HER-2 Positive Breast Cancer
Conditions
Keywords
Neoadjuvant Treatment, HER-2 Positive Breast Cancer
Brief summary
This study will evaluate the safety and efficacy of eribulin in combination with carboplatin and trastuzumab in the neoadjuvant setting in subjects who are human epidermal growth factor receptor (HER)2 positive and are clinically stage IIA to IIIB. The study regimen will be administered every 3 weeks for a total of 6 cycles followed by definitive surgery.
Detailed description
During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle. Carboplatin area under the curve (AUC) 6 will be administered IV over 15 to 30 minutes on Day 1 of each cycle. Trastuzumab will be administered as an IV infusion on Day 1 of each cycle. A loading dose of 8 mg/kg of trastuzumab will be administered over 90 minutes on Cycle 1 Day 1. Then, a maintenance dose of 6 mg/kg of trastuzumab will be administered over 30 to 90 minutes on Day 1 of Cycles 2 - 6. eribulin: During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle. carboplatin: Carboplatin area under the curve
Interventions
DRUGeribulin
During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle.
DRUGcarboplatin
Carboplatin area under the curve (AUC) 6 will be administered IV over 15 to 30 minutes on Day 1 of each cycle.
DRUGtrastuzumab
Trastuzumab will be administered as an IV infusion on Day 1 of each cycle. A loading dose of 8 mg/kg of trastuzumab will be administered over 90 minutes on Cycle 1 Day 1. Then, a maintenance dose of 6 mg/kg of trastuzumab will be administered over 30 to 90 minutes on Day 1 of Cycles 2 - 6.
Sponsors
Eisai Inc.
Vector Oncology
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
* Written informed consent * Females; 18 years of age or greater * Histologically proven invasive breast cancer * American Joint Committee on Cancer (AJCC) clinical stage IIA - IIIB * Tumor size greater than 10 millimeters * HER2 positive * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Estrogen receptor (ER) positive or negative * Ejection fraction greater than or equal to lower limit of normal for the institution by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) * Less than or equal to Grade 1 neuropathy according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 * Planned lumpectomy or mastectomy * Eligible for radiation therapy * No prior treatment for invasive breast cancer * Adequate organ system function per protocol as determined within 7 days prior to first dose of study treatment * Women of childbearing potential must have a negative pregnancy test within 7 days prior to the first dose of study treatment and must agree to use adequate contraception methods during study treatment and for a minimum of 6 months following trastuzumab discontinuation * Female subjects who are lactating should discontinue nursing prior to the first dose of study treatment and should refrain from nursing throughout the treatment period
Exclusion criteria
* Fine needle cytology only without other histologic evidence of invasive breast cancer * Inflammatory breast cancer * AJCC clinical stage T1a-b breast cancer (primary tumor less than or equal to 10 millimeters) * Evidence of metastatic disease * HER2 negative * Ejection fraction less than lower limit of normal for the institution by ECHO or MUGA * Corrected QT interval greater than 480 milliseconds * Pre-existing cardiac dysfunction * Prior history of invasive cancer within the past 3 years * Synchronous bilateral breast cancer * Pre-existing CTCAE v4.0 Grade 2 or greater neuropathy * Hypersensitivity to halichondrin B or halichondrin B chemical derivative * History of severe allergic reactions to cisplatin or other platinum containing compounds, or mannitol * Mild, moderate, or severe hepatic impairment * Moderate or severe renal impairment * Hypokalemia or hypomagnesemia if it cannot be corrected prior to the first dose of study treatment * Organ allografts requiring immunosuppression * Known positive human immunodeficiency virus (HIV) status * Prior major surgery within 28 days prior to the first dose of study treatment and/or presence of any non-healing wound, fracture, or ulcer * Minor surgery or radiation therapy within 14 days prior to the first dose of study treatment * Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Response | Assessed at time of definitive surgery, approximately 21-26 weeks from study treatment start | Definitive surgery will be performed 3 to 8 weeks after completion of study treatment. The pathology report will be scored for pathologic response: complete pathologic response (no invasive cancer in breast or lymph nodes; residual DCIS or LCIS is acceptable), partial pathologic response (residual invasive cancer in breast and/or lymph nodes), or no response (pathologic staging is equal to or worse than pretreatment clinical staging). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response | Assessed prior to definitive surgery, approximately 18 weeks from study treatment start. | Clinical assessment of response will be performed 3 weeks after completion of study treatment. The treating physician will assess clinical response using physical examination and radiologic evaluation. Clinical response options are complete response (no invasive tumor in breast and lymph nodes), partial response (\> 50% reduction in longest diameter of pretreatment tumor), no response (\< 50% response to 10% growth of tumor as determined by longest diameter of pretreatment tumor size), and progression. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Eribulin in Combination With Carboplatin and Trastuzuamb | Approximately 22 days from study treatment start, per subject | The MTD is defined as the dose at which \<= 1 of 6 subjects experience DLT (Dose Limiting Toxicity) and above which \>= 2 of 6 subjects experience DLT. |
| Dose Limiting Toxicity (DLT) | Approximately 22 days from study treatment start, per subject | DLT is defined as grade 4 thrombocytopenia; grade 4 anemia; grade 4 neutropenia lasting \> 5 days; or any grade 3 or 4 non-hematologic toxicity occurring during Cycle 1 which is attributable to eribulin, carboplatin, trastuzumab or the combination, or the inability to deliver all three agents at the assigned dose and scheduled time during Cycle 1.The following events are excluded from the DLT definition: grade 3 nausea and/or vomiting responsive to antiemetics; grade 3 fever or infection; grade 3 diarrhea responsive to antidiarrheal therapy. |
Countries
United States
Participant flow
Recruitment details
This study was open to enrollment at four community oncology centers in the United States from July 2011 to June 2014.
