Breast Cancer
Conditions
Keywords
stage IV breast cancer, male breast cancer, recurrent breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as gemcitabine and paclitaxel albumin-stabilized nanoparticle formulation, 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. Giving combination chemotherapy together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine together with bevacizumab works in treating patients with metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * To determine the 6-month progression-free survival rate of patients with metastatic breast cancer treated with paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and bevacizumab. Secondary * To determine the overall survival of patients treated with this regimen. * To determine the progression-free survival of patients treated with this regimen. * To determine the confirmed response rate in patients treated with this regimen. * To determine the duration of response in patients treated with this regimen. * To determine the time to treatment failure in patients treated with this regimen. * To determine the quality of life of patients treated with this regimen. OUTLINE: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and after every other course, and then after completion of treatment. After completion of study treatment, patients are followed periodically for 5 years.
Interventions
BIOLOGICALbevacizumab
DRUGgemcitabine hydrochloride
DRUGpaclitaxel albumin-stabilized nanoparticle formulation
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
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
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed infiltrating breast cancer * Clinical evidence of metastatic disease * Measurable disease, defined as at least one measurable lesion per RECIST criteria * No non-measurable disease only, defined as all other lesions, including small lesions (longest diameter \< 2 cm) and truly non-measurable lesions, including any of the following: * Bone lesions * Leptomeningeal disease * Ascites * Pleural/pericardial effusion * Inflammatory breast disease * Lymphangitis cutis/pulmonis * Abdominal masses that are not confirmed and followed by imaging techniques * Cystic lesions * Patients with HER-2/neu positive tumors, must have received prior treatment with trastuzumab (Herceptin®) or have a contraindication for trastuzumab * No evidence of active brain metastasis, including leptomeningeal involvement, on MRI or CT scan * CNS metastasis controlled by prior surgery and/or radiotherapy allowed * Must be asymptomatic for ≥ 2 months with no evidence of progression prior to study entry * Hormone receptor status not specified PATIENT CHARACTERISTICS: * Menopausal status not specified * Life expectancy ≥ 12 weeks * ECOG performance status 0-1 * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9.0 g/dL * AST and ALT ≤ 2.5 times upper limit of normal (ULN) * Alkaline phosphatase ≤ 2.5 times ULN * Total bilirubin ≤ 1.5 times ULN * Creatinine ≤ 1.5 mg/dL * Urine protein:creatinine ratio \< 1 or urinalysis \< 1+ protein * Patients discovered to have ≥ 1+ proteinuria at baseline must demonstrate 24-hour urine protein \< 1 g * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 30 days after completion of study therapy * Able to complete questionnaires alone or with assistance * No peripheral neuropathy \> grade 1 * No history of allergy or hypersensitivity to albumin-bound paclitaxel, paclitaxel, gemcitabine hydrochloride, bevacizumab, albumin, drug product excipients, or chemically similar agents * No stage III or IV invasive, non-breast malignancy within the past 5 years * No other active malignancy, except nonmelanoma skin cancer or carcinoma in situ of the cervix * Patient must not be receiving other specific treatment for a prior malignancy * No uncontrolled hypertension (i.e., blood pressure \[BP\] \> 160/90 mm Hg on ≥ 2 occasions at least 5 minutes apart) * Patients who have recently started or adjusted antihypertensive medications are eligible providing that BP is \< 140/90 mm Hg on any new regimen for ≥ 3 different observations in ≥ 14 days * No bleeding diathesis or uncontrolled coagulopathy * No hemoptysis within the past 6 months * No prior arterial or venous thrombosis within the past 12 months * No history of cerebrovascular accident * No history of hypertensive crisis or hypertensive encephalopathy * No abdominal fistula or gastrointestinal perforation within the past 6 months * No serious non-healing wound, ulcer, or fracture * No clinically significant cardiac disease, defined as any of the following: * Congestive heart failure * Symptomatic coronary artery disease * Unstable angina * Cardiac arrhythmias not well controlled with medication * Myocardial infarction within the past 12 months * No comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for study entry or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior chemotherapy for metastatic disease * May have received one prior adjuvant chemotherapy regimen * Prior neoadjuvant chemotherapy allowed * More than 6 months since prior adjuvant or neoadjuvant taxane (i.e., docetaxel or paclitaxel) therapy * Prior hormonal therapy in either adjuvant or metastatic setting allowed * More than 4 weeks since prior radiotherapy (except if to a non-target lesion only, or single dose radiation for palliation) * Prior radiotherapy to a target lesion is allowed provided there has been clear progression of the lesion since radiotherapy was completed * More