Male Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer
Conditions
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.
Interventions
BIOLOGICALoblimersen sodium
Given IV
DRUGdoxorubicin hydrochloride
Given IV
DRUGdocetaxel
Given IV
BIOLOGICALfilgrastim
Given SC
BIOLOGICALpegfilgrastim
Given SC
PROCEDUREtherapeutic conventional surgery
Undergo surgical resection
OTHERpharmacological study
Optional correlative studies
OTHERlaboratory biomarker analysis
Optional correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: May 16, 2003 to August 25, 2005; All recruited at UT MD Anderson Cancer Center.
Pre-assignment details
Of the 31 participants enrolled, one participant was ineligible for treatment.
Participants by arm
| Arm | Count |
|---|---|
| Neoadjuvant G3139, Doxorubicin and Docetaxel Patients with locally advanced breast cancer received intravenous G3139 in combination with doxorubicin and docetaxel . Cycles were repeated every 21 days x 6. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 1 |
Baseline characteristics
| Characteristic | Neoadjuvant G3139, Doxorubicin and Docetaxel |
|---|---|
| Age, Continuous | 49 years |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 30 / 30 |
Outcome results
Primary
Number of Participants With Pathologic Complete Response (pCR)
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 \[JNCI 92(3):205-216, 2000\]
Time frame: At time of definitive surgery (after 6 courses of neoadjuvant therapy in 3 week cycles), approximately 18 weeks
Population: Intention to treat eligible participants per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oblimersen Plus Doxorubicin + Docetaxel | Number of Participants With Pathologic Complete Response (pCR) | 0 Participants |
Primary
Number of Participant With Toxicities
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oblimersen Plus Doxorubicin + Docetaxel | Number of Participant With Toxicities | 30 Participants |
Secondary
Bcl-2 Expression in Breast Cancer Tissue
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.
Time frame: before treatment and at 3-5 days after oblimersen treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oblimersen Plus Doxorubicin + Docetaxel | Bcl-2 Expression in Breast Cancer Tissue | 30 participants |
Secondary
Clinical Imaging Responses
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.
Time frame: After 3 and 6 courses of 21 day treatments (up to 18 weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oblimersen Plus Doxorubicin + Docetaxel | Clinical Imaging Responses | CR | 30 participants |
| Oblimersen Plus Doxorubicin + Docetaxel | Clinical Imaging Responses | PR | 0 participants |