Safety and Efficacy Study of Eribulin in Combination With Bevacizumab for Second-line Treatment HER2- MBC Patients

Metastatic Breast Cancer Clinical Trial

— GIM11-BERGI  

Official title:

A Phase II Single Arm Trial Evaluating the Efficacy and Safety of Eribulin in Combination With Bevacizumab for 2-Line Treatment of HER 2-Negative Metastatic Breast Cancer Progressing After 1-Line Therapy With Bevacizumab and Paclitaxel

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02175446
• Other study ID #: GIM11-BERGI
• Secondary ID: 2013-003194-10
• Status: Recruiting
• Phase: Phase 2
• First received: June 9, 2014
• Last updated: June 14, 2016
• Start date: September 2014
• Est. completion date: December 2017

Study information

• Verified date: June 2016
• Source: Consorzio Oncotech
• Contact: Clinical Research Technology
• Phone: 0039089301545
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

In the second-line treatment setting for MBC, many agents, including antitubulin drugs (Taxanes, Vinorelbine) and antimetabolites (Capecitabine, Gemcitabine), have demonstrated activity, but no agent is clearly superior. Although some combinations of cytotoxic agents provide a small progression-free survival advantage, none has demonstrated an OS advantage, and toxicity is generally greater than for single agents. At present, there is no standard for this treatment setting. New treatments that could delay disease progression without systemic toxicity would represent a significant advancement.

Description:

Metastatic breast cancer (MBC) is incurable, and the majority of patients succumb to their disease within 2 years of diagnosis.

Patients with MBC usually receive treatment with endocrine or cytotoxic chemotherapeutic agents, and treatment decisions are generally guided by the hormone receptor and Human Epidermal Growth Factor Receptor 2-Negative status of the disease, the number and location of metastases, and prior treatment history in both adjuvant and metastatic settings. In first- and second-line treatment settings of Metastatic Breast Cancer, numerous cytotoxic chemotherapy agents have demonstrated activity, including anti-tubulin drugs (Taxanes, Vinorelbine), Anthracyclines, and anti-metabolites (Capecitabine, Gemcitabine). However, no single agent has demonstrated a clear survival advantage over another, and use of sequential single-agent therapies is the most frequent approach. The choice of chemotherapy agent(s) is often determined by a number of factors, including history of prior therapy, treatment-free interval, and patient preference. Thus, no single standard treatment exists for patients with advanced disease. Patients who progress during or after their first treatment for Metastatic Brest Cancer typically have a short progression-free interval of 4-6 months and survive for 8-12 months. New treatment modalities are needed to improve clinical outcome and maintain the quality of life for these patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 61
• Est. completion date: December 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed informed consent prior to initiation of any study-specific procedures or treatment, as confirmation of the patient's awareness and willingness to comply with the study requirements.

• Female patients =18 years of age.

• Histologically confirmed Human Epidermal Growth Factor Receptor 2-Negative adenocarcinoma of the breast with documented progression of disease per investigator assessment following or during first-line treatment with Bevacizumab in combination with Paclitaxel for MBC; patients can have measurable or non-measurable disease. A minimum of 4 cycles of Bevacizumab 15 mg/kg or 6 cycles 10 mg/kg received in the first-line setting.

• Patients must have received Bevacizumab in combination with Paclitaxel as first line treatment. As part of their first line maintenance treatment, patients may have received:

• Bevacizumab monotherapy

• Bevacizumab in combination with endocrine treatment

• Nothing (for a period = 6 weeks from the last Bevacizumab treatment)

• ECOG performance status (PS) of 0-2.

• At least 28 days since prior radiation therapy or surgery and recovery from treatment.

• Patients must have measurable disease which must be evaluable per RECIST v1.1.

• Estimated life expectancy of =12 weeks.

Exclusion Criteria:

Disease-specific exclusions

• Patients who have received anti-angiogenic therapy [e.g. tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factors (anti-VEGFs)] other than Bevacizumab for the first-line treatment of MBC.

• Patients who have exclusively received endocrine treatment in combination with Bevacizumab until the first progression.

• Positive or unknown Human Epidermal Growth Factor Receptor 2/neu status or for whom determination of Human Epidermal Growth Factor Receptor 2 status is not possible. In general, Human Epidermal Growth Factor Receptor 2 positive status will be identified by a FISH assay as evaluated at the institution, or, if FISH is unavailable, a 2+ or 3+ immunohistochemistry result (but method of identification may vary by region or institution).

• Current, recent (within 4 weeks or 2 half-lives, whichever is greater, before day 1) or planned participation in an experimental drug study - other than a Bevacizumab breast cancer study.

• Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix or breast within the last 5 years.

• Any laboratory values at baseline as described in the protocol;

• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would prevent the patient from meeting the study requirements.

• Serious active infection requiring i.v. antibiotics and/or hospitalization at study entry.

• Patients who are treated with any medicinal product that contraindicates the use of any of the study drugs, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications.

