Eribulin in Brain Metastases From HER2-negative Breast Cancer

Metastatic Breast Cancer Clinical Trial

— ERIBRAIN  

Official title:

A Phase II Study of Eribulin in Brain Metastases From HER2-negative Breast Cancer Pre-treated With Anthracyclines and Taxanes

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03637868
• Other study ID #: ERIBRAIN-IPC 2017-014
• Secondary ID: 2018-001027-40
• Status: Withdrawn
• Phase: Phase 2
• Start date: February 26, 2019
• Est. completion date: April 14, 2020

Study information

• Verified date: May 2020
• Source: Institut Paoli-Calmettes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the efficacy of eribulin for treatment of HER2-negative breast cancer brain metastases (BCBM)

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

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: April 14, 2020
• Est. primary completion date: April 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer
• Neoplasm Metastasis

Intervention

Drug:
• Eribulin
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.

Locations

Country	Name	City	State
France	Institut de Cancerologie de L'Ouest - Paul Papin	Angers
France	Institut Sainte Catherine	Avignon
France	CHU Besançon	Besançon
France	Institut Paoli-Calmettes	Marseille
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

Sponsors (2)

Lead Sponsor	Collaborator
Institut Paoli-Calmettes	Eisai Inc.

Country where clinical trial is conducted

France, 

References & Publications (19)

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Chang AY, Ying XX. Brain Metastases from Breast Cancer and Response to Treatment with Eribulin: A Case Series. Breast Cancer (Auckl). 2015 May 24;9:19-24. doi: 10.4137/BCBCR.S21176. eCollection 2015. — View Citation

Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. doi: 10.1016/S0140-6736(11)60070-6. Epub 2011 Mar 2. — View Citation

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Joly F, Lange M, Rigal O, Correia H, Giffard B, Beaumont JL, Clisant S, Wagner L. French version of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3. Support Care Cancer. 2012 Dec;20(12):3297-305. doi: 10.1007/s00520-012-1439-2. Epub 2012 May 2. — View Citation

Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005 Jul;4(7):1086-95. — View Citation

Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. doi: 10.1200/JCO.2013.52.4892. Epub 2015 Jan 20. — View Citation

Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M, Brown PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi FS, Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, Mehta MP, Schiff D, Soffietti R, Suh JH, van den Bent MJ, Vogelbaum MA, Wen PY; Response Assessment in Neuro-Oncology (RANO) group. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015 Jun;16(6):e270-8. doi: 10.1016/S1470-2045(15)70057-4. Epub 2015 May 27. Review. — View Citation

Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, Cristofanilli M, Dontu G, Bidaut L, Valero V, Hortobagyi GN, Yu D. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009 Jun 15;69(12):4951-3. doi: 10.1158/0008-5472.CAN-09-0099. Epub 2009 May 26. — View Citation

Matsuoka H, Tsurutani J, Tanizaki J, Iwasa T, Komoike Y, Koyama A, Nakagawa K. Regression of brain metastases from breast cancer with eribulin: a case report. BMC Res Notes. 2013 Dec 18;6:541. doi: 10.1186/1756-0500-6-541. — View Citation

Narayan S, Carlson EM, Cheng H, Condon K, Du H, Eckley S, Hu Y, Jiang Y, Kumar V, Lewis BM, Saxton P, Schuck E, Seletsky BM, Tendyke K, Zhang H, Zheng W, Littlefield BA, Towle MJ, Yu MJ. Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1639-43. doi: 10.1016/j.bmcl.2011.01.096. Epub 2011 Jan 26. — View Citation

Pivot X, Marmé F, Koenigsberg R, Guo M, Berrak E, Wolfer A. Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy. Ann Oncol. 2016 Aug;27(8):1525-31. doi: 10.1093/annonc/mdw203. Epub 2016 May 13. — View Citation

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Thavarajah N, Bedard G, Zhang L, Cella D, Beaumont JL, Tsao M, Barnes E, Danjoux C, Sahgal A, Soliman H, Chow E. Psychometric validation of the functional assessment of cancer therapy--brain (FACT-Br) for assessing quality of life in patients with brain metastases. Support Care Cancer. 2014 Apr;22(4):1017-28. doi: 10.1007/s00520-013-2060-8. Epub 2013 Nov 28. — View Citation

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* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Progression-free survival for non-CNS disease	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.	from Eribulin initiation until the date of first documented extra-cranial disease progression or date of death from any cause - up to 28 months
Other	Bi-compartmental progression-free survival (PFS)	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	from Eribulin initiation until the date of first documented progression or date of death from any cause - up to 28 months
Other	Overall response rate for extra-CNS disease	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	from Eribulin initiation until 30 days after completion of treatment
Other	Clinical benefit for both CNS and extra-CNS disease	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	partial response or complete response or disease stabilization > 6 months
Other	Eribulin efficacy according to hormone receptors expression	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	from Eribulin initiation until 30 days after completion of treatment
Other	Efficacy comparison between patients with and without non-CNS disease	CNS objective response rates will be assessed according the presence of non-CNS disease ('CNS only' vs 'not CNS only').	from Eribulin initiation until 30 days after completion of treatment
Primary	Efficacy of eribulin for treatment of HER2-negative BCBM	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)	from inclusion until 30 days after completion of treatment
Secondary	Safety of Eribulin in this population	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	from Eribulin initiation until 30 days after completion of treatment
Secondary	Time to WBRT (cohort A and B)	Time to WBRT will be defined as the time from Eribulin initiation to WBRT start	from Eribulin initiation to the time of the first dose of whole brain radiation therapy - up to 28 months
Secondary	CNS progression-free survival	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	from Eribulin initiation until the date of first documented CNS disease progression or date of death from any cause - up to 28 months
Secondary	Overall survival	Overall survival will be defined as the time from Eribulin initiation to death from any cause	from Eribulin initiation to death
Secondary	Change in cognitive function	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)	From Eribulin initiation up to 7 days after study treatment discontinuation
Secondary	Quality of life measured by Functional Assessment of Cancer Therapy-Brain Metastasis	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	From Eribulin initiation up to 7 days after study treatment discontinuation