than 4 weeks since prior cytotoxic chemotherapeutic agent or investigational drug * More than 2 weeks since prior and no concurrent acetylsalicylic acid, anticoagulants, or thrombolytic agents (except for once-daily 81 mg acetylsalicylic acid) * More than 6 weeks since prior major surgery, chemotherapy, or immunologic therapy * More than 1 week since prior minor surgery (e.g., core biopsy) * Placement of a vascular access device within 7 days is allowed * More than 3 months since prior neurosurgery * No concurrent treatment in a different clinical study in which investigational procedures are performed or investigational therapies are administered * Trials related to symptom management (Cancer Control) which do not employ hormonal treatments or treatments that may block the path of the targeted agents used in this study may be allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-month Progression-free Survival (PFS) Rate | at 6 months | The primary endpoint of this trial is the 6-month progression-free survival rate. A patient is considered to be a 6-month progression-free survivor if the patient is 6 months from registration without a documentation of disease progression (note, the patient need not be on study treatment at 6 months to be considered a success). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated using the properties of the binomial distribution. Progression is defined using the RECIST Criteria, as at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Time | Up to 5 years | Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. The distribution of time to progression will be estimated using the method of Kaplan-Meier (1958). Progression is defined using the RECIST Criteria, as at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. |
| Confirmed Response (Complete or Partial Response) Rate | Up to 5 years | A confirmed response is defined to be either a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 8 weeks apart. The confirmed response rate (percentage) will be estimated by the number of confirmed responses in evaluable patients divided by the total number of evaluable patients multiplied by 100. The appropriate confidence interval will be calculated based on the binomial distribution. |
| Overall Survival Time | Up to 5 years | Overall Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier (1958). |
| Time to Treatment Failure | Up to 5 years | Time to treatment failure is defined to be the time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they were removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier (1958). Progression is defined using the RECIST Criteria, as at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. |
| Quality of Life, as Measure by the Mean Change in FACT-B TOI Score at Cycle 8 | From baseline to end of Cycle 8; Up to 24 weeks | Quality of life (QOL) as measured by the mean change (from baseline) in FACT-B (TOI) Trial Outcome Index at Cycle 8 (24 weeks). FACT-B was scored according to the published scoring (\*) criteria with higher scores representing better QOL. The FACT-B TOI was the sum of the following FACT-B subscale/scale scores: physical (score range 0-28), functional (score range 0-28), and Breast Cancer Subscale (score range 0-40); range of the FACT-B TOI is 0-96 (the change scores have a possible range of -96 to 96). The mean change and 95% confidence interval are reported below. A one-sample t-test is used to compare the change from baseline to a value of 0. (\*)= Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, Deasy S, Cobleigh M, Shiomoto G. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality of life instrument. J Clin Oncol 1997;15:974-986. |
| Duration of Response | Up to 5 years | Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. If a patient dies subsequent to the confirmed response without a documentation of disease progression, the patient will be considered to have had disease progression at the time of their death. In the case of a patient failing to return for evaluations before a documentation of disease progression, the patient will be censored for progression on the date of last evaluation. The distribution of duration of response will be estimated using the method of Kaplan-Meier (1958). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab Patients receive 125 mg/m\^2 paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and 1000 mg/m\^2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Cancel prior to beginning treatment | 1 |
| Overall Study | Ineligible | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Paclitaxel + Gemcitabine + Bevacizumab |
|---|---|
| Age, Continuous | 55.5 years |
| Region of Enrollment United States | 48 participants |
| Sex: Female, Male Female | 48 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 | 49 / 49 |
| serious Total, serious adverse events | 20 / 49 |
Outcome results
Primary
6-month Progression-free Survival (PFS) Rate
The primary endpoint of this trial is the 6-month progression-free survival rate. A patient is considered to be a 6-month progression-free survivor if the patient is 6 months from registration without a documentation of disease progression (note, the patient need not be on study treatment at 6 months to be considered a success). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated using the properties of the binomial distribution. Progression is defined using the RECIST Criteria, as at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions.
