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Combination Chemotherapy and Cetuximab or Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fox Chase Cancer Center
ClinicalTrials.gov Identifier:
NCT01280643
First received: January 20, 2011
Last updated: April 12, 2013
Last verified: April 2013
  Purpose

RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, oxaliplatin, capecitabine, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different combinations may kill more tumor cells. Monoclonal antibodies, such as bevacizumab and 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. Giving combination chemotherapy together with bevacizumab or cetuximab may kill more tumor cells.

PURPOSE:To evaluate the use of standard (KRAS) and experimental (thymidine phosphorylase, ERCC1 and BRAF) tumor testing can aid in selecting chemotherapy regimens


Condition Intervention
Metastatic Colorectal Cancer
Drug: fluorouracil
Drug: leucovorin calcium
Drug: oxaliplatin
Drug: irinotecan hydrochloride
Biological: bevacizumab
Biological: cetuximab
Drug: capecitabine
Genetic: mutation analysis
Genetic: gene expression analysis
Other: laboratory biomarker analysis
Other: immunohistochemistry staining method
Genetic: nucleic acid sequencing
Genetic: protein expression analysis
Genetic: polymerase chain reaction
Genetic: DNA analysis

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Exploratory Study of Chemotherapy for Metastatic Colorectal Cancer Based Upon Thymidine Phosphorylase Expression, KRAS and BRAF Mutation Status, and ERCC1 Expression

Resource links provided by NLM:


Further study details as provided by Fox Chase Cancer Center:

Primary Outcome Measures:
  • Feasibility, defined as a sufficient proportion of subjects having available tissue and an acceptable composite assay success rate among tested subjects [ Time Frame: Over 21 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Best overall response via RECIST [ Time Frame: Over 21 months ] [ Designated as safety issue: No ]
  • Time to failure of treatment strategy [ Time Frame: Over 21 months ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: Over 21 months ] [ Designated as safety issue: No ]

Enrollment: 11
Study Start Date: March 2010
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
Patients receive FOLFIRI chemotherapy comprising fluorouracil intravenously (IV) over 46 hours continuously, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive cetuximab IV over 60-120 minutes on days 1 and 8.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm B
Patients receive FOLFOX chemotherapy comprising fluorouracil IV over 46 hours continuously on day 1 and leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on days 1 and 15. Patients also receive cetuximab IV over 60-120 minutes on days 1 and 8.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm C
Patients receive FOLFIRI chemotherapy as in Arm A and bevacizumab IV over 30-90 minutes on days 1 and 15.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm D
Patients receive FOLFOX chemotherapy as in Arm B and bevacizumab IV over 30-90 minutes on days 1 and 15.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm E
Patients receive CapeIRI chemotherapy comprising capecitabine orally (PO) twice daily (BID) on days 1-14 and irinotecan hydrochloride IV over 90 minutes on days 1 and 8. Patients also receive cetuximab IV over 60-120 minutes on days 1 and 8.
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Drug: capecitabine
Given PO
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm F
Patients receive CapeOX chemotherapy comprising capecitabine PO BID on days 1-14 and oxaliplatin IV over 2 hours on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 1 and 8.
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Drug: capecitabine
Given PO
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: ARM G
Patients receive CapeIRI chemotherapy as in Arm E and bevacizumab IV over 30-90 minutes on day 1.
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: capecitabine
Given PO
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm H
Patients receive CapeOX chemotherapy as in Arm F and bevacizumab IV over 30-90 minutes on day 1.
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: capecitabine
Given PO
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies
Experimental: Arm I
Patients receive treatment as in Arm D.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Genetic: mutation analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
Genetic: protein expression analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Genetic: DNA analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the feasibility, as defined by completion of three specific marker assays and generation of clinically meaningful endpoints, of selecting treatment regimen components based on biologic tumor characteristics in chemotherapy-naïve patients with metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. To investigate the response rate associated with genotype/phenotype guided therapy using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

II. To investigate the time to failure of treatment strategy associated with genotype/phenotype guided therapy, defined as the time from initiation of investigational treatment strategy until death, disease progression, initiation of a new therapeutic agent, or disease progression while on a partial or complete treatment holiday.

III. To investigate the progression-free survival associated with genotype/phenotype guided therapy, defined as the time from enrollment to time of progression of disease or death.

OUTLINE: Patients are assigned to treatment groups based on marker assay results.

