Combination Chemotherapy With or Without Trastuzumab in Treating Women With Metastatic Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00004888
First received: March 7, 2000
Last updated: May 7, 2014
Last verified: December 2012
  Purpose

Phase II trial to study the effectiveness of combination chemotherapy with or without trastuzumab in treating women who have metastatic breast cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells.


Condition Intervention Phase
Recurrent Breast Cancer
Stage IV Breast Cancer
Drug: pegylated liposomal doxorubicin hydrochloride
Drug: docetaxel
Biological: trastuzumab
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Safety and Efficacy Study of Doxil and Taxotere ± Herceptin in Advanced Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Grades of Cardiotoxicity Events in the Subset of Patients Reporting a Cardiotoxicity Event [ Time Frame: Baseline, after cycle 4 (~84 days), after cycle 8 (~168 days), and 30 or more days after last cycle of induction therapy ] [ Designated as safety issue: Yes ]
    This table summarizes the cardiotoxicity events of different grades. Grade 1 is a decline of left ventricular ejection fraction(LVEF) >=10% but <20% of baseline value. Grade 2 is LVEF below LLN (50%) or decline of LVEF >=20% of baseline value. Grade 3 is congestive heart failure responsive to treatment. Please note that only a subset of patients reported cardiotoxic events so the totals will not add up to the total number of participants.

  • Summary of Left Ventricular Ejection Fraction Values [ Time Frame: Baseline, after cycle 4, after cycle 8, and 30 or more days after last cycle of induction therapy. ] [ Designated as safety issue: Yes ]
    This table summarizes the LVEF information at baseline, post Cycle 4, post Cycle 8, and 30 or more days after Cycle 8 on all treated patients and on the eligible subset. LVEF drops reported are absolute (not relative) drops.


Secondary Outcome Measures:
  • Best Overall Response Using Eastern Cooperative Group Solid Tumor Response Criteria. [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of Nov 21, 2007 is used for this report. Please note that best overall response is reported in the table. ] [ Designated as safety issue: No ]
    Please note that overall response includes CR and PR. CR is defined as complete disappearance of all clinically detectable malignant disease for at least 4 weeks. PR is greater than or equal to 50% decrease in tumor size for at least 4 weeks without increase in size of any area of known malignant disease of greater than 25%, or appearance of new areas of malignant disease. No change is defined as no significant change in measurable or evaluable disease for at least 4 weeks. Progression is defined as a significant increase in size of lesions present at the start of therapy or after a response.

  • Overall Survival [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of November 21, 2007 is used for this report. ] [ Designated as safety issue: No ]
  • Progression-Free Survival [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of November 21, 2007 is used for this report. ] [ Designated as safety issue: No ]
    Progression-Free Survival was defined as time from study entry to progression or to death without documentation of progression. A progression is defined as a significant increase in size of lesions present at the start of therapy or after a response.

  • Duration of Response [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of November 21, 2007 is used for this report. ] [ Designated as safety issue: No ]
    Defined as time from onset of PR or CR, whichever occurred first, until objective evidence of progression.


Enrollment: 84
Study Start Date: January 2001
Study Completion Date: May 2009
Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (combination chemotherapy)

Patients receive doxorubicin hydrochloride liposome IV over 30 minutes followed by docetaxel IV over 1 hour. Treatment is repeated every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity.

Patients may receive maintenance therapy of docetaxel IV over 1 hour either weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity.

Drug: pegylated liposomal doxorubicin hydrochloride
Given IV
Other Names:
  • CAELYX
  • Dox-SL
  • DOXIL
  • doxorubicin hydrochloride liposome
  • LipoDox
Drug: docetaxel
Given IV
Other Names:
  • RP 56976
  • Taxotere
  • TXT
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm II (combination chemotherapy, trastuzumab)

Patients receive trastuzumab IV over 90 minutes on day 1, with subsequent doses over 30 minutes. Patients receive doxorubicin HCl liposome IV over 30 minutes followed by docetaxel IV over 1 hour on day 2 of course 1, followed by subsequent doses on day 1 of each course. Antibody therapy continues weekly and chemotherapy every 3 weeks for 8 courses.

Patients may receive maintenance therapy of trastuzumab IV over 30 minutes weekly followed by docetaxel IV over 1 hour weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity.

Drug: pegylated liposomal doxorubicin hydrochloride
Given IV
Other Names:
  • CAELYX
  • Dox-SL
  • DOXIL
  • doxorubicin hydrochloride liposome
  • LipoDox
Drug: docetaxel
Given IV
Other Names:
  • RP 56976
  • Taxotere
  • TXT
Biological: trastuzumab
Given IV
Other Names:
  • anti-c-erB-2
  • Herceptin
  • MOAB HER2
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and feasibility of the combination of liposomal doxorubicin (Doxil) and Taxotere (Taxotere) ± trastuzumab (Herceptin), particularly with respect to cardiotoxicity.

II. To evaluate the overall objective response rate, response duration, time to treatment failure, and median survival of patients with metastatic breast cancer treated with Doxil and Taxotere ± Herceptin.

III. To determine the overall toxicity of Doxil and Taxotere ± Herceptin in patients with advanced breast cancer.

IV. To determine whether there is an association between trough plasma levels of cTnT (cardiac troponin T) and NT-proBNP (brain natriuretic peptide) and any cardiac event (CHF or LVEF decrease).