Pre-assignment details
Informed consent was obtained from all subjects. Subjects must have had no prior treatment for invasive breast cancer.
Participants by arm
| Arm | Count |
|---|---|
| Eribulin 1.1 mg/m2 Subjects assigned to receive a starting dose of eribulin 1.1 mg/m2 | 6 |
| Eribulin 1.4 mg/m2 Subjects assigned to receive a starting dose of eribulin 1.4 mg/m2 | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
Baseline characteristics
| Characteristic | Eribulin 1.1 mg/m2 | Eribulin 1.4 mg/m2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Continuous | 53.2 years STANDARD_DEVIATION 7.47 | 53.0 years STANDARD_DEVIATION 9.14 | 53.1 years STANDARD_DEVIATION 7.96 |
| Body Mass Index | 32.4 kg/m^2 STANDARD_DEVIATION 6.79 | 32.4 kg/m^2 STANDARD_DEVIATION 4.59 | 32.4 kg/m^2 STANDARD_DEVIATION 5.52 |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 | 3 / 6 |
Outcome results
Primary
Pathologic Response
Definitive surgery will be performed 3 to 8 weeks after completion of study treatment. The pathology report will be scored for pathologic response: complete pathologic response (no invasive cancer in breast or lymph nodes; residual DCIS or LCIS is acceptable), partial pathologic response (residual invasive cancer in breast and/or lymph nodes), or no response (pathologic staging is equal to or worse than pretreatment clinical staging).
Time frame: Assessed at time of definitive surgery, approximately 21-26 weeks from study treatment start
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eribulin 1.1 mg/m2 | Pathologic Response | Complete Response | 16.7 percentage of participants |
| Eribulin 1.1 mg/m2 | Pathologic Response | Partial Response | 83.3 percentage of participants |
| Eribulin 1.4 mg/m2 | Pathologic Response | Complete Response | 16.7 percentage of participants |
| Eribulin 1.4 mg/m2 | Pathologic Response | Partial Response | 83.3 percentage of participants |
Secondary
Clinical Response
Clinical assessment of response will be performed 3 weeks after completion of study treatment. The treating physician will assess clinical response using physical examination and radiologic evaluation. Clinical response options are complete response (no invasive tumor in breast and lymph nodes), partial response (\> 50% reduction in longest diameter of pretreatment tumor), no response (\< 50% response to 10% growth of tumor as determined by longest diameter of pretreatment tumor size), and progression.
Time frame: Assessed prior to definitive surgery, approximately 18 weeks from study treatment start.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eribulin 1.1 mg/m2 | Clinical Response | Complete Response | 16.7 percentage of participants |
| Eribulin 1.1 mg/m2 | Clinical Response | Partial Response | 83.3 percentage of participants |
| Eribulin 1.1 mg/m2 | Clinical Response | Missing | 0 percentage of participants |
| Eribulin 1.4 mg/m2 | Clinical Response | Complete Response | 50.0 percentage of participants |
| Eribulin 1.4 mg/m2 | Clinical Response | Partial Response | 33.3 percentage of participants |
| Eribulin 1.4 mg/m2 | Clinical Response | Missing | 16.7 percentage of participants |
Other Pre-specified
Dose Limiting Toxicity (DLT)
DLT is defined as grade 4 thrombocytopenia; grade 4 anemia; grade 4 neutropenia lasting \> 5 days; or any grade 3 or 4 non-hematologic toxicity occurring during Cycle 1 which is attributable to eribulin, carboplatin, trastuzumab or the combination, or the inability to deliver all three agents at the assigned dose and scheduled time during Cycle 1.The following events are excluded from the DLT definition: grade 3 nausea and/or vomiting responsive to antiemetics; grade 3 fever or infection; grade 3 diarrhea responsive to antidiarrheal therapy.
Time frame: Approximately 22 days from study treatment start, per subject
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eribulin 1.1 mg/m2 | Dose Limiting Toxicity (DLT) | Inability to deliver all 3 agents at assigned dose | 0 participants |
| Eribulin 1.1 mg/m2 | Dose Limiting Toxicity (DLT) | Grade 4 thrombocytopenia | 1 participants |
| Eribulin 1.4 mg/m2 | Dose Limiting Toxicity (DLT) | Grade 4 thrombocytopenia | 1 participants |
| Eribulin 1.4 mg/m2 | Dose Limiting Toxicity (DLT) | Inability to deliver all 3 agents at assigned dose | 2 participants |
Other Pre-specified
Maximum Tolerated Dose (MTD) of Eribulin in Combination With Carboplatin and Trastuzuamb
The MTD is defined as the dose at which \<= 1 of 6 subjects experience DLT (Dose Limiting Toxicity) and above which \>= 2 of 6 subjects experience DLT.
Time frame: Approximately 22 days from study treatment start, per subject
Population: The MTD of ECH as neoadjuvant therapy for HER2+ breast cancer was determined per protocol definitions; however, due to the combination of increased hematologic toxicity and possible reduced efficacy, Phase II of this trial was not initiated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eribulin 1.1 mg/m2 | Maximum Tolerated Dose (MTD) of Eribulin in Combination With Carboplatin and Trastuzuamb | 1.1 mg/m^2 |