ARM A: TP-/uncertain, KRAS and BRAF wild-type, ERCC1 high ARM B: TP-/uncertain, KRAS and BRAF wild-type, ERCC1 low/uncertain ARM C: TP-/uncertain, KRAS or BRAF mutant/uncertain, ERCC1 high ARM D: TP-/uncertain, KRAS or BRAF mutant/uncertain, ERCC1 low/uncertain ARM E: TP+, KRAS and BRAF wild-type, ERCC1 high ARM F: TP+, KRAS and BRAF wild-type, ERCC1 low/uncertain ARM G: TP+, KRAS or BRAF mutant/uncertain, ERCC1 high ARM H: TP+, KRAS or BRAF mutant/uncertain, ERCC1 low/uncertain ARM I: TP uninterpretable, KRAS or BRAF uninterpretable, ERCC1 uninterpretable

KRAS testing is standard of care in patients with metastatic colorectal cancer; tymidine phosphorylase, ERCC1 and BRAF testing assays are still experimental.

Courses in arms A-D and arm I repeat every 28 days and courses in arms E-H repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 18 months.

  Eligibility

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

Inclusion Criteria:

  • Patients must have histologically confirmed colon or rectal cancer that has metastasized; no biopsy of metastatic site(s) are required if presentation is consistent with metastatic disease
  • Available archived tissue block or slides from the primary colon or rectal cancer; approximately 25 slides from the primary tumor tissue are necessary for testing of all markers
  • Patients must have measurable disease by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with computed tomography (CT) scan or clinical exam with calipers; lymph nodes must be 15 mm in shortest dimension as measured on CT scan
  • Patients may not have received prior therapy for metastatic colorectal cancer; prior adjuvant therapy (including any of the study agents) is permitted if completed > 6 months from the initial detection of metastatic disease
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 2 X institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 3 X institutional ULN or =< 5 X ULN if known liver metastases
  • Creatinine clearance >= 50 mL/min (as calculated by Cockroft and Gault formula)
  • Urine protein:creatinine (UPC) ratio < 1.0 at screening (as calculated from urine protein concentration and urine creatinine concentration); patients with a UPC ratio >= 1 will undergo a 24-hour urine collection, which must be adequate and demonstrate < 1 gram in order to participate
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had previous chemotherapy for metastatic colorectal cancer
  • Uncontrolled hypertension (>150/100 mmHg) despite a stable regimen of anti-hypertensive medication
  • History of cardiovascular disease, defined as previous myocardial infarction, cerebrovascular accident, uncontrolled congestive heart failure (New York Heart Association > Class II), clinically significant ventricular arrhythmia requiring medication, clinically significant peripheral vascular disease, or unstable angina within 6 months of study enrollment
  • Underlying neuropathy >= grade 2
  • Serious non-healing wounds, ulcers, or fistulas
  • Major surgery, open biopsy, or major traumatic injury within 28 days of registration, or anticipation of need for surgical procedure during course of study, and core biopsy or fine needle aspiration within 7 days of registration; closed biopsy or access port placement is acceptable
  • A history of thrombotic or hemorrhagic disorder; patients with elevated international normalized ratio (INR) (2.0 to 3.0) on stable doses of therapeutic anticoagulation are eligible
  • Untreated brain metastases; patients with treated brain metastases who have completed radiation therapy, are clinically and radiographically stable, and are off steroid therapy may be enrolled
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab, oxaliplatin, capecitabine, or other agents used in the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded; breastfeeding should be discontinued if the mother is treated with chemotherapy
  • Human Immunodeficiency Virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Patients must not have a history of another neoplasm < 5 years prior to enrollment, except for non-metastatic, non-melanoma skin cancer or carcinoma in situ of the cervix
  • Patients of child-bearing potential who are unwilling or unable to utilize contraceptive measures including barrier contraception
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01280643

Locations
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111-2497
Sponsors and Collaborators
Fox Chase Cancer Center
Investigators
Principal Investigator: Crystal Denlinger Fox Chase Cancer Center
  More Information

No publications provided

Responsible Party: Fox Chase Cancer Center
ClinicalTrials.gov Identifier: NCT01280643     History of Changes
Other Study ID Numbers: IRB 09-033, NCI-2011-00046
Study First Received: January 20, 2011
Last Updated: April 12, 2013
Health Authority: United States: Federal Government

Keywords provided by Fox Chase Cancer Center:
stage IVA colon cancer
stage IVA rectal cancer
stage IVB colon cancer
stage IVB rectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Antibodies
Antibodies, Monoclonal
Bevacizumab
Camptothecin
Capecitabine
Cetuximab
Fluorouracil
Irinotecan
Leucovorin
Levoleucovorin
Oxaliplatin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors

ClinicalTrials.gov processed this record on November 27, 2014