Eribulin Mesylate Followed by Doxorubicin Hydrochloride and Cyclophosphamide in Treating Patients with HER2-Negative Inflammatory Breast Cancer before Surgery
This phase II trial studies how well eribulin mesylate works in combination with doxorubicin hydrochloride and cyclophosphamide in treating patients with human epidermal growth factor receptor 2 (HER2)-negative inflammatory breast cancer before surgery. Eribulin mesylate works by interfering with cancer cell division, growth, and spread. Drugs used in chemotherapy, such as doxorubicin hydrochloride and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving eribulin mesylate together with doxorubicin hydrochloride and cyclophosphamide before surgery may be an effective treatment in HER2-negative inflammatory breast cancer patients.
Inclusion Criteria
- Participants must have histologically confirmed invasive breast cancer; all histologic subtypes are eligible
- Participants must NOT have HER2 positive status based on American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines defined as: * Immunohistochemistry (IHC) 3+ based on circumferential membrane staining that is complete, intense -AND/OR – * Fluorescence in situ hybridization (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
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 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
- Left ventricular ejection fraction (LVEF) >= 50% calculated by echocardiogram (ECHO)
- Patients may have bilateral breast cancer so long as one breast meets criteria for inflammatory breast cancer, and neither breast cancer has 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 childbearing 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 eribulin administration
- Ability to understand and the willingness to sign a written informed consent document
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
- Human immunodeficiency virus (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 > 500 ms; patients with left bundle branch block that is deemed not clinically significant may be enrolled with corrected QT > 500
- 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 paclitaxel, doxorubicin, or cyclophosphamide as antineoplastic therapy
Additional locations may be listed on ClinicalTrials.gov for NCT02623972.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To determine pathologic complete response (pCR) rate after preoperative therapy with eribulin (eribulin mesylate) followed by doxorubicin hydrochloride and cyclophosphamide (AC) for HER2-negative inflammatory breast cancer.
SECONDARY OBJECTIVES:
I. To determine the efficacy of preoperative therapy for HER2-negative inflammatory breast cancer (IBC) defined as disease-free survival (DFS), time to treatment failure (TTF), and overall survival (OS).
II. To assess the residual cancer burden (RCB) after preoperative therapy in HER2-negative inflammatory breast cancer.
CORRELATIVE OBJECTIVES:
I. To correlate levels of expression of a panel of 20 pre-selected genes encoding for proteins involved with angiogenesis or epithelial-to-mesenchymal transition (EMT) with disease outcome (pCR, RCB, DFS, OS).
II. To correlate changes in imaging (Ktrans ve, vp, and initial area under the curve [iAUC]) with genomic changes determined on core biopsies of the breast sampled at the same time points.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A: Patients receive eribulin intravenously (IV) over 2-5 minutes on days 1 & 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV over 3-5 minutes and cyclophosphamide IV on day 1. Treatment repeats every 2 or 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 3 -5 weeks after the last dose of doxorubicin and cyclophosphamide, patients undergo surgery followed by radiation therapy and endocrine therapy.
COHORT B: Patients receive doxorubicin IV over 3-5 minutes and cyclophosphamide IV on day 1. Treatment repeats every 2 or 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive eribulin IV over 2-5 minutes on days 1 & 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 3 -5 weeks after the last dose of eribulin, patients undergo surgery followed by radiation therapy and endocrine therapy.
After completion of the study treatment, patients are followed up for every 3 months for 1 year, then every 6 months for 4 years, then annually thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorFilipa Lynce
- Primary ID15-292
- Secondary IDsNCI-2016-00329
- ClinicalTrials.gov IDNCT02623972