Metastatic Breast Cancer
Conditions
Keywords
HER2-negative breast cancer, brain metastases
Brief summary
To evaluate the efficacy of eribulin for treatment of HER2-negative breast cancer brain metastases (BCBM)
Detailed description
This study will explore eribulin in three specific cohorts of patients with HER2-negative metastatic breast cancer harboring BCBM, pretreated with anthracyclines and taxanes: * Cohort A = Newly diagnosed, untreated BCBM, not candidate to initial surgery or stereotactic radiosurgery (SRS) and with pauci-symptomatic disease not requiring immediate whole-brain radiation therapy (WBRT) * Cohort B = BCBM pretreated with SRS and/or surgery alone, without WBRT, and not requiring immediate WBRT * Cohort C = BCBM pretreated with WBRT
Interventions
DRUGEribulin
Patients will receive eribulin 1.4 mg/m² administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.
Sponsors
Eisai Inc.
Institut Paoli-Calmettes
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, national, multicenter, open-label, uncontrolled, multi-cohort phase II trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. At least 18 years of age. 2. Life expectancy of 3 months or longer. 3. ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2. 4. HER2-negative (IHC 0/1+ or 2+ and in situ hybridization negative) metastatic breast cancer 5. Locally advanced or metastatic breast cancer that have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments. (no limit to the number of previous lines of therapy, no need for extracranial disease) 6. At least 2 weeks washout period post chemotherapy, targeted or biologic therapy, or radiation therapy is required prior to study entry 7. Patient with untreated CNS disease or previous SRS/surgery without WBRT (cohorts A and B) * At least 1 measurable CNS lesion ≥ 10 mm on T1-weighted gadolinium-enhanced MRI, OR * At least one CNS tumor measuring 5-9 mm in longest diameter, plus one or two additional CNS tumors measuring ≥ 3 mm in longest diameter, for which the sum of the longest diameters is ≥ 10 mm. 8. Patient with progressive disease harboring brain metastases after previous WBRT (cohort C) * At least 1 measurable CNS lesion ≥ 10 mm on T1-weighted gadolinium-enhanced MRI, OR * At least one CNS tumor measuring 5-9 mm in longest diameter, plus one or two additional CNS tumors measuring ≥ 3 mm in longest diameter, for which the sum of the longest diameters is ≥ 10 mm. 9. Adequate organ function as evidenced by: * Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L without granulocyte-colony-stimulating factor G-CSF (filgrastim, pegfilgrastim, or equivalent) support within 7 days * Hemoglobin (Hgb) ≥ 9.0 g/dL (90 g/L) without blood transfusion within 7 days * Platelet count ≥ 100 x 10e9/L without platelet transfusion within 7 days * Bilirubin ≤ 1.5 X upper limit of normal (ULN), except for patients with documented history of Gilbert's disease who may have DIRECT bilirubin ≤ 1.5 X ULN * Alanine aminotransferase (ALT) ≤ 2.5 X ULN, except ≤ 5 X ULN for patients with liver metastases * Aspartate aminotransferase (AST) ≤ 2.5 X ULN, except ≤ 5 X ULN for patients with liver metastases * Serum creatinine ≤ 1.5 X ULN; or calculated creatinine clearance ≥ 50 mL/min (using MDRD formula), or measured creatinine clearance ≥ 50 mL/min
Exclusion criteria
1. Prior therapy with eribulin. 2. Patients should not have had major surgery or radiotherapy (therapeutic and/or palliative) within 14 days prior to initiation of study treatment, including CNS-directed radiation therapy. (Minor procedures, such as tumor biopsy, thoracentesis, or intravenous catheter placement are allowed with no waiting period) 3. Patients may not have the following co morbid disease or concurrent illness: * Known cirrhosis, defined as Child Pugh class A or higher liver disease * Other active malignancy, except for non-melanoma skin cancer and carcinoma in situ (of the cervix or bladder) * Any other severe/uncontrolled inter current illness or significant co morbid conditions that in the opinion of the investigator would impair study participation or cooperation * Patients with the presence of an active infection, abscess or fistula * Known leptomeningeal disease or CNS midline shifts. * Any evidence of severe or uncontrolled systemic disease such as clinically significant cardiovascular, pulmonary, hepatic, renal or metabolic disease. * Severe conduction abnormality including significant corrected QT interval QTc prolongation \>450ms. * Patients with grade 3/4 peripheral neuropathy. 4. Patient candidate to SRS and or surgical resection 5. Major clinical symptoms requiring immediate WBRT as defined by local tumor board 6. Increase in corticosteroid dose in the week prior to baseline brain MRI 7. Patients with pacemaker or implantable cardioverter-defibrillator devices incompatible with MRI assessment. 8. Contraindication to Gadolinium infusion. 