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An Exploratory Study of Chemotherapy for Metastatic Colorectal Cancer Based Upon Thymidine Phosphorylase Expression, KRAS and BRAF Mutation Status, and ERCC1 Expression

18 Years
Not Enrolling
Metastatic Colorectal Cancer

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Trial Information

An Exploratory Study of Chemotherapy for Metastatic Colorectal Cancer Based Upon Thymidine Phosphorylase Expression, KRAS and BRAF Mutation Status, and ERCC1 Expression


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.


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.

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

- 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

- Patients of child-bearing potential who are unwilling or unable to utilize
contraceptive measures including barrier contraception

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Feasibility, defined as a sufficient proportion of subjects having available tissue and an acceptable composite assay success rate among tested subjects

Outcome Time Frame:

Over 21 months

Safety Issue:


Principal Investigator

Crystal Denlinger

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fox Chase Cancer Center


United States: Federal Government

Study ID:

IRB 09-033



Start Date:

March 2010

Completion Date:

Related Keywords:

  • Metastatic Colorectal Cancer
  • stage IVA colon cancer
  • stage IVA rectal cancer
  • stage IVB colon cancer
  • stage IVB rectal cancer
  • Colorectal Neoplasms



Fox Chase Cancer Center Philadelphia, Pennsylvania  19111