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

Phase 2

• Conditions: Metastatic Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Interventions: Drug: Bevacizumab and eribulin

• Registration Number: NCT02175446
• Lead Sponsor: Consorzio Oncotech

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2014-06-09
• Study First Submitted QC: 2014-06-25
• Study First Posted: 2014-06-26
• Study Start: 2014-09
• Status Verified: 2016-06
• Last Update Submitted: 2016-06-14
• Last Update Posted: 2016-06-15
• Primary Completion: 2016-12
• Study Completion: 2017-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 61

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.

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental1	Bevacizumab and eribulin	Bevacizumab and eribulin In this study all patients will receive: * Eribulin 1.23 mg/m2 on days 1, 8 every 3 weeks intravenously * Bevacizumab 15 mg/kg every 3 weeks intravenously or Bevacizumab 10 mg/kg every 2 weeks intravenously

Primary Outcome Measures

Name	Time	Method
Overall Response rate	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	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.

Secondary Outcome Measures

Name	Time	Method
Quality of life	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	QoL and symptom control will be assessed using the FACT-B questionnaire.
Progression free survival	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	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.
Clinical Benefit Rate	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	Clinical Benefit Rate is the proportion of patients with a complete or partial response or with stable disease at 24 weeks.
Safety	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	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.
Overall Survival	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	OS is defined as the time from first dosing in second line to death from any cause.
Duration of response	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 30 months	Duration of response measures the length of the response in those patients who responded to treatment.

Trial Locations

Locations (17)

Istituto Regina Elena per lo studio e la cura dei tumori; 🇮🇹 Roma, Italy

I.R.C.C.S. A.O.U. San Martino - I.S.T.; 🇮🇹 Genova, Italy

Azienda Ospedaliera Universitaria Pisana - Ospedale S. Chiara; 🇮🇹 Pisa, Italy

Ospedale 'F. Spaziani'; 🇮🇹 Frosinone, Italy

Azienda Ospedaliera Istituti Ospitalieri di Cremona; 🇮🇹 Cremona, 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

Istituto Nazionale Tumori - IRCCS "Fondazione G.Pascale"; 🇮🇹 Napoli, Italy

Presidio Ospedaliero Felice Lotti Pontedera; 🇮🇹 Pontedera, Italy

Azienda Ospedaleira Universitaria San Giovanni di Dio e Ruggi d'aragona; 🇮🇹 Salerno, Italy

Azienda Ospedaliera Universitaria Santa Maria della Misericordia di Udine; 🇮🇹 Udine, Italy

I.R.C.C.S. Fondazione Salvatore Maugeri; 🇮🇹 Pavia, Italy

AORN - Ospedali dei Colli Monaldi-Cotugno - C.T.O.; 🇮🇹 Napoli, Italy

Ospedale 'SS. Trinità'; 🇮🇹 Sora, Italy