9. Treatment ongoing with other chemotherapy, hormonal therapy, immunotherapy, other investigational agents, or biologic agents for the treatment of cancer except bisphosphonates or denosumab. 10. Pregnant or breast-feeding patients 11. Women of child-bearing potential without effective contraception method. 12. Patient unable to express their consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of eribulin for treatment of HER2-negative BCBM | from inclusion until 30 days after completion of treatment | By estimating central nervous system (CNS) objective response rate per RANO-BM criteria. CNS objective response rate will be defined as the rate of patients with a partial response or a complete response as defined by RANO-BM criteria (Lin et al. 2015) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Eribulin in this population | from Eribulin initiation until 30 days after completion of treatment | Toxicity will be evaluated before every chemotherapy infusion according to NCI CTCAE v5.0 criteria. All treatment-related adverse events will be collected. The rate of grade 3 to 5 adverse events will be analyzed |
| Time to WBRT (cohort A and B) | from Eribulin initiation to the time of the first dose of whole brain radiation therapy - up to 28 months | Time to WBRT will be defined as the time from Eribulin initiation to WBRT start |
| CNS progression-free survival | from Eribulin initiation until the date of first documented CNS disease progression or date of death from any cause - up to 28 months | CNS progression-free survival will be defined as the time from Eribulin initiation to CNS disease progression according to RANO-BM criteria or death from any cause |
| Overall survival | from Eribulin initiation to death | Overall survival will be defined as the time from Eribulin initiation to death from any cause |
| Change in cognitive function | From Eribulin initiation up to 7 days after study treatment discontinuation | Cognitive function will be evaluated by self-report Fact-Cog v3.0 questionnaires (French validated version;(Joly et al. 2012)) that will have to be filled every two cycles (before every day 1 infusion) |
| Quality of life measured by Functional Assessment of Cancer Therapy-Brain Metastasis | From Eribulin initiation up to 7 days after study treatment discontinuation | Quality of life will be measured by Functional Assessment of Cancer Therapy-Brain Metastasis (FACT-Br v4.0, (Thavarajah et al. 2014)) questionnaire. This questionnaire will be filled every two cycles |
Other
| Measure | Time frame | Description |
|---|---|---|
| Bi-compartmental progression-free survival (PFS) | from Eribulin initiation until the date of first documented progression or date of death from any cause - up to 28 months | Bi-compartmental PFS will be defined as the time from Eribulin initiation to CNS disease progression according to RANO-BM criteria or non-CNS disease progression according to RECIST 1.1 criteria or death from any cause |
| Overall response rate for extra-CNS disease | from Eribulin initiation until 30 days after completion of treatment | The overall response rate for non-CNS disease will be defined as the rate of patients with a partial response or a complete response according to RECIST 1.1 criteria |
| Clinical benefit for both CNS and extra-CNS disease | partial response or complete response or disease stabilization > 6 months | The clinical benefit rate will be defined as the rate of patients with a partial response or a complete response or disease stabilization \> 6 months. Clinical benefit will be assessed for both CNS (using RANO-BM criteria) and non-CNS disease (using RECIST 1.1 criteria), separately |
| Eribulin efficacy according to hormone receptors expression | from Eribulin initiation until 30 days after completion of treatment | CNS objective response rates will be assessed according to hormone receptors expression (positive vs negative). A case will be defined as hormone receptors negative if both estrogen receptor and progesterone receptor expression are expressed by less than 10% of tumor cells |
| Efficacy comparison between patients with and without non-CNS disease | from Eribulin initiation until 30 days after completion of treatment | CNS objective response rates will be assessed according the presence of non-CNS disease ('CNS only' vs 'not CNS only'). |
| Progression-free survival for non-CNS disease | from Eribulin initiation until the date of first documented extra-cranial disease progression or date of death from any cause - up to 28 months | Extracranial progression-free survival will be defined as the time from Eribulin initiation to disease progression according to RECIST 1.1 criteria (Schwartz et al. 2016) or death from any cause. Thoracic and abdominal CT-scans will be performed as recommended in each participating center (usually every 6 weeks) to assess non CNS disease (extracranial PFS, non-CNS response rate, and clinical benefit). Non-CNS disease will be evaluated according to investigator assessment. |
Countries
France
Outcome results
None listed