HER2-normal
Conditions
Keywords
Breast Cancer, HER2-normal Stage I to III invasive breast cancer
Brief summary
The purpose of this study is to assess the feasibility of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate for adjuvant treatment of early stage breast cancer.
Detailed description
This is a multicenter, single-arm Phase II trial to assess the feasibility of dose-dense adjuvant chemotherapy in subjects with early stage (I-III), HER-2 normal breast cancer. A total of 80 adult subjects will be enrolled in order to have 73 subjects who start the eribulin portion of the adjuvant study regimen. After completion of 4 cycles of AC, each subject will begin 4 cycles of eribulin mesylate 1.4 mg/m2 intravenously over 2 to 5 minutes on Days 1 and 8 of every 21 day cycle.
Interventions
DRUGeribulin mesylate
Dose dense doxorubicin and cyclophosphamide for 4 cycles during the first 8 weeks followed by eribulin mesylate 1.4mg/m2 for 4 cycles during the next 12 weeks.
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects aged greater than or equal to (\>=) 18 years * Histologically confirmed Stage I to III invasive breast cancer. Subjects may have more than one synchronous primary breast tumor. * HER-2 normal as determined by fluorescence in situ hybridization (FISH) or 0 or 1+ by immunohistochemistry (IHC) staining. * Subject is a candidate for chemotherapy in the adjuvant setting. Adjuvant therapy must begin within 84 days of the final surgical procedure for breast cancer. * Adequate cardiac function, defined by baseline LVEF \>=50 percent (%) by Multiple Gated Acquisition (MUGA) scan or echocardiogram. * ECOG performance status of 0 or 1. * Adequate renal function as evidenced by serum creatinine less than or equal to (\<=) 1.5 mg/dL or calculated creatinine clearance \>=40 mL/min per the Cockcroft and Gault formula. * Adequate bone marrow function as evidenced by ANC \>=1.5 x 10\^9/L, hemoglobin \>=10.0 g/dL, and platelet count \>=100 x 10\^9/L. * Adequate liver function as evidenced by bilirubin \<=1.5 times the upper limits of normal (ULN) and alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \<=3 x ULN. * Females of childbearing potential must have a negative urine or beta-human chorionic gonadotropin serum pregnancy test within 2 weeks prior to Cycle 1, Day 1. A urine pregnancy test should be repeated prior to chemotherapy if not conducted within 72 hours of start of treatment. Female subjects of childbearing potential must agree to be abstinent or to use a highly effective method of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, intrauterine device (IUD), or have a vasectomized partner) having started for at least one menstrual cycle prior to starting study drug and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Perimenopausal women must be amenorrheic for at least 12 months to be considered of nonchildbearing potential. Male subjects who are not abstinent or who have undergone a successful vasectomy, who are partners of women of childbearing potential must use, or their partners must use, a highly effective method of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, IUD) starting for at least one menstrual cycle prior to starting study drug and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Subjects with partners using hormonal contraceptives must also be using an additional approved method of contraception (as described previously). * Subjects willing and able to comply with the study protocol for the duration of the study and provide written informed consent prior to any study-specific screening procedures with the understanding that the subject may withdraw consent at any time without prejudice.
Exclusion criteria
* Stage IV breast cancer. * Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for current breast cancer. * Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study therapy drugs. * Subjects with a concurrently active second malignancy other than adequately treated nonmelanoma skin cancers or in situ cervical cancer. * Subjects with known positive human immunodeficiency virus (HIV) status. * Pregnancy or breast feeding at the time of study enrollment. Eligible subjects of reproductive potential (both sexes) must agree to use adequate contraceptive methods during study therapy. * Subjects with known allergy or hypersensitivity to doxorubicin, cyclophosphamide, or eribulin mesylate. * Inability to comply with the study and/or follow-up procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Feasibility | From date of first dose, up to 3 years after the last dose of study treatment, or up to approximately 4 years 2 months | The regimen was considered feasible if the participant was able to complete the eribulin portion without dose delay or reduction. Dose delay was defined as a delay due to eribulin-related adverse event (AE) for more than 2 days for subsequent doses (cycles after the initiation of full dose of eribulin, except holidays, scheduling difficulties and nonclinical logistical issues). If a participant had more than 1 dose omission, delay or reduction due to eribulin-related AE, these events were collectively counted as one entity in the same participant. Participants were followed for approximately 3 years after the last dose of the study treatment. Feasibility rates were calculated with or without growth factor support. In both cohorts, the percentage of participants who completed the eribulin portion of the regimen without a dose omission, delay or reduction due to eribulin-related AE was estimated via the observed completion rate and an exact 90% confidence interval (CI) was constructed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | From date of first dose up to 30 days after the last dose of study treatment, or up to approximately 4 years 2 months | Safety assessments consisted of monitoring and recording all AEs and SAEs, clinical laboratory results, vital signs, physical examinations, Eastern Cooperative Oncology Group (ECOG) performance status, electrocardiograms (ECGs), and left-ventricular ejection fracture (LVEF) by multigated acquisition scan (MUGA) or echocardiogram. An AE was considered a treatment emergent adverse event (TEAE) if the AE onset date was on or after the first dose of study drug and up to 30 days after receiving the last dose of study drug. Treatment-related TEAEs included TEAEs that were considered by the Investigator to be possibly or probably related to eribulin mesylate and/or doxorubicin/cyclophosphamide, or missing causality. Standardized Medical Dictionary for Regulatory Activities Queries (SMQ). |