V. To determine tissue and plasma levels of HER2 using several assays and explore potential correlation with protocol treatment toxicity and/or response.

OUTLINE: Patients are assigned to one of two treatment arms according to HER2 overexpression status.

Arm I (HER2 nonoverexpressed): Patients receive doxorubicin hydrochloride liposome IV over 30 minutes followed by docetaxel IV over 1 hour. Treatment is repeated every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity.

Patients may receive maintenance therapy of docetaxel IV over 1 hour either weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity.

Arm II (HER2 overexpressed): Patients receive trastuzumab IV over 90 minutes on day 1, with subsequent doses over 30 minutes. Patients receive doxorubicin HCl liposome IV over 30 minutes followed by docetaxel IV over 1 hour on day 2 of course 1, followed by subsequent doses on day 1 of each course. Antibody therapy continues weekly and chemotherapy every 3 weeks for 8 courses.

Patients may receive maintenance therapy of trastuzumab IV over 30 minutes weekly followed by docetaxel IV over 1 hour weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 89 patients were accrued for this study.

  Eligibility

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

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the breast with manifestations of metastatic progression
  • HER2 expression status in primary breast tissue and/or site(s) of metastasis must be determined by the ECOG Pathology Coordinating Office; (these are the results that will be used at time of registration); NOTE: for this protocol, HER2/neu non-overexpressed status will be defined as 0 and 1+ scores using the DAKO HercepTest; HER2 overexpressed status will be defined as 2+ score (if confirmed amplified by FISH) or 3+ score using the DAKO HercepTest
  • Cytologically positive pleural or peritoneal effusions are considered evaluable disease provided local intra-cavitary treatment is not introduced at the onset of therapy; to be considered as evaluable disease, pleural effusions may not have been previously drained or sclerosed
  • Blastic or mixed blastic/lytic osseous metastases only are evaluable disease provided they are accompanied by an analgesic requirement or a decrease in performance status, and will not require radiation treatment within two cycles from the start of protocol; pure osteolytic disease is evaluable; bone disease must be x-ray proven for the site to be evaluable; patients whose only evidence of metastatic disease is an abnormal bone scan without confirmatory x-rays are not eligible for this study
  • No prior chemotherapy for advanced disease; prior adjuvant chemotherapy (including taxanes) allowed, if completed > 6 months before the diagnosis of metastatic disease; no prior adjuvant anthracycline, nor any prior exposure to other anthracycline- (e.g., epirubicin, any liposomal doxorubicin formulation), nor any anthracenedione- (e.g., mitoxantrone) containing regimen allowed; no prior therapy with Herceptin allowed; NOTE: chemotherapy after ipsilateral breast recurrence following breast conservation surgery would not be considered chemotherapy for advanced disease; however, in post-mastectomy patients chemotherapy for local/regional recurrence is considered treatment for advanced disease
  • No prior radiotherapy other than to the conserved breast, to the post-mastectomy chest wall, or to a limited field involving < 25% of marrow-containing bone; NOTE: previous post-mastectomy radiation therapy involving chest wall ± internal mammary lymph node chain (IMN) is allowed; however, patients who received photon IMN treatment are ineligible; NOTE: radiotherapy must be completed >= 2 weeks prior to registration; it may not be given concurrently with Doxil, Taxotere, or Herceptin
  • Prior hormonal therapy in either a metastatic or adjuvant setting is allowed, but patients must have been off such therapy for >= 2 weeks prior to registration
  • Disease-free of prior non-breast invasive malignancies for >= 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
  • ECOG performance status of 0, 1, or 2
  • At least two weeks after any major surgery (including mastectomy) and recovered from all toxicity
  • Creatinine =< 1.5 mg/dl
  • Granulocytes >= 1,500/mm³
  • Platelets >= 100,000/mm³
  • SGOT(AST) =< 2.5 x the upper limit of normal
  • Bilirubin within normal limits for institution
  • No history of deep venous thrombosis, pulmonary thromboembolism, or other thromboembolic condition
  • Women must not be pregnant or breastfeeding; the effect of Herceptin to the fetus is unknown; Doxil is known to be harmful to the fetus
  • Women of childbearing potential must be advised to use an accepted and effective method of contraception
  • No patients with untreated brain metastasis or brain metastasis undergoing radiation or for whom brain metastasis represent the sole site of disease; patients with previously treated brain metastasis who have responded to brain radiotherapy and/or surgery and continue in response are eligible, provided the brain is not the only site of disease
  • The left ventricular ejection fraction must be at or above the lower institutional limits of normal (as assessed by MUGA scan or echocardiogram obtained within six weeks prior to registration); patient will not be eligible if baseline LVEF assessment not performed
  • No prior history of myocardial infarction, congestive heart failure, or arrhythmia requiring medication; no history of hypertension or systolic or diastolic dysfunction; no EKG evidence of ventricular hypertrophy, conduction abnormality, or serious arrhythmia; patient will not be eligible if baseline EKG assessment not performed within 4 weeks
  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: NCT00004888

Locations
United States, Massachusetts
Eastern Cooperative Oncology Group
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Investigators
Principal Investigator: Antonio Wolff Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00004888     History of Changes
Other Study ID Numbers: NCI-2012-02949, NCI-2012-02949, E3198, E3198, U10CA021115
Study First Received: March 7, 2000
Results First Received: June 21, 2011
Last Updated: May 7, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 21, 2014