Time frame: at 6 months
Population: The ineligible patient was included in the final analysis with participants who completed the study as specified in the Participant Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | 6-month Progression-free Survival (PFS) Rate | 0.792 proportion of patients progression-free |
Secondary
Confirmed Response (Complete or Partial Response) Rate
A confirmed response is defined to be either a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 8 weeks apart. The confirmed response rate (percentage) will be estimated by the number of confirmed responses in evaluable patients divided by the total number of evaluable patients multiplied by 100. The appropriate confidence interval will be calculated based on the binomial distribution.
Time frame: Up to 5 years
Population: The ineligible patient was included in the final analysis with participants who completed the study as specified in the Participant Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | Confirmed Response (Complete or Partial Response) Rate | 70.8 percentage of patients with CR or PR |
Secondary
Duration of Response
Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. If a patient dies subsequent to the confirmed response without a documentation of disease progression, the patient will be considered to have had disease progression at the time of their death. In the case of a patient failing to return for evaluations before a documentation of disease progression, the patient will be censored for progression on the date of last evaluation. The distribution of duration of response will be estimated using the method of Kaplan-Meier (1958).
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | Duration of Response | 9.7 months |
Secondary
Overall Survival Time
Overall Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier (1958).
Time frame: Up to 5 years
Population: The ineligible patient was included in the final analysis with participants who completed the study as specified in the Participant Flow.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | Overall Survival Time | 24.4 months |
Secondary
PFS Time
Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. The distribution of time to progression will be estimated using the method of Kaplan-Meier (1958). Progression is defined using the RECIST Criteria, as at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions.
Time frame: Up to 5 years
Population: The ineligible patient was included in the final analysis with participants who completed the study as specified in the Participant Flow.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | PFS Time | 11.2 months |
Secondary
Quality of Life, as Measure by the Mean Change in FACT-B TOI Score at Cycle 8
Quality of life (QOL) as measured by the mean change (from baseline) in FACT-B (TOI) Trial Outcome Index at Cycle 8 (24 weeks). FACT-B was scored according to the published scoring (\*) criteria with higher scores representing better QOL. The FACT-B TOI was the sum of the following FACT-B subscale/scale scores: physical (score range 0-28), functional (score range 0-28), and Breast Cancer Subscale (score range 0-40); range of the FACT-B TOI is 0-96 (the change scores have a possible range of -96 to 96). The mean change and 95% confidence interval are reported below. A one-sample t-test is used to compare the change from baseline to a value of 0. (\*)= Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, Deasy S, Cobleigh M, Shiomoto G. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality of life instrument. J Clin Oncol 1997;15:974-986.
Time frame: From baseline to end of Cycle 8; Up to 24 weeks
Population: Of the participants evaluable for primary analysis, the Overall Number of Participants Analyzed reflects the number of subjects evaluable for this secondary outcome (with a FACT-B Trial Outcome Index score at baseline and at Cycle 8).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | Quality of Life, as Measure by the Mean Change in FACT-B TOI Score at Cycle 8 | -7.4 units on a scale |
p-value: 0.003t-test, 2 sided
Secondary
Time to Treatment Failure
Time to treatment failure is defined to be the time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they were removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier (1958). Progression is defined using the RECIST Criteria, as at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions.
Time frame: Up to 5 years
Population: The ineligible patient was included in the final analysis with participants who completed the study as specified in the Participant Flow.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Paclitaxel + Gemcitabine + Bevacizumab | Time to Treatment Failure | 6.9 months |