Oblimersen Plus Doxorubicin and Docetaxel in Treating Patients With Metastatic or Locally Advanced Breast Cancer

PRIMARY OBJECTIVES:

I. To evaluate the pharmacokinetics of G3139, doxorubicin and docetaxel in breast cancer
patients receiving G3139/AT therapy. (Phase I) II. To determine the safety of bcl-2 antisense
oligonucleotide G3139 (GenasenseTM) together with docetaxel plus doxorubicin (AT) in patients
with metastatic and locally advanced breast cancer (LABC). (Phase I) III. To determine the
therapeutic efficacy of neoadjuvant G3139 in combination with AT chemotherapy in patients
with LABC. (Phase II) IV. To further evaluate the safety of bcl-2 antisense oligonucleotide
G3139 (GenasenseTM) together with docetaxel plus doxorubicin (AT) in patients with locally
advanced breast cancer (LABC). (Phase II)

SECONDARY OBJECTIVES:

I. To determine the clinical and imaging response to neoadjuvant G3139/AT in the breast and
the axillary lymph nodes. (Phase II) II. To determine the disease-free survival of breast
cancer patients treated with neoadjuvant G3139/AT. (Phase II) III. To further define the
pharmacokinetics of G3139/AT. (Phase II) IV. To evaluate the role of Bcl-2 expression as a
predictor of response to neoadjuvant G3139/AT therapy. (Phase II) V. To obtain serial breast
cancer samples from patients treated with G3139. (Phase II)

OUTLINE: This is an open-label, dose-escalation study of oblimersen.

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.

Inclusion Criteria:

- PHASE I: Patients must have histologically or cytologically confirmed breast cancer

- PHASE I: 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

- PHASE I: Measurable disease is not required for patients participating in the phase I
component

- PHASE I: Prior G3139, taxane or anthracycline therapy is not allowed

- PHASE I: Patients may have received up to 3 prior chemotherapy regimens for breast
cancer (excluding anthracyclines and taxanes), either as adjuvant/neoadjuvant therapy
or for metastatic disease

- PHASE I: Life expectancy of greater than 6 months

- PHASE I: ECOG performance status =< 2 (Karnofsky >= 60%)

- PHASE I: Leukocytes >= 3,000/L

- PHASE I: Absolute neutrophil count >= 1,500/L

- PHASE I: Platelets >= 100,000/L

- PHASE I: Total bilirubin =< 1.5 mg/dl

- PHASE I: ALT(SGPT) =< 2.5 X upper limit of normal

- PHASE I: Creatinine =< 2.0 mg/dl

- PHASE I: Normal cardiac function (LVEF >= 45%) as documented by MUGA scan and/or
echocardiogram

- PHASE I: The effects of G3139 on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason and because anthracycline and taxanes
used in this trial are known to be teratogenic, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately

- PHASE I: Ability to understand and the willingness to sign a written informed consent
document

- PHASE II: Patients must have histologically or cytologically confirmed breast cancer

- PHASE II: 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

- PHASE II: Measurable disease is required; disease will be measured prior to initiation
of G3139/doxorubicin/docetaxel therapy by physical exam, mammography and ultrasound of
the affected areas; pathologic response will be measured at the time of definitive
surgery

- PHASE II: Prior G3139 therapy is not allowed

- PHASE II: Prior chemotherapy, hormone therapy, definitive surgery, or radiation
therapy for breast cancer are not allowed

- PHASE II: Life expectancy of greater than 6 months

- PHASE II: ECOG performance status =< 2 (Karnofsky >= 60%)

- PHASE II: Leukocytes >= 3,000/L

- PHASE II: Absolute neutrophil count >= 1,500/L

- PHASE II: Platelets >= 100,000/L

- PHASE II: Total bilirubin =< 1.5 mg/dl

- PHASE II: ALT(SGPT) =< 2.5 X upper limit of normal

- PHASE II: Creatinine =< 2.0 mg/dl

- PHASE II: Normal cardiac function (LVEF >= 45%) as documented by MUGA scan and/or
echocardiogram

- PHASE II: The effects of G3139 on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason and because anthracycline and taxanes
used in this trial are known to be teratogenic, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately

- PHASE II: Ability to understand and the willingness to sign a written informed consent
document

Exclusion Criteria:

- PHASE I: Patients who 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

- PHASE I: Patients may not be receiving any other investigational agents

- PHASE I: Patients with known brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events

- PHASE I: Leptomeningeal disease

- PHASE I: Symptomatic lymphangitic pulmonary metastases

- PHASE I: 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)

- PHASE I: 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 study requirements

- PHASE I: Patients with neuropathy grade 2 or higher

- PHASE I: 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

- PHASE II: Patients may not be receiving any other investigational agents

- PHASE II: 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)

- PHASE II: 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 study requirements

- PHASE II: Patients with neuropathy grade 2 or higher

- PHASE II: 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