Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Inflammatory Breast Cancer
Conditions
Keywords
inflammatory breast cancer, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
Brief summary
This research study is studying a drug called eribulin combined with standard treatment as a possible preoperative treatment for HER2 negative inflammatory breast cancer.
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. Eribulin works by interfering with cancer cell division, growth, and spread. The goal of this research study is to evaluate inflammatory breast cancer's response to treatment with eribulin followed by AC chemotherapy (Cohort A) and also the response to treatment with AC followed by Eribulin (Cohort B) when given as a preoperative chemotherapy treatment for participants with HER2 negative inflammatory breast cancer.
Interventions
DRUGEribulin
administered IV for 4 cycles
DRUGAdriamycin
administered IV with cyclophosphamide for 4 cycles
DRUGCyclophosphamide
administered IV with adriamycin for 4 cycles
Sponsors
Dana-Farber Cancer Institute
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Participants must have histologically confirmed invasive breast cancer. All histologic subtypes are eligible. \-- Patients must NOT have HER2 positive status based on ASCO/CAP guidelines defined as: IHC 3+ based on circumferential membrane staining that is complete, intense and/or FISH positive based on one of the three following criteria: Single-probe average HER2 copy number ≥ 6.0 signals/cell; OR Dual-probe HER2/CEP17 ratio \<2.0 with an average HER2 copy number ≥ 6.0 signals/cell; OR Dual-probe HER2/CEP17 ratio ≥2.0 * Age ≥18 years. Because no dosing or adverse event data are currently available on the use of eribulin in participants \<18 years of age, children are excluded from this study * ECOG performance status ≤1 (Karnofsky ≥70%) * Participants must have normal organ and marrow function as defined below: * leukocytes ≥3,000/mcL * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine ≤1.5 × institutional upper limit of normal \--- OR * creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. * Patients must have the clinical diagnosis of inflammatory breast cancer. * Patients must be without evidence of visceral or bone involvement with metastatic cancer on physical exam or any diagnostic study. Extensive nodal involvement (distant or regional) is allowed. * LVEF \> 50% calculated by echocardiogram (ECHO) * Patients may have bilateral breast cancer so long as one breast meets criteria for inflammatory breast cancer, and the breast with inflammatory breast cancer has never received prior therapy. * The effects of eribulin on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of chemotherapy administration. * Ability to understand and the willingness to sign a written informed consent document. * Both men and women of all races and ethnic groups are eligible for this trial. Because breast cancer predominantly affects females, it is anticipated that male enrollment will be \< 5% of the overall study population.
Exclusion criteria
* Participants who are receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to eribulin or other agents used in study. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because eribulin is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with eribulin, breastfeeding should be discontinued if the mother is treated with eribulin. These potential risks may also apply to other agents used in this study. * HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with eribulin. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. * A baseline corrected QT interval of \> 470 ms. * Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. * Patients may not have received eribulin, paclitaxel, doxorubicin, or cyclophosphamide as anti-neoplastic therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response Rate | Assessed after preoperative therapy with either 4 cycles of eribulin mesylate (3 wks) followed by 4 cycles of doxorubicin/cyclophosphamide (2 wks) or after 4 cycles of AC(2 wks) followed by 4 cycles of eribulin(3 wks). As such up to 20 weeks. | Complete pathologic disease response (pCR) is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy, based upon pathological assessment of surgical specimens. Those with invasive carcinoma present within the breast and axillary lymph nodes, and participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival | DFS is assessed every cycle for 8 cycles. After protocol therapy, assessed every 3 months for 1 year, then every 6 months for 4 years, then annually until death.The DFS measurement duration is anticipated to last for at least 5 years. | Disease-free survival (DFS) is defined for the participants who undergo surgery, as the duration of time from surgery until ipsilateral local-regional, contralateral or distant invasive recurrence or death from any cause; in the absence of an event, DFS will be censored at the date last know alive and free from recurrence. |
