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

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

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: paclitaxel

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 Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre - Singapore
  • Singapore, Singapore
    • KK Women's and Children Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pathological complete response rate	Pathological response will be assessed by evaluation of surgical specimen after completion of protocol treatment.

Secondary Outcome Measures

Outcome Measure	Time Frame
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.

Collaborators and Investigators

• Sponsor: 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

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: January 3, 2008
• First Submitted That Met QC Criteria: January 5, 2008
• First Posted (Estimate): January 9, 2008

Study Record Updates

• Last Update Posted (Estimate): June 19, 2013
• Last Update Submitted That Met QC Criteria: June 18, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Carboplatin; Paclitaxel; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: CDR0000579522; SINGAPORE-NCC-0701