Breast Cancer
Conditions
Keywords
metastatic breast cancer
Brief summary
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
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.
Interventions
DRUGEribulin
Sponsors
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Response (TTR) | 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). | 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. |
| Duration of Overall Response (DOR) | 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. | 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. |
| Percentage of Participants With Grade 1-3 Treatment-Related Peripheral Sensory Neuropathy | 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) | 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. |
| Progression-Free Survival (PFS) | 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. | 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. |
| Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Assessed at baseline and on treatment day 1 of cycles 2, 3, 5, 7, 9 and 11 | 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. |
| Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Assessed at baseline and on treatment day 1 of cycles 2, 3, 5, 7, 9 and 11 | 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. |
| Percentage of Participants With Grade 1-3 Treatment-Related Peripheral Motor Neuropathy | 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) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between May 2013 and March 2016.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: HR+/HER2- 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. | 45 |
| Cohort 2: TNBC 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. | 38 |
| Total | 83 |
Baseline characteristics
| Characteristic | Cohort 1: HR+/HER2- | Cohort 2: TNBC | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 5 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 33 Participants | 68 Participants |
| Age, Continuous | 59 years | 53 years | 56 years |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) ECOG PS0 | 33 Participants | 26 Participants | 59 Participants |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) ECOG PS1 | 11 Participants | 12 Participants | 23 Participants |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) ECOG PS2 | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants | 35 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 42 Participants | 34 Participants | 76 Participants |
| Region of Enrollment United States | 45 participants | 38 participants | 83 participants |
| Sex: Female, Male Female | 45 Participants | 38 Participants | 83 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 45 | 9 / 38 |
| other Total, other adverse events | 45 / 45 | 37 / 38 |
| serious Total, serious adverse events | 22 / 45 | 13 / 38 |
Outcome results
Primary
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.
Time frame: 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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HR+/HER2- | Overall Response Rate (ORR) | 35.6 percentage of participants |
| Cohort 2: TNBC | Overall Response Rate (ORR) | 13.2 percentage of participants |
Comparison: Using a one sample binomial design, with 45 patients there was 90% power to detect a null hypothesis 30% overall response rate (historical control) versus an alternative hypothesis of 53% overall response rate assuming a two-sided 10% alpha.~Of note, cohort 2: TNBC did not fully accrue 45 patients so a testing was not done.p-value: 0.42Fisher Exact
Secondary
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.
Time frame: 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.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HR+/HER2- | Duration of Overall Response (DOR) | 6.5 months |
| Cohort 2: TNBC | Duration of Overall Response (DOR) | 1.9 months |
Secondary
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.
Time frame: Assessed at baseline and on treatment day 1 of cycles 2, 3, 5, 7, 9 and 11
Population: The analysis dataset is comprised of all participants who completed both QOL assessments required to calculate change from baseline. Per protocol, the cohorts were combined for this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Cycle 2 Change from Baseline | 1.0 units on a scale | Standard Deviation 4.6 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Cycle 3 Change from Baseline | 0.6 units on a scale | Standard Deviation 5.1 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Cycle 5 Change from Baseline | 0.1 units on a scale | Standard Deviation 4.4 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Cycle 7 Change from Baseline | 0.6 units on a scale | Standard Deviation 3.2 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Cycle 9 Change from Baseline | 1.8 units on a scale | Standard Deviation 5 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Breast Cancer Subscale (FACT-BCS) Change Score From Baseline | Cycle 11 Change from Baseline | 1.1 units on a scale | Standard Deviation 2.9 |
Secondary
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.
Time frame: Assessed at baseline and on treatment day 1 of cycles 2, 3, 5, 7, 9 and 11
Population: The analysis dataset is comprised of all participants who completed both QOL assessments required to calculate change from baseline. Per protocol, the cohorts were combined for this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Cycle 2 Change from Baseline | -0.1 units on a scale | Standard Deviation 3 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Cycle 3 Change from Baseline | -0.3 units on a scale | Standard Deviation 4.7 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Cycle 5 Change from Baseline | -1.6 units on a scale | Standard Deviation 5.5 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Cycle 7 Change from Baseline | -4.5 units on a scale | Standard Deviation 6.4 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Cycle 9 Change from Baseline | -1.8 units on a scale | Standard Deviation 5.9 |
| Cohort 1: HR+/HER2- | Functional Assessment of Cancer Therapy-Neurotoxicity Subscale (FACT-Ntx) Change Score From Baseline | Cycle 11 Change from Baseline | -1.6 units on a scale | Standard Deviation 4.7 |
Secondary
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.
Time frame: 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)
Population: The analysis dataset is comprised of all treated participants.Per protocol, the cohorts were combined for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HR+/HER2- | Percentage of Participants With Grade 1-3 Treatment-Related Peripheral Motor Neuropathy | 22.9 percentage of participants |
Secondary
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.
Time frame: 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)
Population: The analysis dataset is comprised of all treated participants. Per protocol, the cohorts were combined for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HR+/HER2- | Percentage of Participants With Grade 1-3 Treatment-Related Peripheral Sensory Neuropathy | 36.1 percentage of participants |
Secondary
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.
Time frame: 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.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1: HR+/HER2- | Progression-Free Survival (PFS) | 6.2 months |
| Cohort 2: TNBC | Progression-Free Survival (PFS) | 4.0 months |
Secondary
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.
Time frame: 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).
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HR+/HER2- | Time to First Response (TTR) | 10.6 months |
| Cohort 2: TNBC | Time to First Response (TTR) | NA months |
Post Hoc
Overall Survival
OS based on Kaplan-Meier is defined as the time from study entry to death or censored at date last known alive.
Time frame: Overall median survival follow-up was 5.9 months including a maximum of 27 months for Cohort 1 and 15 months for Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HR+/HER2- | Overall Survival | 20 months |
| Cohort 2: TNBC | Overall Survival | 11.3 months |