| Time to Treatment Failure | TTF is assessed every cycle for 8 cycles. After protocol therapy, assessed every 3 months for 1 year, then every 6 months for 4 years, then annually until death. The TTF measurement duration is anticipated to last for at least 5 years. | Time to treatment failure (TTF) will be defined among all participants, as the duration of time from treatment initiation to a DFS event or progressive disease during preoperative therapy or treatment disease that is not surgically resectable; in the absence of an event, TTF will be censored at the date last know alive and free from recurrence or progression. |
| Overall Survival | OS is assessed every cycle for 8 cycles. After protocol therapy, assessed every 3 months for 1 year, then every 6 months for 4 years, then annually until death. The OS measurement duration is anticipated to last for at least 5 years. | Overall Survival (OS) will be defined two ways: among patients who undergo surgery, as time from surgery until death from any cause; and among all patients, as the time from treatment initiation until death from any cause. Censoring will use the date last known alive. |
| Residual Cancer Burden (RCB) | Assessed after preoperative therapy with either 4 cycles of eribulin mesylate (3 wks) followed by 4 cycles of doxorubicin/cyclophosphamide (2 wks) or after 4 cycles of AC(2 wks) followed by 4 cycles of eribulin(3 wks). As such summed up to 20 weeks. | Residual cancer burden is calculated and then categorized based on level of residual disease after neoadjuvant therapy and several other factors as assessed by pathologists. This method uses tumor size, the proportion of that tumor that is invasive carcinoma, the number of axillary lymph nodes containing metastatic carcinoma and the diameter of the largest metastasis in an axillary lymph node. This index is divided into 4 categories: RCB-0, RCB-I, RCB-II, and RCB-III.(RCB category "Unknown" if unable to determine RCB or missing data.) The previous categories are in order of increasing severity of RCB. Measurement of residual breast cancer burden can predict survival after neoadjuvant chemotherapy. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFilipa Lynce, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
February 2016 to December 2020
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Eribulin Followed by AC * Eribulin-Administered via iv, at predetermined dosage and schedule per cycle
* Two research breast biopsies
* Adriamycin (doxorubicin) via iv a predetermined dosage and schedule per cycle
* Cyclophosphamide via iv a predetermined dosage and schedule per cycle
* Surgical Removal of the breasts (Mastectomy) and axillary lymph node dissection
* Radiation Therapy
* Endocrine Therapy (if applicable)
* Optional 5 Patient-Optional DCE-MRI (Dynamic Contrast Enhanced-Magnetic Resonance Imaging) scans
Eribulin: administered IV for 4 cycles
Adriamycin: administered IV with cyclophosphamide for 4 cycles
Cyclophosphamide: administered IV with adriamycin for 4 cycles | 16 |
| Arm B: AC Followed by Eribulin * Adriamycin (doxorubicin) via iv a predetermined dosage and schedule per cycle
* Cyclophosphamide via iv a predetermined dosage and schedule per cycle
* Two research breast biopsies
* Eribulin-Administered via iv, at predetermined dosage and schedule per cycle
* Surgical Removal of the breasts (Mastectomy) and axillary lymph node dissection
* Radiation Therapy
* Endocrine Therapy (if applicable)
* Optional 5 Patient-Optional DCE-MRI (Dynamic Contrast Enhanced-Magnetic Resonance Imaging) scans
Eribulin: administered IV for 4 cycles
Adriamycin: administered IV with cyclophosphamide for 4 cycles
Cyclophosphamide: administered IV with adriamycin for 4 cycles | 6 |
| Total | 22 |
Baseline characteristics
| Characteristic | Arm A: Eribulin Followed by AC | Total | Arm B: AC Followed by Eribulin |
|---|---|---|---|
| Age, Continuous | 57 years | 58 years | 59 years |
| Breast Cancer Stage IIIB | 14 Participants | 17 Participants | 3 Participants |
| Breast Cancer Stage IIIC | 2 Participants | 3 Participants | 1 Participants |
| Breast Cancer Stage IV | 0 Participants | 1 Participants | 1 Participants |
| Breast Cancer Stage Unknown | 0 Participants | 1 Participants | 1 Participants |
| Estrogen Receptor Status <1% | 3 Participants | 3 Participants | 0 Participants |
| Estrogen Receptor Status >10% | 13 Participants | 18 Participants | 5 Participants |
| Estrogen Receptor Status 1-10% | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 22 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 21 Participants | 5 Participants |
| Region of Enrollment United States | 16 participants | 22 participants | 6 participants |
| Sex: Female, Male Female | 16 Participants | 22 Participants | 6 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 | 1 / 16 | 0 / 6 |
| other Total, other adverse events | 16 / 16 | 6 / 6 |
| serious Total, serious adverse events | 5 / 16 | 1 / 6 |
Outcome results
Primary
Pathologic Complete Response Rate
Complete pathologic disease response (pCR) is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy, based upon pathological assessment of surgical specimens. Those with invasive carcinoma present within the breast and axillary lymph nodes, and participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR.