Countries
United States
Participant flow
Pre-assignment details
A total of 81 participants were enrolled out of which 2 participants did not receive eribulin mesylate and were excluded from the eribulin-treated analysis sets (79 participants made up the Eribulin-treated Analysis Set and Eribulin-treated Safety Analysis Set).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed Participants initially received doxorubicin (60 mg/m\^2) plus cyclophosphamide (600 mg/m\^2) intravenously (IV) on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m\^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician's discretion if neutropenia occurred that recovered to Grade ≤2. | 55 |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim Participants initially received doxorubicin (60 mg/m\^2) plus cyclophosphamide (600 mg/m\^2) IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m\^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort filgrastim was used with eribulin therapy at a dose of 300 micrograms for participants ≤60 kg or 480 micrograms for participants \>60 kg, administered subcutaneously on Days 3 and 4 and Days 10 and 11 of each eribulin cycle. | 26 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Disease progression | 1 | 0 |
| Overall Study | Moved before end of treatment visit | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Subject choice | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Total |
|---|---|---|---|
| Age, Continuous | 49.4 Years STANDARD_DEVIATION 9.09 | 50.1 Years STANDARD_DEVIATION 9.33 | 49.6 Years STANDARD_DEVIATION 9.12 |
| Sex: Female, Male Female | 55 Participants | 26 Participants | 81 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 | 3 / 55 | 0 / 26 |
| other Total, other adverse events | 55 / 55 | 26 / 26 |
| serious Total, serious adverse events | 6 / 55 | 4 / 26 |
Outcome results
Primary
Percentage of Participants With Feasibility
The regimen was considered feasible if the participant was able to complete the eribulin portion without dose delay or reduction. Dose delay was defined as a delay due to eribulin-related adverse event (AE) for more than 2 days for subsequent doses (cycles after the initiation of full dose of eribulin, except holidays, scheduling difficulties and nonclinical logistical issues). If a participant had more than 1 dose omission, delay or reduction due to eribulin-related AE, these events were collectively counted as one entity in the same participant. Participants were followed for approximately 3 years after the last dose of the study treatment. Feasibility rates were calculated with or without growth factor support. In both cohorts, the percentage of participants who completed the eribulin portion of the regimen without a dose omission, delay or reduction due to eribulin-related AE was estimated via the observed completion rate and an exact 90% confidence interval (CI) was constructed.
Time frame: From date of first dose, up to 3 years after the last dose of study treatment, or up to approximately 4 years 2 months
Population: The eribulin-treated analysis set included all participants who received at least 1 dose of eribulin mesylate at the starting dose of 1.4 mg/m\^2. This was the primary analysis set for the feasibility evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Percentage of Participants With Feasibility | 70.4 Percentage of participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Percentage of Participants With Feasibility | 60.0 Percentage of participants |
p-value: 0.4422Fisher Exact
Secondary
Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs)
Safety assessments consisted of monitoring and recording all AEs and SAEs, clinical laboratory results, vital signs, physical examinations, Eastern Cooperative Oncology Group (ECOG) performance status, electrocardiograms (ECGs), and left-ventricular ejection fracture (LVEF) by multigated acquisition scan (MUGA) or echocardiogram. An AE was considered a treatment emergent adverse event (TEAE) if the AE onset date was on or after the first dose of study drug and up to 30 days after receiving the last dose of study drug. Treatment-related TEAEs included TEAEs that were considered by the Investigator to be possibly or probably related to eribulin mesylate and/or doxorubicin/cyclophosphamide, or missing causality. Standardized Medical Dictionary for Regulatory Activities Queries (SMQ).
Time frame: From date of first dose up to 30 days after the last dose of study treatment, or up to approximately 4 years 2 months
Population: The Safety Analysis Set included all participants who were enrolled, received at least 1 dose of study treatments and had at least 1 post-treatment safety assessment. This was the primary analysis set for all safety evaluations including issues related to cyclophosphamide and doxorubicin (AC) or eribulin treatments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Alopecia | 40 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Peripheral neuropathy (SMQ) | 40 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | SAEs | 6 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | All TEAEs | 55 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | AC-related TEAEs | 55 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Eribulin-related TEAEs | 54 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Neutropenia (SMQ) | 20 Participants |
| Cohort 1: Eribulin Mesylate With Filgrastim as Needed | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Grade ≥3 TEAEs | 31 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Neutropenia (SMQ) | 11 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | AC-related TEAEs | 26 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Grade ≥3 TEAEs | 18 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Alopecia | 19 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | All TEAEs | 26 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Peripheral neuropathy (SMQ) | 15 Participants |
| Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim | Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs) | Eribulin-related TEAEs | 23 Participants |