Neoadjuvant Biweekly Treatment Followed by Weekly Treatment of Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Chao Family Comprehensive Cancer Center, University of California, Irvine
ClinicalTrials.gov Identifier:
NCT00256243
First received: November 17, 2005
Last updated: January 28, 2014
Last verified: January 2014
  Purpose

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. 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. Two of the smaller trials suggested a survival advantage for patients treated with neoadjuvant chemotherapy. Other studies, including the largest trial (1,523 patients) run by the NSABP, found no differences in disease-free and overall survival.

Induction of a Microscopic path clinical response (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.

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 granulocyte colony-stimulating factor (G-CSF). 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 clinical response (CR). 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. 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 herceptin has demonstrated a survival advantage over paclitaxel and herceptin 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 herceptin and paclitaxel resulted in a six-month improvement in the time it took for the disease to progress, compared to the standard herceptin and paclitaxel regimen. The study found median survival in the herceptin 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. Therefore, we propose to use 4 cycles of AC q 2 weeks, as used in the dose dense adjuvant study with Granulocyte-macrophage colony-stimulating factor (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 overexpressors by FISH 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.

In a separate trial, GM-CSF was used in breast cancer patients treated with adriamycin based chemotherapy as the preferred growth factor in a neoadjuvant setting. The initial results are suggestive of improved survival of breast cancer patients given 6 versus 5 versus 4 cycles of chemotherapy with GM-CSF 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.


Condition Intervention Phase
Inflammatory Breast Cancer
Locally Advanced Breast Cancer
Drug: Doxorubicin
Drug: Cyclophosphamide
Drug: Paclitaxel
Drug: Carboplatin
Drug: GM-CSF
Drug: Trastuzumab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University of California, Irvine:

Primary Outcome Measures:
  • Clinical Response Rate [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    Clinical response (CR): Normal breast on physical exam. No mass, no thickening, no erythema, no peau d'orange.


Secondary Outcome Measures:
  • Microscopic Pathological Response Rate [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    pathological response rate: No evidence of microscopic invasive tumor at the primary tumor site in the surgical specimen.


Enrollment: 48
Study Start Date: April 2004
Study Completion Date: July 2012
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • Patients must meet one of the criteria defined below (indicate one):

    1. 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.
    2. Stage IIIB (T4, Any N, M0) or (Any T, N3, M0) disease.
  • Physical examination, chest x-ray and any x-rays or scans needed for tumor assessment must be performed within 90 days prior to registration.
  • 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.
  • 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.
  • 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.
  • Patients must have a performance status of 0-2 by Zubrod criteria
  • 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.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00256243

Locations
United States, California
Chao Family Comprehensive Cancer Center
Orange, California, United States, 92868
Sponsors and Collaborators
University of California, Irvine
Investigators
Principal Investigator: Rita Mehta, MD Chao Family Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Chao Family Comprehensive Cancer Center, Cancer Center, University of California, Irvine
ClinicalTrials.gov Identifier: NCT00256243     History of Changes
Other Study ID Numbers: UCI 03-70, 2004-3517
Study First Received: November 17, 2005
Results First Received: August 28, 2009
Last Updated: January 28, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Inflammatory Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Liposomal doxorubicin
Trastuzumab
Carboplatin
Cyclophosphamide
Doxorubicin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 01, 2014