Time frame: Assessed after preoperative therapy with either 4 cycles of eribulin mesylate (3 wks) followed by 4 cycles of doxorubicin/cyclophosphamide (2 wks) or after 4 cycles of AC(2 wks) followed by 4 cycles of eribulin(3 wks). As such up to 20 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Eribulin followed by AC | Pathologic Complete Response Rate | 6.25 percentage of participants |
| Arm B: AC followed by Eribulin | Pathologic Complete Response Rate | 0 percentage of participants |
Comparison: Null Hypothesis: the proportion of participants experiencing pCR is ≤ 0.02, Alternative hypothesis that proportion pCR ≥ 0.23. Hypothesized False Positive Rate(α)=5%; Hypothesized False Negative Rate(1-β)=10%.Simon minimax two-stage design
Comparison: Null Hypothesis: the proportion of participants experiencing pCR is ≤ 0.10, Alternative hypothesis that proportion pCR ≥ 0.30. Hypothesized False Positive Rate(α)=10%; Hypothesized False Negative Rate(1-β)=10%.Simon minimax two-stage design
Secondary
Disease Free Survival
Disease-free survival (DFS) is defined for the participants who undergo surgery, as the duration of time from surgery until ipsilateral local-regional, contralateral or distant invasive recurrence or death from any cause; in the absence of an event, DFS will be censored at the date last know alive and free from recurrence.
Time frame: DFS is assessed every cycle for 8 cycles. After protocol therapy, assessed every 3 months for 1 year, then every 6 months for 4 years, then annually until death.The DFS measurement duration is anticipated to last for at least 5 years.
Secondary
Overall Survival
Overall Survival (OS) will be defined two ways: among patients who undergo surgery, as time from surgery until death from any cause; and among all patients, as the time from treatment initiation until death from any cause. Censoring will use the date last known alive.
Time frame: OS is assessed every cycle for 8 cycles. After protocol therapy, assessed every 3 months for 1 year, then every 6 months for 4 years, then annually until death. The OS measurement duration is anticipated to last for at least 5 years.
Secondary
Residual Cancer Burden (RCB)
Residual cancer burden is calculated and then categorized based on level of residual disease after neoadjuvant therapy and several other factors as assessed by pathologists. This method uses tumor size, the proportion of that tumor that is invasive carcinoma, the number of axillary lymph nodes containing metastatic carcinoma and the diameter of the largest metastasis in an axillary lymph node. This index is divided into 4 categories: RCB-0, RCB-I, RCB-II, and RCB-III.(RCB category Unknown if unable to determine RCB or missing data.) The previous categories are in order of increasing severity of RCB. Measurement of residual breast cancer burden can predict survival after neoadjuvant chemotherapy.
Time frame: Assessed after preoperative therapy with either 4 cycles of eribulin mesylate (3 wks) followed by 4 cycles of doxorubicin/cyclophosphamide (2 wks) or after 4 cycles of AC(2 wks) followed by 4 cycles of eribulin(3 wks). As such summed up to 20 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Eribulin followed by AC | Residual Cancer Burden (RCB) | RCB-I | 12.5 percentage of participants |
| Arm A: Eribulin followed by AC | Residual Cancer Burden (RCB) | RCB-III | 56.25 percentage of participants |
| Arm A: Eribulin followed by AC | Residual Cancer Burden (RCB) | RCB-II | 25 percentage of participants |
| Arm A: Eribulin followed by AC | Residual Cancer Burden (RCB) | Unknown | 0 percentage of participants |
| Arm A: Eribulin followed by AC | Residual Cancer Burden (RCB) | RCB-0 | 6.25 percentage of participants |
| Arm B: AC followed by Eribulin | Residual Cancer Burden (RCB) | Unknown | 16.67 percentage of participants |
| Arm B: AC followed by Eribulin | Residual Cancer Burden (RCB) | RCB-0 | 0 percentage of participants |
| Arm B: AC followed by Eribulin | Residual Cancer Burden (RCB) | RCB-I | 0 percentage of participants |
| Arm B: AC followed by Eribulin | Residual Cancer Burden (RCB) | RCB-II | 50 percentage of participants |
| Arm B: AC followed by Eribulin | Residual Cancer Burden (RCB) | RCB-III | 33.33 percentage of participants |
Secondary
Time to Treatment Failure
Time to treatment failure (TTF) will be defined among all participants, as the duration of time from treatment initiation to a DFS event or progressive disease during preoperative therapy or treatment disease that is not surgically resectable; in the absence of an event, TTF will be censored at the date last know alive and free from recurrence or progression.
Time frame: TTF is assessed every cycle for 8 cycles. After protocol therapy, assessed every 3 months for 1 year, then every 6 months for 4 years, then annually until death. The TTF measurement duration is anticipated to last for at least 5 years.