Paclitaxel, Doxorubicin, and Cyclophosphamide With Or Without Carboplatin in Treating Women With Locally Advanced Breast Cancer That Can Be Removed by Surgery

Sponsor

National Cancer Centre, Singapore (Other)

Overall Status

Terminated

CT.gov ID

NCT00589238

Collaborator

(none)

Enrollment

Locations

Arms

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, doxorubicin, cyclophosphamide, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether combination chemotherapy is more effective with or without carboplatin in treating breast cancer.

PURPOSE: This randomized phase II trial is studying giving paclitaxel together with doxorubicin and cyclophosphamide to see how well it works compared to giving paclitaxel together with doxorubicin, cyclophosphamide, and carboplatin in treating women with locally advanced breast cancer that can be removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: carboplatin Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: paclitaxel	Phase 2

Detailed Description

OBJECTIVES:

Primary

To evaluate tumor pathological complete response rate after neoadjuvant paclitaxel with vs without carboplatin followed by cyclophosphamide and doxorubicin hydrochloride in women with basal-type subtype primary breast cancer.

Secondary

To evaluate the clinical and pathological overall response rate.
To evaluate safety and toxicity.
To evaluate disease-free survival and overall survival.
To correlate low BRCA1 expression (protein and mRNA), p53 mutation, positive CK5/6, positive CK 14, basal-like gene expression profile, and response to carboplatin-based treatment.

OUTLINE: This is a multicenter study. Patients are stratified according to clinical stage (T2-3 vs T4). Patients are randomized to 1 of 2 treatment arms.

Arm I (standard therapy): Patients receive paclitaxel IV over 1 hour once weekly in weeks 1-12. Patients then receive doxorubicin hydrochloride IV and cyclophosphamide IV on days 1, 8, and 15. Treatment with doxorubicin hydrochloride and cyclophosphamide repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II (experimental therapy): Patients receive paclitaxel IV over 1 hour and carboplatin IV over 15 to 20 minutes on days 1, 8, and 15. Treatment with paclitaxel and carboplatin repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin hydrochloride and cyclophosphamide as in arm I.

All patients will then undergo surgical resection of the tumor.

Patients undergo biopsy for correlative studies. Samples are analyzed for estrogen receptor and progesterone receptor status, and molecular endpoints (CK 5/6, CK14, p53, BRCA, and EGFR) by RT-PCR, immunohistochemistry, protein expression, and gene expression profiling.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Study Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomised Phase II Trial of Neoadjuvant Weekly Paclitaxel Plus Carboplatin Compared to Weekly Paclitaxel Alone Followed in Both Arms by Doxorubicin and Cyclophosphamide for Operable or Locally Advanced Basal-like Subtype Breast Cancer Correlating BRCA-1 mRNA and Protein Expression With Carboplatin Response

Study Start Date :

Jan 1, 2008

Actual Primary Completion Date :

Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Other: Arm 1 (Standard Arm) Arm 1 (Standard Arm) Preoperative (primary/ neoadjuvant) intravenous weekly paclitaxel 80 mg/m2 for 12 weeks followed by doxorubicin 60 mg/m2 in combination with cyclophosphamide 600 mg/m2 every 21 days for 4 cycles.	Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: paclitaxel
Experimental: Arm 2 (Experimental Arm) Arm 2 (Experimental Arm) Preoperative intravenous weekly paclitaxel 80 mg/m2 in combination with carboplatin AUC 2 on D1, D8 and D15 every 28 days for 4 cycles followed by doxorubicin 60 mg/m2 in combination with cyclophosphamide 600 mg/m2 every 21 days for 4 cycles.	Drug: carboplatin Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: paclitaxel

Arm

Intervention/Treatment

Other: Arm 1 (Standard Arm)

Arm 1 (Standard Arm) Preoperative (primary/ neoadjuvant) intravenous weekly paclitaxel 80 mg/m2 for 12 weeks followed by doxorubicin 60 mg/m2 in combination with cyclophosphamide 600 mg/m2 every 21 days for 4 cycles.

