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Phase 2 Randomized Study of Adriamycin & Docetaxel in the First-line Treatment of Locally Advanced or Metastatic Breast Cancer Patients With Measurable Primary Breast Tumor to Validate Gene Expression & Proteomic Signatures Predictive of Treatment Response

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Phase 2 Randomized Study of Adriamycin & Docetaxel in the First-line Treatment of Locally Advanced or Metastatic Breast Cancer Patients With Measurable Primary Breast Tumor to Validate Gene Expression & Proteomic Signatures Predictive of Treatment Response

Many chemotherapeutic agents are active in breast cancer, although response rate to any
individual drug is only 30-50%. The choice of chemotherapy is empirical, and development of
a chemosensitivity assay is desirable, to reduce costs, unnecessary toxicity, and loss of
window of opportunity to cure. Single molecular markers to predict sensitivity are not
highly accurate, as chemotherapy resistance mechanisms likely involve complex pathways.
High-throughput technologies such as gene expression microarray and Proteinchip array allow
simultaneous analysis of thousands of genes, and hundreds of proteins, and may be more
informative. We previously conducted a study on patients with measurable primary breast
tumor who received primary chemotherapy with an alternating regimen of adriamycin and
docetaxel, and generated tumor genomic and tumor and plasma proteomic signatures that
predicted for clinical and pathological response using high throughput discovery platforms.
This protocol aims to recruit 20 patients as an independent test set to validate the genomic
and proteomic signatures generated previously. Half the patients will be randomized to
receive 4 cycles of pre-operative adriamycin (Arm A) allowing validation of the
adriamycin-specific signatures, while the other half will be randomized to receive 4 cycles
of pre-operative docetaxel (Arm B) allowing validation of the docetaxel-specific signatures.
Subjects will then undergo resection of the primary breast tumor, followed by 4 cycles of
adjuvant therapy with the alternative drug (docetaxel in Arm A, adriamycin in Arm B). Serial
tumor and plasma samples will be obtained for genomic and proteomic analysis. The previously
generated genomic and proteomic signatures will be applied to this independent dataset to
categorize patients into good and poor responders, and the prediction correlated with actual
treatment responses. Secondary goals include the correlation of patient genotype with drug
pharmacokinetics, and the correlation of chemotherapy-induced peripheral blood mononuclear
cell gene expression changes with treatment response and toxicities

Inclusion Criteria:

Patients may be included in the study only if they meet all of the following criteria:

- Female, age 18 years or above.

- Histologic or cytologic diagnosis of breast carcinoma.

- T2-4 breast cancer with measurable primary breast tumor, defined as palpable tumor
with both diameters 2.0cm or greater as measured by caliper.

- Patients must not have received prior chemotherapy or hormonal therapy for the
treatment of breast cancer.

- Karnofsky performance status of 70 or higher.

- Estimated life expectancy of at least 12 weeks.

- Adequate organ function including the following:

- Bone marrow:

- Absolute neutrophil (segmented and bands) count (ANC)>= 1.5 x 10 9/L

- Platelets >= 100 x 10 9/L

- Hepatic:

- Bilirubin <= 1.5 x upper limit of normal (ULN),

- ALT or AST <= 2.5x ULN, (or <= 5 X with liver metastases)

- Renal:

- creatinine <= 1.5x ULN

- Left ventricular ejection fraction >= 50%

- Signed informed consent from patient or legal representative.

- Patients with reproductive potential must use an approved contraceptive method if
appropriate (eg, intrauterine device, birth control pills, or barrier device) during
and for three months after the study. Females with childbearing potential must have a
negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

Patients will be excluded from the study for any of the following reasons:

- Prior treatment for locally advanced or metastatic breast cancer.

- Treatment within the last 30 days with any investigational drug.

- Concurrent administration of any other tumor therapy, including cytotoxic
chemotherapy, hormonal therapy, and immunotherapy.

- Active infection that in the opinion of the investigator would compromise the
patient's ability to tolerate therapy.

- Pregnancy.

- Breast feeding.

- Serious concomitant disorders that would compromise the safety of the patient or
compromise the patient's ability to complete the study, at the discretion of the

- Poorly controlled diabetes mellitus.

- Second primary malignancy that is clinically detectable at the time of consideration
for study enrollment.

- Symptomatic brain metastasis.

- History of significant neurological or mental disorder, including seizures or

- Peripheral neuropathy of CTC grade 2 or above (NCI CTC version 3).

- History of hypersensitivity to drugs formulated in Tween 80, the vehicle used for
commercial docetaxel formulations.

Type of Study:


Study Design:

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

Outcome Measure:

Clinical and pathological response rate

Outcome Description:

Clinical and pathological response rate to four cycles of pre-operative chemotherapy.

Outcome Time Frame:

12 weeks

Safety Issue:


Principal Investigator


Investigator Role:

Principal Investigator

Investigator Affiliation:

National University Hospital, Singapore


Singapore: Domain Specific Review Boards

Study ID:




Start Date:

February 2007

Completion Date:

February 2014

Related Keywords:

  • Breast Cancer
  • Breast Neoplasms