Trial Information

Neoadjuvant Biweekly Doxorubicin and Cyclophosphamide With GMCSF Followed by Weekly Carboplatin/Nab-Paclitaxel Plus or Minus Trastuzumab (Herceptin) and Plus or Minus Bevacizumab (Avastin) in Treatment of Large or Inflammatory Breast Cancer-a Phase II Study

Background

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 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 the
use of G-CSF (1). There is no best standard neoadjuvant treatment yet. Generally patients
receive AC (NSABP 14) on 3-weekly regimens in the neoadjuvant setting. In addition,
incorporation of taxanes on a 3 weekly schedule has resulted in statistically higher
pathological CR (2,3). 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 (4). Moreover, the
combination of carboplatin and paclitaxel has been found to be synergistic both in
three-weekly regimens and weekly regimens. In fact, the combination of carboplatin,
paclitaxel and trastuzumab has demonstrated a survival advantage over paclitaxel and
trastuzumab alone. The Phase III study, which the preliminary results 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 the
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 (5). 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 a 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 since this combination has been found to be synergistic in
advanced breast cancer with improved clinical outcome. In a small study, higher
pathological response rates were achieved in patients who received trastuzumab with
chemotherapy compared to chemotherapy alone in the neoadjuvant. This study had a total of
34 patients who completed therapy. One arm received neoadjuvant chemotherapy with four
cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and
cyclophosphamide. In the second arm, the patients received the same chemotherapy regimen
with the addition of trastuzumab on a weekly schedule for twenty-four weeks. A pCR was
achieved at 65.2% in the trastuzumab plus chemotherapy compared to 25% in the chemotherapy
alone arm.

In metastatic breast cancer, the administration of bevacizumab to capecitabine has shown in
a significant increase in response rates. The combination arm of bevacizumab plus
capecitabine demonstrated a response rate of 19.8% compared to 9.1% in the capecitabine arm
alone. However, the prolonged free survival or overall survival were comparable in both
treatment arms. In a separate trial, the addition of bevacizumab to standard chemotherapy
regimen (carboplatin and paclitaxel) in patients with advanced or relapsed non-small cell
lung cancer demonstrate improved overall response and time to progression. In the
bevacizumab plus standard chemotherapy, higher response rates (31.5% vs. 18.8%), longer
median time to progression (7.4 vs. 4.2 months), and a modest increase in survival (17.7 vs.
14.9 months were found).

In a press release, South San Francisco, California, and Basil, Switzerland on March 14,
2005, an interim analysis of a Phase III trial showed bevacizumab plus paclitaxel and
carboplatin improved overall survival compared to chemotherapy alone as a first-line therapy
for non-squamous, non-small cell lung cancer. These results were presented at the ASCO
meeting, May 13-17, 2005. This was a randomized, controlled, multicenter trial that
enrolled 878 patients who had not received previous chemotherapy for non-small cell lung
cancer, and compared standard chemotherapy with paclitaxel and carboplatin with or without
bevacizumab. The trial was sponsored by the National Cancer Institute (NCI), part of the
National Institutes of Health, under a Cooperative Research and Development Agreement
between NCI and Genentech, Inc., and conducted by the Eastern Cooperative Oncology Group
(ECOG).

At the San Antonio Breast Cancer Conference on December 8, 2004, Dr. Mehta et al. presented
the sequential use of doxorubicin and cyclophosphamide (AC) followed by paclitaxel,
carboplatin, and trastuzumab (TCH) in patient with Her-2 positive breast cancer. A
pathological complete remission (pCR) was seen in 7 of 8 patients. All patients received
2-4 cycles of AC followed by 4 cycles of 3 weekly TCH regimens. Only 1 of 8 patients had a
3mm residual invasive carcinoma in the biopsy scan. Moreover, 7 of 7 patients with palpable
lymph nodes demonstrated no residual cancer after this neoadjuvant regimen.

On April 18, 2005, an interim analysis of the first Phase III randomized study confirmed a
significant benefit in the use of bevacizumab as first-line treatment for metastatic breast
cancer. This multi-center study enrolled 722 women with previously untreated metastatic
breast cancer and randomized the patients to receive adjuvant paclitaxel with or without
bevacizumab. The trial excluded women who had her-2/neu positive breast cancer unless they
received trastuzumab previously or were unable to receive this medication. The interim
analysis showed a progression-free survival and early indication of survival benefit with
the addition of bevacizumab to chemotherapy compared to chemotherapy alone. These findings
were presented at ASCO this year.

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, patient 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.