Breast Cancer
Conditions
Keywords
stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation and carboplatin, 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 find tumor cells and help kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying the side effects and how well giving paclitaxel albumin-stabilized nanoparticle formulation and carboplatin together with bevacizumab works in treating women undergoing surgery for stage II or stage III breast cancer.
Detailed description
OBJECTIVES: Primary * To determine the complete pathological response (pCR) in the breast/axillary lymph nodes in women with stage II or III breast cancer treated with neoadjuvant therapy comprising paclitaxel albumin-stabilized nanoparticle formulation, carboplatin, and bevacizumab followed by surgery and adjuvant bevacizumab. * To determine the side effects of this regimen in these patients. Secondary * To evaluate dynamic contrast-enhanced magnetic resonance imaging in assessing pCR. * To measure LZTS1 gene expression before and after neoadjuvant therapy to evaluate whether LZTS1 gene expression correlates with pCR. * To evaluate the feasibility and toxicity of adjuvant bevacizumab when administered for 6 months. OUTLINE: * Neoadjuvant therapy: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and carboplatin IV over 30 minutes on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for 5 courses. After completion of course 5, patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and carboplatin IV over 30 minutes on days 1, 8, and 15. Patients then proceed to surgery. * Surgery: Approximately 4-5 weeks after completion of neoadjuvant therapy, patients undergo definitive surgery (either lumpectomy or mastectomy). Patients with node-positive disease or inflammatory breast cancer at baseline also undergo axillary lymph node dissection. Patients then proceed to adjuvant therapy. * Adjuvant therapy: Beginning approximately 6 weeks after surgery, patients receive bevacizumab IV over 30-90 minutes once every 3 weeks for 6 months. Patients with hormone receptor-positive disease also receive endocrine therapy. Patients may also receive additional adjuvant chemotherapy or radiotherapy at the discretion of the treating physician. Patients undergo dynamic contrast-enhanced magnetic resonance imaging at baseline, after course 2 of neoadjuvant therapy, and after completion of neoadjuvant therapy (prior to definitive surgery) for assessment of tumor response. Tumor tissue is collected at baseline and during surgery for correlative laboratory studies. LZST1 gene expression is assessed by immunohistochemistry before and after neoadjuvant therapy.
Interventions
DRUGbevacizumab
bevacizumab 10 mg/kg on days 1 and 15 administered every 28 days \[1 cycle\] for 5 cycles
DRUGcarboplatin
AUC 2 IV on days 1, 8, and 15
DRUGnab-paclitaxel
100 mg/M2 IV
PROCEDURESurgery
lumpectomy or mastectomy along with axillary lymph node dissection approximately 4-5 weeks after completion of NCT.
DRUGAdjuvant chemotherapy
All hormone receptor positive patients will receive endocrine therapy. All patients will receive 6 months of adjuvant bevacizumab at 15 mg/kg IV every 3 weeks. If using an adjuvant anthracycline-containing regimen then bevacizumab will be administered ≥ 3 weeks after completing the regimen.
Sponsors
Celgene Corporation
Genentech, Inc.
Ohio State University Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: * Histologically confirmed breast cancer * Clinically or radiographically measurable residual tumor after core biopsy * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Age ≥18 yrs * Absolute neutrophil count ≥ 1,500/mm³ * Hemoglobin ≥ 9 g/dL * Platelet count ≥ 100,000/ mm³ * Creatinine ≤ 1.5 times upper limit of normal (ULN) * Urine protein:creatinine ratio \< 1.0 * AST (aspartate aminotransferase) and ALT ≤ 2.5 times ULN * Alkaline phosphatase ≤ 2.5 times ULN * Bilirubin normal * Women of childbearing potential must use effective contraception * Left ventricular ejection fraction (LVEF) normal by echocardiogram or MUGA Exclusion: * No residual tumor after initial biopsy * Peripheral neuropathy of grade 2 or higher * HER-2 neu overexpression either by IHC 3+ or FISH+ * No history of any prior treatment of breast cancer. * No history of unstable angina or myocardial infarction within the past 12 months * Pregnant or nursing women * Anticoagulation therapy within the last 6 months * History of gastrointestinal bleeding * Recent hemoptysis * No known hepatitis B or HIV seropositivity * No inadequately controlled hypertension, defined as systolic blood pressure (BP) \> 150 mm Hg and/or diastolic BP \> 100 mm Hg despite antihypertensive medications * History of hypertensive crisis or hypertensive encephalopathy * New York Heart Association class II-IV congestive heart failure * History of stroke or transient ischemic attack at any time * Significant vascular disease (e.g., aortic aneurysm or aortic dissection) * No symptomatic peripheral vascular disease * Evidence of bleeding diathesis or coagulopathy * Significant traumatic injury within the past 28 days * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * Serious, non-healing wound, ulcer, or bone fracture * Known hypersensitivity to any component of bevacizumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Pathologic Complete Response (pCR) | every 4 weeks | pCR was defined as the absence of viable invasive tumor cells in the surgical breast specimen and axillary lymph nodes. |
| Side Effects of Weekly Nab-paclitaxel, Carboplatin and Bevacizumab | Up to 4 weeks | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Dynamic Contrast-enhanced Magnetic Resonance Imaging in Assessing pCR at Baseline and After 2 Cycles of Neoadjuvant Therapy | after 2 cycles of therapy | Relative angiogenic volume (AV) was defined as the ratio of AV to the geometric volume of the tumor in the breast. |
| Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | prior to surgery | LZTS1 expression in breast cancer cells collected prior to NCT |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neoadjuvant, Surgery, Adjuvant Neoadjuvant chemotherapy : Nab-paclitaxel and carboplatin on days 1, 8, and 15 in combination with bevacizumab on days 1 and 15 administered every 28 days for 5 cycles followed by 1 cycle with Nab-paclitaxel and carboplatin on days 1, 8, and 15. Definitive surgery with either lumpectomy or mastectomy along with axillary lymph node dissection for all pre neo adjuvant chemotherapy node-positive patients approximately 4-5 weeks after the completion of NCT (Neoadjuvant chemotherapy). Use of additional adjuvant chemotherapy and/or radiation therapy depends upon the treating physicians' judgment. Radiation therapy should begin no sooner than 6 weeks after breast cancer surgery. All hormone receptor positive patients will receive endocrine therapy. All patients will receive 6 months of adjuvant bevacizumab every 3 weeks. If using an adjuvant anthracycline-containing regimen then bevacizumab will be administered ≥ 3 weeks after completing the regimen. | 33 |
| Total | 33 |
Baseline characteristics
| Characteristic | Neoadjuvant, Surgery, Adjuvant |
|---|---|
| Age, Continuous | 48 years |
| Axillary lymph node status before NCT Negative by core biopsy | 5 patients |
| Axillary lymph node status before NCT Negative by SLNB | 8 patients |
| Axillary lymph node status before NCT Not evaluated | 1 patients |
| Axillary lymph node status before NCT Positive by core biopsy | 15 patients |
| Axillary lymph node status before NCT Positive by SLNB | 4 patients |
| Menopausal status Postmenopausal | 12 patients |
| Menopausal status Premenopausal | 21 patients |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Receptor status (all HER2/neu negative) ER and PR positive | 21 patients |
| Receptor status (all HER2/neu negative) Triple negative | 12 patients |
| Region of Enrollment United States | 33 patients |
| Sex: Female, Male Female | 33 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 | 33 / 33 |
| serious Total, serious adverse events | 0 / 33 |
Outcome results
Primary
Number of Patients With Pathologic Complete Response (pCR)
pCR was defined as the absence of viable invasive tumor cells in the surgical breast specimen and axillary lymph nodes.
Time frame: every 4 weeks
Population: Includes patients with triple negative breast cancer and ER+/PR+ breast cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoadjuvant, Surgery, Adjuvant | Number of Patients With Pathologic Complete Response (pCR) | 6 patients |
Primary
Side Effects of Weekly Nab-paclitaxel, Carboplatin and Bevacizumab
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
Time frame: Up to 4 weeks
Population: all grade 3 adverse events
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoadjuvant, Surgery, Adjuvant | Side Effects of Weekly Nab-paclitaxel, Carboplatin and Bevacizumab | hypersensitivity reaction | 1 patients |
| Neoadjuvant, Surgery, Adjuvant | Side Effects of Weekly Nab-paclitaxel, Carboplatin and Bevacizumab | hypertension | 2 patients |
| Neoadjuvant, Surgery, Adjuvant | Side Effects of Weekly Nab-paclitaxel, Carboplatin and Bevacizumab | infection at mastectomy site | 1 patients |
Secondary
Evaluation of Dynamic Contrast-enhanced Magnetic Resonance Imaging in Assessing pCR at Baseline and After 2 Cycles of Neoadjuvant Therapy
Relative angiogenic volume (AV) was defined as the ratio of AV to the geometric volume of the tumor in the breast.
Time frame: after 2 cycles of therapy
Population: Data only available for 20 of the 28 evaluable patients
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Neoadjuvant, Surgery, Adjuvant | Evaluation of Dynamic Contrast-enhanced Magnetic Resonance Imaging in Assessing pCR at Baseline and After 2 Cycles of Neoadjuvant Therapy | Baseline DCE-MRI | 0.65 ratio | Standard Deviation 0.18 |
| Neoadjuvant, Surgery, Adjuvant | Evaluation of Dynamic Contrast-enhanced Magnetic Resonance Imaging in Assessing pCR at Baseline and After 2 Cycles of Neoadjuvant Therapy | Relative AV at end of cycle 2 | .4 ratio | Standard Deviation 0.33 |
Secondary
Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry
LZTS1 expression in breast cancer cells collected prior to NCT
Time frame: prior to surgery
Population: LZTS1 expression in breast cancer cells collected prior to NCT was assessed in 27 patients who had evaluable core biopsies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoadjuvant, Surgery, Adjuvant | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | 0 | 2 patients |
| Neoadjuvant, Surgery, Adjuvant | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +1 | 0 patients |
| Neoadjuvant, Surgery, Adjuvant | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +2 | 3 patients |
| Neoadjuvant, Surgery, Adjuvant | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +3 | 6 patients |
| Patients With pCR | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +3 | 1 patients |
| Patients With pCR | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | 0 | 2 patients |
| Patients With pCR | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +2 | 2 patients |
| Patients With pCR | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +1 | 0 patients |
| Patients With Hormone-responsive BC | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +3 | 6 patients |
| Patients With Hormone-responsive BC | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +1 | 2 patients |
| Patients With Hormone-responsive BC | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | +2 | 2 patients |
| Patients With Hormone-responsive BC | Overall Expression of LZTS1 Before and After Neoadjuvant Therapy as Assessed by Immunohistochemistry | 0 | 6 patients |