RATIONALE: Drugs used in chemotherapy, such as doxorubicin and docetaxel, work in different
ways to stop tumor cells from dividing so they stop growing or die. Oblimersen may increase
the effectiveness of doxorubicin and docetaxel by making the tumor cells more sensitive to
PURPOSE: This phase I/II trial is studying the side effects and best dose of oblimersen when
given together with doxorubicin and docetaxel and to see how well they work in treating
women with metastatic or locally advanced breast cancer.
Phase I (completed as of 8/16/04):
- Determine the pharmacokinetics of oblimersen, doxorubicin, and docetaxel in patients
with metastatic or locally advanced breast cancer.
- Determine the maximum tolerated dose (MTD) of oblimersen in combination with
doxorubicin and docetaxel in these patients.
- Determine the safety of this regimen in these patients.
- Determine the therapeutic efficacy of this regimen at the MTD of oblimersen in a
neoadjuvant setting, in terms of pathologic complete response rate, in patients with
locally advanced breast cancer.
- Determine the clinical and imaging response in the breast and axillary lymph nodes of
patients treated with this regimen.
- Determine the disease-free survival of patients treated with this regimen.
- Determine the role of Bcl-2 expression as a predictor of response to this regimen in
OUTLINE: This is an open-label, dose-escalation study of oblimersen.
- Phase I (phase I completed as of 8/16/04): Patients receive oblimersen IV continuously
on days 1-6 interrupted only to administer doxorubicin IV over 15 minutes and docetaxel
IV over 60 minutes on day 6. Patients also receive filgrastim (G-CSF) subcutaneously
(SC) on days 7-13 or pegfilgrastim SC on day 7. Treatment repeats every 21 days for up
to 6 courses in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of oblimersen until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.
- Phase II: Patients receive doxorubicin, docetaxel, G-CSF or pegfilgrastim, and
oblimersen at the MTD as in phase I.
Patients with resectable tumors after 6 courses undergo surgical resection.
Patients are followed every 3-6 months for 5 years.
PROJECTED ACCRUAL: A total of 69 patients (9 patients for phase I [phase I portion of the
study completed as of 8/16/04] and 60 patients for phase II) will be accrued for this study
within 2 years.
1. Patients must have histologically or cytologically confirmed breast cancer.
2. To be eligible for the phase I component of this study, patients must have stage
IIIB, IIIC or IV breast cancer. These include patients with T4, any N, M0; any T, N3,
M0; any T, any N, M1.
3. To be eligible for the phase II component, patients must have stage IIIA, IIIB, or
IIIC breast cancer. These include patients with T4, any N, M0; any T, N2-3, M0; T3,
N1, M0. Patients with ipsilateral supraclavicular lymph node metastases (IIIC) are
eligible. Patients with evidence of distant metastases (stage IV) are not eligible.
4. Measurable disease is not required for patients participating in the phase I
component. Measurable disease is required for the phase II component.
5. Prior G3139, taxane or anthracycline therapy is not allowed.
6. Life expectancy of greater than 6 months.
7. ECOG performance status 0, 1, or 2 (Karnofsky >60%; see Appendix A).
8. Patients must have normal organ and marrow function, as defined in the protocol.
9. Normal cardiac function (LVEF 45% or greater) as documented by MUGA scan and/or
1. Patients with metastatic breast cancer participating in the phase I component may not
have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the phase I study or those who have not recovered from
adverse events due to agents administered more than 4 weeks earlier.
2. For patients with locally advanced breast cancer participating in the phase II
component may not have received any chemotherapy for breast cancer.
3. Patients may not be receiving any other investigational agents.
4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to G3139 or other agents used in the study. Patients are excluded if
known hypersensitivity to drugs formulated in polysorbate 80 (Tween 80).
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
6. Patients with neuropathy grade 2 or higher.
7. Pregnant women are excluded from this study because G3139 is an oligonucleotide agent
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with G3139, breastfeeding should be discontinued if the
mother is treated with G3139. These potential risks may also apply to other agents
used in this study, such as doxorubicin and docetaxel.