Eribulin in HER2 Negative Metastatic BrCa

Study Overview
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Brief Summary
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Improvements in outcomes with metastatic breast cancer (MBC) have been observed in the last 30 years, however, overall prognosis remains poor with median survival of 2 to 3 years. Long term complete responses are observed only for a minority of MBC patients (2-5%) and MBC remains an incurable disease for most patients. Eribulin is a chemotherapy approved by the US FDA in November of 2010 to treat patients with MBC who have received at least two prior chemotherapy regimens. In this research study, the investigators are looking to see how well eribulin helps participants with MBC in an earlier-line setting. Eribulin works by interfering with cancer cell division, growth and spread.

Detailed Description
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Based on positive results in heavily pre-treated MBC patients, eribulin is being studied as first-line or second-line chemotherapy treatment. This is a non-randomized, open label study with participants enrolled in one of two cohorts: Cohort 1. Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) or Cohort 2: Triple negative breast cancer (TNBC) meaning HR-negative/HER2-negative (HR-/HER2-). HR- means progesterone receptor-negative (PR-) and estrogen receptor-negative (ER-). Beyond efficacy as measured primarily by response to treatment, investigators will evaluate safety, tolerability and quality of life. In particular, it is hypothesized that eribulin may have lower rates of neuropathy, a common side effect of many of the major chemotherapeutics with activity in MBC. The investigators will study the effect eribulin has on the nerves through regular questionnaires that ask about any nerve-related symptoms. The investigators also plan to send blood samples to explore if gene markers may indicate increased sensitivity to the nerve effects of eribulin.

Official Title
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A Phase 2 Study of Eribulin in Patients With HER2-Negative, Metastatic Breast Cancer: Evaluation of Efficacy, Toxicity and Patient-Reported Outcomes

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven invasive breast cancer, locally recurrent or metastatic, with at least one measureable lesion according to RECIST v1.1 Hormone receptor positive or hormone receptor negative HER2-negative disease Up to one prior line of chemotherapy for advanced disease is allowed (discontinued at least 14 days prior to initiation of protocol therapy) Prior bevacizumab in the neo/adjuvant or metastatic setting is acceptable No limit on prior lines of endocrine therapy, but must be discontinued at least 7 days prior to initiation of protocol therapy Must have completed any prior radiotherapy at least 2 weeks prior to initiation of protocol therapy Must have recovered from reversible effects of prior therapies to no more than grade 1 toxicity, with the exception of alopecia Agree to use adequate contraception for the duration of study participation Exclusion Criteria: Pregnant or breastfeeding Prior treatment with eribulin Prior malignancy other than carcinoma in situ of the cervix or nonmelanoma skin cancer unless diagnosed and definitively treated at least 3 years before enrollment in this study Clinically significant cardiovascular impairment Active brain metastases or unevaluated neurologic symptoms suggestive of brain metastases Pulmonary dysfunction requiring the use of oxygen Prior organ allograft requiring immunosuppression HIV positive on combination antiretroviral therapy Pre-existing grade 3 or 4 neuropathy Hypersensitivity to halichondrin B or halichondrin B chemical derivative Uncontrolled intercurrent illness Inability to read in English

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is not a randomized trial rather participants are enrolled based on disease histology. Participants in each arm receive the same treatment regimen.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: HR+/HER2-<br>Eribulin: 1.4 mg/m2 administered intravenously over 2-5 minutes on days 1 and 8 of each 21 day cycle Participants remained on single agent eribulin until disease progression or withdrawal for other reasons. | Drug: Eribulin<br> <br> * Other names: NSC-707389;|
| Experimental: Cohort 2: TNBC<br>Eribulin: 1.4 mg/m2 administered intravenously over 2-5 minutes on days 1 and 8 of each 21 day cycle Participants remained on single agent eribulin until disease progression or withdrawal for other reasons. | Drug: Eribulin<br> <br> * Other names: NSC-707389;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. | Disease was evaluated radiologically at baseline and every 9 weeks on treatment; Maximum treatment duration was 38 cycles/26 months (Cohort 1) and 17 cycles/12 months (Cohort 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Participants alive without PD are censored at date of last disease assessment. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions. | Disease was evaluated radiologically at baseline and every 9 weeks on and off treatment; Median (maximum) PFS follow-up was 12.6 (27.1) months in Cohort 1 and 12.4 (14.3) months in Cohort 2. | 
| Time to First Response (TTR) | TTR is defined as the time from first dose of study treatment until the earliest date that complete response (CR) or partial response (PR) based on RECIST 1.1 criteria is objectively documented. Non-CR, non-PR participants are censored at date of last disease assessment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response requires 4 week or later confirmation and assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. | Disease was evaluated radiologically at baseline and every 9 weeks on treatment; Maximum treatment duration was 38 cycles/26 months (Cohort 1) and 17 cycles/12 months (Cohort 2). | 
| Duration of Overall Response (DOR) | DOR is defined as the that response criteria for CR or PR (whichever is recorded first) are first met until the date that PD or death from any cause is first objectively documented. Participants who do not have PD will be censored on date of last disease assessment. | Disease was evaluated radiologically at baseline and every 9 weeks on and off treatment; Median (maximum) DOR follow-up was 12.6 (27.1) months in Cohort 1 and 12.4 (14.3) months in Cohort 2. | 
| Percentage of Participants With Grade 1-3 Treatment-Related Peripheral Sensory Neuropathy | The percentage of treated participants experiencing grade 1-3 peripheral sensory neuropathy with treatment attribution of possible, probable or definite based on Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms. | Adverse events were assessed every cycle throughout treatment. Maximum treatment duration was 38 cycles/26 months (Cohort 1) and 17 cycles/12 months (Cohort 2) | 
| Percentage of Participants With Grade 1-3 Treatment-Related Peripheral Motor Neuropathy | TThe percentage of treated participants experiencing grade 1-3 peripheral motor neuropathy with treatment attribution of possible, probable or definite based on Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms. | Adverse events were assessed every cycle throughout treatment. Maximum treatment duration was 38 cycles/26 months (Cohort 1) and 17 cycles/12 months (Cohort 2) | 
| Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | The FACT-BCS is a validated, self-administered questionnaire which captures quality of life (QOL) concerns specific to breast cancer patients. (Brady MJ, et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. JCO 1997; 15:974-86). The FACT-BCS has 9-items scored on a 5-point Likert scale (Not at all, A little bit, Somewhat, Quite a bit, Very much) with a maximum score of 36. A higher score indicates better QOL. A minimal clinically important difference is 3-5 points. | Assessed at baseline and on treatment day 1 of cycles 2, 3, 5, 7, 9 and 11 | 
| Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | The FACT-Ntx is a validated, self-administered questionnaire which captures quality of life (QOL) concerns specific to patients suffering from neurotoxicity. (Calhoun EA, et al. Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 2003; 13:741-8). The FACT-Ntx has 11-items scored on a 5-point Likert scale (Not at all, A little bit, Somewhat, Quite a bit, Very much) with a maximum score of 44. A higher score indicates better QOL. A minimal clinically important difference is 3-5 points. | Assessed at baseline and on treatment day 1 of cycles 2, 3, 5, 7, 9 and 11 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic breast cancer