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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00063934
First received: July 8, 2003
Last updated: May 6, 2014
Last verified: December 2012
  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. 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.


Condition Intervention Phase
Male Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Biological: oblimersen sodium
Drug: doxorubicin hydrochloride
Drug: docetaxel
Biological: filgrastim
Biological: pegfilgrastim
Procedure: therapeutic conventional surgery
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Bcl-2 Antisense Oligonucleotide G3139 in Combination With Doxorubicin and Docetaxel in Metastatic and Locally Advanced Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Participant Toxicity [ Time Frame: From baseline to study completion, every 3 weeks ] [ Designated as safety issue: Yes ]
    Incidence of toxicity summarized using NCI Common Toxicity Criteria, version 3.0 every 3 weeks.

  • Number of Participants With Pathologic Complete Response (pCR) [ Time Frame: At time of definitive surgery (after 6 courses of neoadjuvant therapy in 3 week cycles), approximately 18 weeks ] [ Designated as safety issue: No ]
    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:
  • Clinical Imaging Responses [ Time Frame: After 3 and 6 courses of 21 day treatments (up to 18 weeks) ] [ Designated as safety issue: No ]
    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 [ Time Frame: before treatment and at 3-5 days after oblimersen treatment ] [ Designated as safety issue: No ]
    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.


Enrollment: 31
Study Start Date: May 2003
Study Completion Date: February 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (oblimersen, doxorubicin, 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.

Biological: oblimersen sodium
Given IV
Other Names:
  • augmerosen
  • G3139
  • G3139 bcl-2 antisense oligodeoxynucleotide
  • Genasense
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: docetaxel
Given IV
Other Names:
  • RP 56976
  • Taxotere
  • TXT
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Biological: pegfilgrastim
Given SC
Other Names:
  • Filgrastim SD-01
  • GCSF-SD01
  • Neulasta
  • SD-01 sustained duration G-CSF
Procedure: therapeutic conventional surgery
Undergo surgical resection
Other: pharmacological study
Optional correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Optional correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00063934

Locations
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: Francisco Esteva M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00063934     History of Changes
Other Study ID Numbers: NCI-2012-02885, NCI-2012-02885, 6023, DM02-700, 6023, P30CA016672, N01CM17003
Study First Received: July 8, 2003
Results First Received: July 10, 2012
Last Updated: May 6, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Liposomal doxorubicin
Doxorubicin
Lenograstim
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 16, 2014