Eribulin in Brain Metastases From HER2-negative Breast Cancer

Phase 2

Withdrawn

• Conditions: Metastatic Breast Cancer
• Interventions: Drug: Eribulin

• Registration Number: NCT03637868
• Lead Sponsor: Institut Paoli-Calmettes

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

Study Timeline

• Study First Submitted: 2018-08-06
• Study First Submitted QC: 2018-08-16
• Study First Posted: 2018-08-20
• Study Start: 2019-02-26
• Primary Completion: 2020-04-14
• Study Completion: 2020-04-14
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-05
• Last Update Posted: 2020-05-06

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Eribulin	Eribulin	eribulin 1.4 mg/m² administered intravenously between 6 and 7 cycles.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (7)

Institut Sainte Catherine; 🇫🇷 Avignon, France

Institut Paoli-Calmettes; 🇫🇷 Marseille, France

CHU Besançon; 🇫🇷 Besançon, France

Institut Du Cancer de Montpellier; 🇫🇷 Montpellier, France

Institut De Cancérologie de l'Ouest; 🇫🇷 Saint-Herblain, France

Institut de Cancerologie de Lorraine Alexis Vautrin; 🇫🇷 Vandœuvre-lès-Nancy, France

Institut de Cancerologie de L'Ouest - Paul Papin; 🇫🇷 Angers, France