Drug: cyclophosphamide

Drug: doxorubicin hydrochloride

Drug: paclitaxel

Experimental: Arm 2 (Experimental Arm)

Arm 2 (Experimental Arm) Preoperative intravenous weekly paclitaxel 80 mg/m2 in combination with carboplatin AUC 2 on D1, D8 and D15 every 28 days for 4 cycles followed by doxorubicin 60 mg/m2 in combination with cyclophosphamide 600 mg/m2 every 21 days for 4 cycles.

Drug: carboplatin

Drug: cyclophosphamide

Drug: doxorubicin hydrochloride

Drug: paclitaxel

Outcome Measures

Primary Outcome Measures

Pathological complete response rate [Pathological response will be assessed by evaluation of surgical specimen after completion of protocol treatment.]

Secondary Outcome Measures

Clinical and pathological overall response rates [Clinical response: Serial 4 weekly clinical examination; Mammography, breast ultrasound: Baseline, 3 weeks after treatment protocol or documented clinical progression. Pathological response: Evaluation of surgical specimen after protocol treatment.]
Overall and disease-free survival [Clinical response: Serial 4 weekly clinical examination; Mammography, breast ultrasound: Baseline, 3 weeks after treatment protocol or documented clinical progression. Pathological response: Evaluation of surgical specimen after protocol treatment.]
Incidence of each toxicity item [Clinical response: Serial 4 weekly clinical examination; Mammography, breast ultrasound: Baseline, 3 weeks after treatment protocol or documented clinical progression. Pathological response: Evaluation of surgical specimen after protocol treatment.]
Correlation between low BRCA1 expression (protein and mRNA), p53 mutation, positive CK5/6, positive CK14, basal like gene expression profile, and response to carboplatin based treatment [Clinical response: Serial 4 weekly clinical examination; Mammography, breast ultrasound: Baseline, 3 weeks after treatment protocol or documented clinical progression. Pathological response: Evaluation of surgical specimen after protocol treatment.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed invasive basal-type breast cancer meeting the following criteria:
Newly diagnosed disease
Locally advanced or operable primary disease > 2 cm, without evidence of metastatic disease
Clinical T2 (> 2 cm), T3 (> 5 cm), or T4 primary tumors with or without clinical lymph node involvement (N0-3)
T4 tumors are defined by any of the following:
Skin ulceration
Satellite nodules
Peau d' orange (skin edema)
Chest wall invasion
Inflammatory breast cancer
Her-2/neu 0-1+ by IHC (or negative by fluorescent in situ hybridization if Her-2 2+ by immunohistochemistry)
No metastatic disease
Hormone receptor status:
Estrogen and progesterone receptor-negative disease

PATIENT CHARACTERISTICS:

Inclusion criteria:

Female
Menopausal status not specified
ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
Life expectancy > 10 years
Leukocytes ≥ 3,000/μL
Absolute neutrophil count ≥ 1,500/μL
Platelets ≥ 100,000/μL
Total bilirubin normal
AST and ALT ≤ 2.5 times upper limit of normal
Creatinine normal OR creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Fertile patients must use effective contraception
Cardiac ejection fraction ≥ 50% as assessed by MUGA scan or 2D echocardiogram

Exclusion criteria:

History of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, carboplatin, or other agents used in the study
Pre-existing peripheral neuropathy
Uncontrolled intercurrent illness including, but not limited to, any of the following:
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia
Psychiatric illness or social situations that would limit compliance with study requirements
Prior malignancies except for basal cell carcinoma of the skin or curatively treated carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

No prior chemotherapy or radiotherapy
No HIV-positive patients receiving combination antiretroviral therapy
No concurrent primary growth factor prophylaxis
No other concurrent investigational agents
No other concurrent chemotherapy, immunotherapy, hormonal cancer therapy, surgery for cancer, or experimental medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Centre - Singapore	Singapore		Singapore	169610
2	KK Women's and Children Hospital	Singapore		Singapore

Sponsors and Collaborators

National Cancer Centre, Singapore

Investigators

Principal Investigator: Wong Nan Soon, MBBS, MRCP, FAMS, National Cancer Centre, Singapore
Principal Investigator: Ann Lee Siew Gek, National Cancer Centre, Singapore