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

Phase 1

Terminated

Conditions: Stage IIIC Breast Cancer
Male Breast Cancer
Stage IIIB Breast Cancer
Stage IIIA Breast Cancer
Stage IV Breast Cancer

Interventions: Biological: oblimersen sodium
Drug: doxorubicin hydrochloride
Drug: docetaxel
Biological: filgrastim
Biological: pegfilgrastim
Procedure: therapeutic conventional surgery
Other: pharmacological study
Other: laboratory biomarker analysis

Registration Number: NCT00063934

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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. 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 the drugs.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 31

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (oblimersen, doxorubicin, docetaxel)	filgrastim	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.
Treatment (oblimersen, doxorubicin, docetaxel)	laboratory biomarker analysis	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.
Treatment (oblimersen, doxorubicin, docetaxel)	oblimersen sodium	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.
Treatment (oblimersen, doxorubicin, docetaxel)	pharmacological study	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.
Treatment (oblimersen, doxorubicin, docetaxel)	pegfilgrastim	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.
Treatment (oblimersen, doxorubicin, docetaxel)	therapeutic conventional surgery	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.
Treatment (oblimersen, doxorubicin, docetaxel)	doxorubicin hydrochloride	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.
Treatment (oblimersen, doxorubicin, docetaxel)	docetaxel	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.

Primary Outcome Measures

Name	Time	Method
Number of Participant With Toxicities	From baseline until the date of first documented toxicity or date of death from any cause, whichever came first, assessed every three weeks up to 2 years and 5 months
Number of Participants With Pathologic Complete Response (pCR)	At time of definitive surgery (after 6 courses of neoadjuvant therapy in 3 week cycles), approximately 18 weeks	Pathologic complete responses (pCR), defined as no evidence of residual invasive tumor, including no residual tumor in the axillary lymph nodes, measured by microscopic evaluation of tissue specimen at time of definitive surgery (after 6 courses of neoadjuvant therapy). Neoadjuvant (preoperative) therapy administered on the first five days of every 3-week cycle. Response Evaluation Criteria in Solid Tumors (RECIST) Committee \[JNCI 92(3):205-216, 2000\]

Secondary Outcome Measures

Name	Time	Method
Clinical Imaging Responses	After 3 and 6 courses of 21 day treatments (up to 18 weeks)	Evaluation target lesions (clinical response) by physical exam/ultrasound measurements of primary tumor and axillary lymph nodes after 3-6 courses: Complete Response: Disappearance of all target lesions; Partial Response: \>30% decrease in sum longest diameter (LD) of target lesions, reference baseline sum LD; Progressive Disease: \>20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of 1\>new lesions; Stable Disease: Neither sufficient shrinkage for PR nor increase for PD, reference smallest sum LD since treatment started.
Bcl-2 Expression in Breast Cancer Tissue	before treatment and at 3-5 days after oblimersen treatment	Number of participant with Bcl-2 Expression in breast cancer tissue by protein and mRNA expression before treatment and at 3-5 days after oblimersen treatment.