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Neoadjuvant Biweekly Treatment Followed by Weekly Treatment of Breast Cancer

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ClinicalTrials.gov Identifier: NCT00256243
Recruitment Status : Completed
First Posted : November 21, 2005
Results First Posted : March 17, 2014
Last Update Posted : March 2, 2018
Sponsor:
Information provided by (Responsible Party):
Rita Sanghvi, Mehta, University of California, Irvine

November 17, 2005
November 21, 2005
August 28, 2009
March 17, 2014
March 2, 2018
April 2004
March 2011   (Final data collection date for primary outcome measure)
Clinical Response Rate [ Time Frame: 5 years ]
Clinical response (CR): Normal breast on physical exam. No mass, no thickening, no erythema, no peau d'orange.
To measure the clinic response rates
Complete list of historical versions of study NCT00256243 on ClinicalTrials.gov Archive Site
Microscopic Pathological Response Rate [ Time Frame: 5 years ]
pathological response rate: No evidence of microscopic invasive tumor at the primary tumor site in the surgical specimen.
To measure the microscopic pathological response rate
Not Provided
Not Provided
 
Neoadjuvant Biweekly Treatment Followed by Weekly Treatment of Breast Cancer
A Pilot Study of Neoadjuvant Biweekly Doxorubicin and Cyclophosphamide (AC) With GMCSF Followed by Weekly Carboplatin/Paclitaxel With Plus or Minus Trastuzumab (TC ± H) in the Treatment of Breast Cancer
We proposed to use 4 cycles of AC q 2 weeks, as used in the dose dense adjuvant study with GM-CSF support on days 3-9 of the cycle. After the completion of AC we plan to administer paclitaxel and carboplatin weekly for a total of 12 doses with one week rest after every 3 weeks of treatment over 12 weeks. Patients who are her-2 over-expressors by FISH (fluorescence in situ hybridization) will also receive Trastuzumab with weekly carboplatin and paclitaxel as the combination TC±H has been found to be synergistic in advanced breast cancer with improved clinical outcome.

Neoadjuvant chemotherapy, also termed primary, induction, or preoperative chemotherapy, is defined as chemotherapy administered before locoregional treatment. It was first used in locally advanced breast cancer 30 years ago. Classically, these tumors were treated with radical surgery and/or radiotherapy. However, despite this aggressive local therapy, most patients relapsed with distant metastases and eventually died (1,2). The aim of neoadjuvant therapy is to reduce the tumor volume in patients before surgical resection, thus increasing the likelihood of breast conservation. More recently, neoadjuvant therapy has been studied as a way of testing the relevance of biological markers in predicting disease outcome.

At least six randomized trials have compared survival in patients managed with either the neoadjuvant or adjuvant approaches(3,4,5,6,7,8,9). Two of the smaller trials suggested a survival advantage for patients treated with neoadjuvant chemotherapy (5,6). Other studies, including the largest trial (1523 patients) run by the NSABP, found no differences in disease-free and overall survival (4,6,9).

Induction of a pCR should be one of the primary goals of neoadjuvant therapy because patients with no evidence of tumor cells in breast and lymph nodes after treatment may have a longer disease-free and overall survival (10).

Biweekly and weekly regimens may enhance dose intensity by minimizing re-growth of cells between cycles of treatment. In fact, dose dense regimens have even shown a survival benefit in an adjuvant setting in lymph node positive breast cancer, made possible with use of G-CSF (11). There is as yet no standard best neoadjuvant treatment. Generally patients receive AC (NSABP 14) on 3-weekly regimens in neoadjuvant setting. In addition, incorporation of taxanes on a 3 weekly schedule has resulted in statistically higher pathological CR (12,13). More recently, weekly paclitaxel regimens have reported increased pathological responses compared to 3 weekly taxane regimens. Carboplatin has also emerged as an effective agent in the treatment of metastatic breast cancer (14). Moreover, the combination of carboplatin and paclitaxel has been found to be synergistic both in three-weekly regimens and weekly regimens. In fact, combination of carboplatin, paclitaxel and trastuzumab has demonstrated a survival advantage over paclitaxel and trastuzumab alone. The Phase III study, the preliminary results of which were presented at the San Antonio Breast Cancer Symposium, show that the addition of carboplatin to trastuzumab and paclitaxel resulted in a six-month improvement in the time it took for the disease to progress, compared to the standard trastuzumab and paclitaxel regimen. The study found median survival in the trastuzumab and paclitaxel arm was 33.5 months, while the group receiving the tripartite therapy had yet to reach that point after 36 months of follow-up. Furthermore, the weekly regimens of these drugs have been found to have significantly improved tolerability over three weekly regimens (15). Therefore, we propose to use 4 cycles of AC q 2 weeks, as used in the dose dense adjuvant study with GM-CSF support on days 5-14 of the cycle. After the completion of AC we plan to administer taxol and carboplatin weekly for a total of 9 doses with one week rest after every 3 weeks of treatment over 12 weeks.

