Clinical trial NCT03637868: Eribulin in Brain Metastases From HER2-negative Breast Cancer
Official title: A Phase II Study of Eribulin in Brain Metastases From HER2-negative Breast Cancer Pre-treated With Anthracyclines and Taxanes
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: HER2-negative breast cancer
brain metastases
Lead sponsor: Institut Paoli-Calmettes
Sponsor class: OTHER
Collaborators: name: Eisai Inc.
First posted: 2018-08-20
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective, national, multicenter, open-label, uncontrolled, multi-cohort phase II trial
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Efficacy of eribulin for treatment of HER2-negative BCBM
timeFrame: from inclusion until 30 days after completion of treatment
Secondary outcomes:
measure: Safety of Eribulin in this population
timeFrame: from Eribulin initiation until 30 days after completion of treatment
measure: Time to WBRT (cohort A and B)
timeFrame: from Eribulin initiation to the time of the first dose of whole brain radiation therapy - up to 28 months
measure: CNS progression-free survival
timeFrame: from Eribulin initiation until the date of first documented CNS disease progression or date of death from any cause - up to 28 months
measure: Overall survival
timeFrame: from Eribulin initiation to death
measure: Change in cognitive function
timeFrame: From Eribulin initiation up to 7 days after study treatment discontinuation
measure: Quality of life measured by Functional Assessment of Cancer Therapy-Brain Metastasis
timeFrame: From Eribulin initiation up to 7 days after study treatment discontinuation
Other outcomes:
measure: Progression-free survival for non-CNS disease
timeFrame: from Eribulin initiation until the date of first documented extra-cranial disease progression or date of death from any cause - up to 28 months
measure: Bi-compartmental progression-free survival (PFS)
timeFrame: from Eribulin initiation until the date of first documented progression or date of death from any cause - up to 28 months
measure: Overall response rate for extra-CNS disease
timeFrame: from Eribulin initiation until 30 days after completion of treatment
measure: Clinical benefit for both CNS and extra-CNS disease
timeFrame: partial response or complete response or disease stabilization > 6 months
measure: Eribulin efficacy according to hormone receptors expression
timeFrame: from Eribulin initiation until 30 days after completion of treatment
measure: Efficacy comparison between patients with and without non-CNS disease
timeFrame: from Eribulin initiation until 30 days after completion of treatment
Locations:
city: Angers
country: France
facility: Institut de Cancerologie de L'Ouest - Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Besançon
country: France
facility: CHU Besançon
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Montpellier
country: France
facility: Institut Du Cancer de Montpellier
city: Saint-Herblain
country: France
facility: Institut De Cancérologie de l'Ouest
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancerologie de Lorraine Alexis Vautrin
Study officials:
affiliation: Institut Paoli-Calmettes
name: Renaud Sabatier, MD
role: PRINCIPAL_INVESTIGATOR
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