ]

Estimated Enrollment:	100
Study Start Date:	October 2007
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I (second-line therapy): Active Comparator Patients receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.	Drug: bevacizumab Given IV Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Arm II (second-line therapy): Experimental Patients receive bevacizumab and modified FOLFOX7 as in arm I. Patients also receive cetuximab IV over 2 hours on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.	Drug: bevacizumab Given IV Drug: cetuximab Given IV Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV

Detailed Description:

OBJECTIVES:

Primary

To assess the efficacy of bevacizumab and cetuximab as first-line treatment for metastatic colorectal cancer, as measured by percentage of patients who remain progression-free at 6 months.

Secondary

To evaluate adverse events, confirmed response, duration of response, time to disease progression, time to treatment failure, and survival of patients treated with bevacizumab and cetuximab.
To evaluate adverse events, confirmed response, duration of response, time to disease progression, time to treatment failure, and survival of patients who are refractory to dual-agent bevacizumab and cetuximab and are subsequently treated with modified FOLFOX7 chemotherapy and bevacizumab with or without cetuximab.
To evaluate quality of life parameters in patients treated with these regimens.
To estimate the direct medical resource utilization and costs.
To assess the reliability of FDG-PET as a measurement of early treatment response, as measured by percentage of patients who are progression-free at 6 months.
To identify circulating angiogenesis biomarkers.
To assay the activity of pro-angiogenic factors in plasma angiogenic assays.

OUTLINE: This is a multicenter study*. Patients are stratified according to ECOG performance status (0-1 vs 2) and number of metastatic sites (1 vs > 1).

NOTE: *Participating site must be PET-qualified.

First-line therapy: Patients receive bevacizumab IV over 30-90 minutes and cetuximab IV over 2 hours on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients with progressive disease proceed to second-line therapy.
Second-line therapy: Patients are randomized* to 1 of 2 treatment arms.
- Arm I (modified FOLFOX7 with bevacizumab only): Patients receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.
- Arm II (modified FOLFOX7 with bevacizumab and cetuximab): Patients receive bevacizumab and modified FOLFOX7 as in arm I. Patients also receive cetuximab IV over 2 hours on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *Randomization occurs prior to receiving first-line therapy.

Patients undergo blood sample collection periodically for translational studies. Samples are analyzed for circulating endothelial cells and endothelial progenitor cells via flow cytometry; angiogenic activity of serum/plasma in angiogenesis-dependent diseases via endothelial proliferation assay and matrigel tube formation assay; and circulating angiogenesis biomarkers (i.e., free VEGF, soluble FLT-1, and KDR) via ELISA.

Quality of life is assessed periodically using the UNISCALE, Skindex-16, and Skin Assessment Questionnaires.

After completion of study treatment, patients are followed every 6 months for up to 3 years.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed stage IV colorectal cancer
Measurable disease, defined as at least one lesion whose longest diameter can be accurately measured as ≥ 2.0 cm by conventional techniques OR ≥ 1.0 cm by spiral CT scan
Must not be a candidate for neoadjuvant therapy
No CNS or brain metastases

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
Life expectancy ≥ 12 weeks
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 10.0 g/dL
Total bilirubin < 1.5 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 3 times ULN
AST ≤ 3 times ULN
Creatinine ≤ 1.5 x times ULN
Proteinuria < 1+ by urinalysis OR proteinuria < 1 g by 24-hour urine collection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
English-speaking patients must have the ability to complete questionnaires by themselves or with assistance
Must be willing to provide blood and tissue samples for research purposes
No history of hypertensive crisis or hypertensive encephalopathy
No blood pressure > 150/100 mm Hg
No New York Heart Association (NYHA) class II-IV congestive heart failure
No myocardial infarction or unstable angina within the past 6 months
No stroke or transient ischemic attack within the past 6 months
No clinically significant vascular disease (e.g., aortic aneurysm or aortic dissection)
No clinically significant peripheral vascular disease
No evidence of bleeding diathesis or coagulopathy
No significant traumatic injury within the past 28 days
No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No serious nonhealing wound, ulcer, or bone fracture

PRIOR CONCURRENT THERAPY:

No prior nonsurgical treatment for stage IV disease
- Adjuvant therapy allowed if completed > 6 months prior to study registration
More than 4 weeks since prior and no concurrent or planned participation in another experimental drug study
No prior therapy that specifically and directly targets the EGFR pathway
No prior monoclonal antibody therapy
More than 28 days since prior major surgery or open biopsy
More than 7 days since prior minor surgery, such as fine-needle aspirations or core biopsies
- Placement of a vascular access device does not have to meet this criterion
No concurrent major surgery

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00571740

Sponsors and Collaborators

North Central Cancer Treatment Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Axel Grothey, MD	Mayo Clinic
Investigator:	Val J. Lowe, MD	Mayo Clinic
Investigator:	Debabrata Mukhopadhyay, PhD	Mayo Clinic

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000578111, NCCTG-N0548
Study First Received:	December 11, 2007
Last Updated:	December 19, 2008
ClinicalTrials.gov Identifier:	NCT00571740
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

stage IV colon cancer
stage IV rectal cancer
recurrent colon cancer
recurrent rectal cancer

Study placed in the following topic categories:

Digestive System Neoplasms
Rectal Neoplasms
Gastrointestinal Diseases
Cetuximab
Colonic Diseases
Leucovorin
Bevacizumab
Intestinal Diseases
Rectal Diseases
Recurrence

Intestinal Neoplasms
Rectal neoplasm
Calcium, Dietary
Oxaliplatin
Digestive System Diseases
Fluorouracil
Gastrointestinal Neoplasms
Rectal cancer
Colorectal Neoplasms

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Vitamin B Complex
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Growth Substances
Physiological Effects of Drugs
Angiogenesis Inhibitors

Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Neoplasms by Site
Therapeutic Uses
Vitamins
Growth Inhibitors
Angiogenesis Modulating Agents
Micronutrients

ClinicalTrials.gov processed this record on January 13, 2009