Patients who are her-2 overexpressors by FISH will also receive Trastuzumab with weekly carboplatin and paclitaxel as the combination has been found to be synergistic in advanced breast cancer with improved clinical outcome.

In a separate trial, GMCSF was used in breast cancer patients treated with adriamycin based chemotherapy as the preferred growth factor in a neoadjuvant setting (16). The initial results are suggestive of improved survival of breast cancer patients given 6 versus 5 versus 4 cycles of chemotherapy with GMCSF support. Higher dendritic cell (DC) trafficking showed a trend toward improved survival. Moreover, intrapatient comparison before and after treatment showed that the percentage of S100+ DC significantly increased over the course of GM-CSF treatment. The results form the basis of current hypothesis that the primary tumor may be an in vivo antigenic stimulus for dendritic cell trafficking, and that the combination of prolonged neoadjuvant chemotherapy with GM-CSF induced immune enhancement may contribute to better tumor control and better survival.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Breast Cancer
  • Drug: Doxorubicin
    60 mg/m2 IV, bolus once every 14 days x 2-4 cycles
  • Drug: Cyclophosphamide
    600 mg/m2 IV once every 14 days x 2-4 cycles
  • Drug: Paclitaxel
    80 mg/m2 IV over 1 hour once weekly for 9-12 doses beginning two weeks after completion of last AC dose
  • Drug: Carboplatin
    Area under the concentration curve (AUC) 2 IV once weekly for 9-12 doses beginning two weeks after completion of last AC dose
  • Drug: GM-CSF
    250 μg/mL IV on day 5-14 of each subcutaneous cycle of doxorubicin and injection cyclophosphamide
  • Drug: Trastuzumab
    AUC 2 IV weekly for 12-16 doses beginning two weeks after completion of last AC dose
Experimental: Chemotherapy with GM-CSF

Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Carboplatin/Paclitaxel with GM-CSF (day 2-6)

This regimen consists of intravenous administration of doxorubicin (Adriamycin) followed by cyclophosphamide (Cytoxan) every 14 days for a total of four cycles, unless stable disease or clinical progression is documented. Two weeks after completion of the last dose of AC, weekly Carboplatin/paclitaxel will be given for 3 weeks, followed by 1 week of rest, for a total of 12. Each clinic visit will last approximately 1 hour.

Patients who are her-2 overexpressors by FISH will also receive Trastuzumab with weekly carboplatin and paclitaxel as the combination has been found to be synergistic in advanced breast cancer with improved clinical outcome.

Interventions:
  • Drug: Doxorubicin
  • Drug: Cyclophosphamide
  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Drug: GM-CSF
  • Drug: Trastuzumab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
48
43
July 2012
March 2011   (Final data collection date for primary outcome measure)

Eligibility Criteria:

  1. Patients must be women with a histologically confirmed diagnosis of locally advanced or inflammatory breast carcinoma. Histologic confirmation shall be by either core needle biopsy or incisional biopsy. Punch biopsy is allowed if invasive breast cancer is documented.
  2. Patients must meet one of the criteria defined below (indicate one):

    a .Selected Stage IIB (T3, N0, M0) or IIIA (T3, N1-2, M0) disease judged primarily unresectable by an experienced breast surgeon; or otherwise deemed appropriate candidates for neoadjuvant treatment.

    b. Stage IIIB (T4, Any N, M0) or (Any T, N3, M0) disease.

  3. Physical examination, chest x-ray and any x-rays or scans needed for tumor assessment must be performed within 90 days prior to registration.
  4. Patients with the clinical diagnosis of congestive heart failure or angina pectoris are NOT eligible. Patients with hypertension or age > 60 years must have a Multiple Gated Acquisition (MUGA) or echocardiogram scan performed within 90 days prior to registration (indicate not applicable (NA) if no MUGA required) and Left Ventricular Ejection Fraction (LVEF) % must be greater than the institutional lower limit of normal.
  5. Patients must have a serum creatinine and bilirubin ≤ the institutional upper limit of normal, and an Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic pyruvic transaminase (SGPT) ≤ 2x the institutional upper limit of normal. These tests must have been performed within 90 days prior to registration.
  6. Patients must have an Absolute neutrophil count (ANC) of ≥ 1,500/μl and a platelet count of ≥ 100,000/μl. These tests must have been performed within 90 days prior to registration.
  7. Patients must have a performance status of 0-2 by Zubrod criteria
  8. Pregnant or nursing women may not participate due to the possibility of fetal harm or of harm to nursing infants from this treatment regimen. Women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. A urine pregnancy test is required for women of childbearing potential.
  9. All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
Sexes Eligible for Study: Female
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00256243
UCI 03-70
2004-3517 ( Other Identifier: University of California, Irvine )
Yes
Not Provided
Not Provided
Rita Sanghvi, Mehta, University of California, Irvine
Rita Sanghvi, Mehta
Not Provided
Principal Investigator: Rita Mehta, MD Chao Family Comprehensive Cancer Center
University of California, Irvine
February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP