Breast Cancer
Conditions
Keywords
stage IV breast cancer, recurrent breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by stopping blood flow to the tumor. It is not yet known whether giving docetaxel together with bevacizumab is more effective than docetaxel alone in treating breast cancer. PURPOSE: This randomized phase II trial is studying how well giving docetaxel together with bevacizumab works compared to docetaxel alone as first-line therapy in treating women with stage IV breast cancer.
Detailed description
This trial began as a 2-arm study with a docetaxel-alone arm. When bevacizumab became widely available, it was converted to a 1-arm open-label trial of docetaxel/bevacizumab. Patients enrolled in the docetaxel-alone arm were permitted to cross over to docetaxel/bevacizumab. Patients received bevacizumab 15 mg/kg and docetaxel 75 mg/m2 intravenously (I.V.) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal.
Interventions
BIOLOGICALbevacizumab
Patients receive bevacizumab 15 mg/kg intravenously (I.V.) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal.
DRUGDocetaxel
docetaxel: 75 mg/m2 IV q3 weeks. Subjects continue on dosing until they experience unacceptable toxicity, disease progression, or withdrawal of patient consent.
Sponsors
University of California, Los Angeles
Translational Oncology Research International
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female 18 and over * Histologically or cytologically confirmed adenocarcinoma of the breast at first diagnosis * Stage IV disease, with at least one measurable lesion according to the RECIST criteria. * HER2-negative disease, by fluorescence in situ hybridization * ECOG performance status 0-1 * Life expectancy of at least 24 weeks * No prior chemotherapy for metastatic breast cancer (prior endocrine therapy is permitted). * Prior adjuvant chemotherapy is permitted. If patients received a taxane in the adjuvant setting, at least 12 months must have elapsed since the completion of adjuvant therapy. * At least 4 weeks since prior surgery, radiotherapy, endocrine therapy, or experimental drug therapy, with complete recovery from the effects of these interventions * If female of childbearing potential, pregnancy test is negative and willing to use effective contraception while on treatment for at least 3 months thereafter. * Patient is accessible and willing to comply with treatment and follow-up. * Patient is willing to provide written informed consent prior to the performance of any study-related procedures. * Required laboratory values * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 9.0 g/dL * Creatinine ≤ 2.0 mg/dL * Total bilirubin \< 1.0 x upper limit of normal (ULN) (patients with documents Gilbert's syndrome are eligible). * Alkaline phosphatase (AP) normal AND Angiotensin Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤ 2.5 times upper limit of normal (ULN) or AP ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN or AP ≤ 5 times ULN AND AST or ALT normal.
Exclusion criteria
* Prior chemotherapy for metastatic breast cancer * Prior treatment with an anti-angiogenic agent * Concurrent therapy with any other non-protocol anti-cancer therapy * Current or prior history of central nervous system or brain metastases * Presence of neuropathy \> grade 2 (NCI- Common Toxicity Criteria (CTC) version 3.0) at baseline * Presence of any non-healing wound, fracture, or ulcer, or the presence of clinically significant (\> grade 2) peripheral vascular disease * History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix * Clinically significant cardiovascular disease (e.g., uncontrolled hypertension \[BP \> 150/100\]), myocardial infarction or stroke within the past 6 months, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication * Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning therapy * Active, uncontrolled infection requiring parenteral antimicrobials * The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications. * Inability to comply with the study protocol or follow-up procedures * Pregnancy or lactation * A history of a severe hypersensitivity reaction to Bevacizumab, or Docetaxel or other drugs formulated with polysorbate 80. * Evidence of bleeding diathesis or coagulopathy * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedure, fine needle aspiration or core biopsy within 7 days prior to beginning therapy * Proteinuria at baseline or clinically significant impairment of renal function. Subjects unexpectedly discovered to have \> 1+ proteinuria at baseline should undergo a 24 hour urine collection, which must be an adequate collection and must demonstrate \<1 gm of protein/24 hour to allow participation in the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Antitumor Activity Based on Time to Tumor Progression (TTP). | From randomization until tumor progression |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Response Rates, Duration of Response, and Overall Survival | Time of death, up to 3 years | — |
| Comparison of Safety and Toxicity | When adverse events occur, up to 30 days after last dose for each subject, up to 3 years from start of study | Evaluated using adverse event (AE) information. Detailed AE information is provided in the AE section. |
Countries
United States
Participant flow
Recruitment details
Recruitment period from March 2005 to September 2006 at academic medical clinics and community medical clinics.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel + Bevacizumab docetaxel: 75 mg/m2 IV q3 weeks. Bevacizumab: 15mg/kg IV q3 weeks. Subjects continue on dosing until they experience unacceptable toxicity, disease progression, or withdrawal of patient consent.
A total of 104 participants were screened for the study. Twenty six participants did not meet eligibility criteria and 2 withdrew consent.
Seventy six participants were registered to the Treatment Period, 7 to arm A and 69 to arm B. Six out of 7 participants randomized to arm A elected to cross over to arm B once bevacizumab became available. Two out of the 69 participants randomized to arm B were found ineligible and taken off study before receiving treatment. As a result, the efficacy analysis was performed on 67 patients. | 67 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Allocation | Ineligible | 2 | 0 |
| Follow-up | Lost to Follow-up | 1 | 0 |
| Follow-up | Withdrawal by Subject | 4 | 0 |
| Treatment | Adverse Event | 18 | 2 |
| Treatment | Death | 2 | 0 |
| Treatment | disease progression | 33 | 4 |
| Treatment | insurance issues | 1 | 1 |
| Treatment | Physician Decision | 6 | 0 |
| Treatment | reqd treatment not permitted by protocol | 6 | 0 |
| Treatment | secondary malignancy | 1 | 0 |
Baseline characteristics
| Characteristic | Docetaxel + Bevacizumab |
|---|---|
| Age, Continuous | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hormone receptor status ER-PR- | 22 participants |
| Hormone receptor status ER-PR+ | 3 participants |
| Hormone receptor status ER+PR- | 13 participants |
| Hormone receptor status Estrogen Receptor(ER)+ Progesterone Receptor(PR)+ | 29 participants |
| Number of metastatic sites less than 3 | 37 participants |
| Number of metastatic sites more than 3 | 30 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 46 Participants |
| Sex: Female, Male Female | 67 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 74 / 74 |
| serious Total, serious adverse events | 13 / 74 |
Outcome results
Primary
Antitumor Activity Based on Time to Tumor Progression (TTP).
Time frame: From randomization until tumor progression
Population: 76 participants were registered to the Treatment, 7 to arm A and 69 to arm B. 6 participants randomized to arm A elected to cross over to arm B once Avastin became available. 2 out of the 69 participants randomized to arm B were found ineligible and taken off study before receiving treatment. Thus, the efficacy analysis performed on 67 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel + Bevacizumab | Antitumor Activity Based on Time to Tumor Progression (TTP). | 9.3 months |
Secondary
Comparison of Response Rates, Duration of Response, and Overall Survival
Time frame: Time of death, up to 3 years
Population: Response rate - the percentage of patients assigned to a treatment arm who experience a CR or PR. Duration of response - the interval from date of initial documented response (CR or PR) to the first documented date of disease progression. Overall survival - the interval from the date of registration and the date of death.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | Overall Duration of Response (DR) | 11.8 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | Overall Observed Response (OR) | 26.3 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | ER+ and/or PgR+ DR | 14.6 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | ER+ and/or PgR+ OR | NA months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | ER-/PgR- DR | 6.2 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | ER-/PgR- OR | 18.6 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | Adjuvantb Chemotherapy Including Taxane DR | 18.2 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | Adjuvantb Chemotherapy Including Taxane OR | 26.1 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | Adjuvantb Chemotherapy Without Taxane DR | 13.2 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | Adjuvantb Chemotherapy Without Taxane OR | NA months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | No Previous Adjuvant Chemo DR | 9.0 months |
| Docetaxel + Bevacizumab | Comparison of Response Rates, Duration of Response, and Overall Survival | No Previous Adjuvant Chemo OR | 26.3 months |
Secondary
Comparison of Safety and Toxicity
Evaluated using adverse event (AE) information. Detailed AE information is provided in the AE section.
Time frame: When adverse events occur, up to 30 days after last dose for each subject, up to 3 years from start of study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel + Bevacizumab | Comparison of Safety and Toxicity | dose reduction of docetaxel for toxicity | 10 subjects |
| Docetaxel + Bevacizumab | Comparison of Safety and Toxicity | dose delay or interruption | 19 subjects |
| Docetaxel + Bevacizumab | Comparison of Safety and Toxicity | discontinued docetaxel and continued to receive be | 10 subjects |
| Docetaxel + Bevacizumab | Comparison of Safety and Toxicity | bevacizumab dose delay or interruption | 24 subjects |
| Docetaxel + Bevacizumab | Comparison of Safety and Toxicity | patients came off of study because of bevacizumab- | 9 subjects |