Bevacizumab-specific exclusions: (see protocol)

Eribulin-specific exclusions: (see protocol)

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Metastatic Breast Cancer

Intervention

Drug:
• Bevacizumab and eribulin
In this study, Bevacizumab and Eribulin are considered to be the "investigational study drugs". Bevacizumab is provided as 25 mg/ml concentrate for infusion. Vials contain 100 mg of Bevacizumab in 4 ml and/or 400 mg in 16 ml. Eribulin is provided as vials containing 1 mg/2 mL Eribulin as a 500 µg/mL solution in ethanol/water

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Istituti Ospitalieri di Cremona	Cremona
Italy	Ospedale `F. Spaziani`	Frosinone
Italy	I.R.C.C.S. A.O.U. San Martino - I.S.T.	Genova
Italy	Ospedale Unico Versilia	Lido di Camaiore
Italy	Ospedale San Luca Istituto Tumori Toscano	Lucca
Italy	Ospedale civile di Macerata	Macerata
Italy	A.O.R.N. "A. Cardarelli"	Naples
Italy	Università degli Studi di Napoli "Federico II"	Naples
Italy	AORN - Ospedali dei Colli Monaldi-Cotugno - C.T.O.	Napoli
Italy	Istituto Nazionale Tumori - IRCCS "Fondazione G.Pascale"	Napoli
Italy	I.R.C.C.S. Fondazione Salvatore Maugeri	Pavia
Italy	Azienda Ospedaliera Universitaria Pisana - Ospedale S. Chiara	Pisa
Italy	Presidio Ospedaliero Felice Lotti Pontedera	Pontedera
Italy	Istituto Regina Elena per lo studio e la cura dei tumori	Roma
Italy	Azienda Ospedaleira Universitaria San Giovanni di Dio e Ruggi d'aragona	Salerno
Italy	Ospedale `SS. Trinità`	Sora
Italy	Azienda Ospedaliera Universitaria Santa Maria della Misericordia di Udine	Udine

Sponsors (2)

Lead Sponsor	Collaborator
Consorzio Oncotech	Clinical Research Technology

Country where clinical trial is conducted

Italy, 

References & Publications (26)

Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D, McDonald DM. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H547-59. Epub 2005 Sep 19. — View Citation

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Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment o — View Citation

Chia SK, Speers CH, D'yachkova Y, Kang A, Malfair-Taylor S, Barnett J, Coldman A, Gelmon KA, O'reilly SE, Olivotto IA. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. C — View Citation

Cigler T, Vahdat LT. Eribulin mesylate for the treatment of breast cancer. Expert Opin Pharmacother. 2010 Jun;11(9):1587-93. doi: 10.1517/14656566.2010.486790. Review. — View Citation

Cohen A, et al. Clinical outcomes in Bevacizumab (BV)-treated patients (pts) with metastatic colorectal cancer (mCRC): Results from ARIES observational cohort study (OCS) and confirmation of BRITE data on BV beyond progression (BBP). ASCO 2010

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Grothey A, Sugrue MM, Purdie DM, Dong W, Sargent D, Hedrick E, Kozloff M. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin O — View Citation

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Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regress — View Citation

Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, Norberg SM, O'Brien SM, Davis RB, Gowen LC, Anderson KD, Thurston G, Joho S, Springer ML, Kuo CJ, McDonald DM. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microva — View Citation

Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res. 2004 Aug — View Citation

Mancuso MR, Davis R, Norberg SM, O'Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006 Oct;116(10):2610-21. — View Citation

Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docet — View Citation

Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously tr — View Citation

Perez EA. Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. Breast Cancer Res Treat. 2009 Mar;114(2):195-201. doi: 10.1007/s10549-008-0005-6. Epub 2008 Apr 29. Review — View Citation

Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for f — View Citation

Saab TB, et al. Bevacizumab (BV) plus chemotherapy (CT) in 2nd line metastatic colorectal cancer (mCRC): Initial results from ARIES a second observational cohort study. ASCO 2010.

Twelves C, Cortes J, Vahdat LT, Wanders J, Akerele C, Kaufman PA. Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin Breast Cancer. 2010 Apr;10(2):160-3. doi: 10.3816/C — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response rate	ORR will be evaluated for those patients who have a response to second-line treatment as defined per RECIST version 1.1 in patients with measurable disease according to RECIST version 1.1. ORR will be based on the best overall response (BOR) as defined by RECIST Guidelines v. 1.1.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	No
Secondary	Progression free survival	Second-line progression-free survival, defined as the time from first dosing to the first documented disease progression or death from any cause, whichever occurs first.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	No
Secondary	Overall Survival	OS is defined as the time from first dosing in second line to death from any cause.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	No
Secondary	Clinical Benefit Rate	Clinical Benefit Rate is the proportion of patients with a complete or partial response or with stable disease at 24 weeks.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	No
Secondary	Duration of response	Duration of response measures the length of the response in those patients who responded to treatment.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	No
Secondary	Safety	Safety of second line treatment will be evaluated by the frequency of AEs and SAEs, cardiac events, clinically significant abnormal laboratory tests, vital signs, and ECOG PS. All patients who received at least one dose of study treatment will be included in the safety analysis.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	Yes
Secondary	Quality of life	QoL and symptom control will be assessed using the FACT-B questionnaire.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	No