Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer - Full Text View

Sponsored by:	Gruppo Oncologico del Nord-Ovest
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00719797

Purpose

RATIONALE: Drugs used in chemotherapy, such as irinotecan, 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. Monoclonal antibodies, such as 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. Giving combination chemotherapy together with bevacizumab may kill more tumor cells.

PURPOSE: This randomized phase III trial is comparing two combination chemotherapy regimens given together with bevacizumab to see how well they work as first-line therapy in treating patients with metastatic colorectal cancer that cannot be removed by surgery.

Condition	Intervention	Phase
Colorectal Cancer	Drug: bevacizumab Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: oxaliplatin	Phase III

MedlinePlus related topics: Cancer Colorectal Cancer

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

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label
Official Title:	A Phase III Randomized Trial of FOLFOXIRI + Bevacizumab Versus FOLFIRI + Bevacizumab as First- Line Treatment for Metastatic Colorectal Cancer.

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

Primary Outcome Measures:

Progression-free survival [ Designated as safety issue: No ]

Secondary Outcome Measures:

Overall response rate [ Designated as safety issue: No ]
Duration of response [ Designated as safety issue: No ]
Secondary R0 surgery rates of metastases [ Designated as safety issue: No ]
Overall survival [ Designated as safety issue: No ]
Surrogate markers predictive of bevacizumab activity [ Designated as safety issue: No ]

Estimated Enrollment:	450
Study Start Date:	July 2008
Estimated Primary Completion Date:	November 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I (FOLFOXIRI): Experimental Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.	Drug: bevacizumab Given IV Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV
Arm II (FOLFIRI): Experimental Patients receive irinotecan hydrochloride IV over 1 hour, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.	Drug: bevacizumab Given IV Drug: fluorouracil Given IV Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV

Detailed Description:

OBJECTIVES:

Primary

To compare the progression-free survival of bevacizumab in combination with oxaliplatin, irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFOXIRI) versus bevacizumab in combination with irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with unresectable, metastatic colorectal cancer.

Secondary

To evaluate the safety profile, including long-term adverse events of these regimens in these patients.
To compare the overall response rate, duration of response, and secondary R0 surgery rates of metastases and overall survival between treatment arms.
To evaluate potential surrogate markers predictive of bevacizumab activity.

OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1-2), prior adjuvant chemotherapy (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

Arm I (FOLFOXIRI): Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.
Arm II (FOLFIRI): Patients receive irinotecan hydrochloride IV over 1 hour, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.

In both arms, treatment repeats every 2 weeks for up to 12 courses. Treatment with bevacizumab, fluorouracil, and leucovorin calcium continues in the absence of disease progression or unacceptable toxicity.

Patients undergo serum extraction and blood sample collection periodically for genotyping studies. Patients also undergo collection of tumoral sections from paraffin embedded primary and/or metastatic lesions periodically for immunohistochemical analyses.

After completion of study treatment, patients are followed every 8 weeks.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed colorectal cancer
- Unresectable metastatic disease
Measurable disease, defined as ≥ 1 measurable lesion according to RECIST criteria
No prior chemotherapy for metastatic disease
No untreated brain metastases, spinal cord compression, or primary brain tumors
No history or evidence of CNS disease by physical examination unless adequately treated (e.g., uncontrolled seizure despite standard medical therapy or history of stroke)

PATIENT CHARACTERISTICS:

Inclusion criteria:

ECOG performance status (PS) 0-2 (≤ 70 years of age) OR ECOG PS 0 (71-75 years of age)
Life expectancy ≥ 12 weeks
Neutrophils ≥ 1.5 x 10^9/L
Platelet count ≥ 100 x 10^9/L
Hemoglobin > 9 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN if f liver metastases present)
Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases present)
Creatinine clearance > 50 mL/min OR serum creatinine ≤ 1.5 times ULN
Proteinuria < 2+ by dipstick OR urine protein ≤ 1 g by 24-hr urine collection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception

Exclusion criteria:

Serious, nonhealing wound, ulcer, or bone fracture
Evidence of bleeding diathesis or coagulopathy
Uncontrolled hypertension
Clinically significant (i.e., active) cardiovascular disease, including any of the following:
- Cerebrovascular accidents within the past 6 months
- Myocardial infarction within the past 6 months
- Unstable angina
- New York Heart Association class II-IV congestive heart failure
- Serious cardiac arrhythmia requiring medication
Known allergy to Chinese hamster ovary cell proteins or any of the components of the study medications
Other co-existing malignancy or malignancy diagnosed within the past 5 years, except for basal cell or squamous cell carcinoma, or carcinoma in situ of the cervix
Symptomatic peripheral neuropathy ≥ grade 1 according to the NCI Common Toxicity Criteria
Lack of physical integrity of the upper gastrointestinal tract
Malabsorption syndrome
Inability to take oral medication
Significant traumatic injury within the past 28 days

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
More than 4 weeks since prior radiotherapy
More than 10 days since prior and no concurrent ongoing treatment with anticoagulants for therapeutic purposes
More than 28 days since prior and no concurrent major surgical procedure
More than 28 days since prior open biopsy
More than 30 days since prior investigational agents
No concurrent chronic daily high-dose acetylsalicylic acid (> 325 mg/day)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00719797

Locations

Italy
Presidio Ospedaliero di Livorno	Recruiting
Livorno, Italy, 57100
Contact: Contact Person 39-058-622-3189

Sponsors and Collaborators

Gruppo Oncologico del Nord-Ovest

Investigators

Principal Investigator:

Alfredo Falcone, MD

Presidio Ospedaliero di Livorno

More Information

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

Study ID Numbers:	CDR0000598582, GONO-TRIBE, ASL608LIOM04, EUDRACT:2008-001537-10
Study First Received:	July 19, 2008
Last Updated:	December 16, 2008
ClinicalTrials.gov Identifier:	NCT00719797
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

stage IV rectal cancer
stage IV colon cancer
stage III rectal cancer
stage III colon cancer

Study placed in the following topic categories:

Digestive System Neoplasms
Rectal Neoplasms
Gastrointestinal Diseases
Irinotecan
Colonic Diseases
Leucovorin
Bevacizumab
Intestinal Diseases
Rectal Diseases
Camptothecin

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
Enzyme Inhibitors
Angiogenesis Inhibitors

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

ClinicalTrials.gov processed this record on January 13, 2009