A Study Comparing Eribulin Mesylate and Ixabepilone in Causing or Exacerbating Neuropathy in Participants With Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study in patients with advanced breast cancer is to compare the incidence and severity of neuropathy adverse events for the two treatment groups (eribulin versus ixabepilone) using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0) grading.

Official Title
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A Phase II, Multicenter, Randomized, Open-Label Study Comparing Eribulin Mesylate and Ixabepilone in Causing or Exacerbating Neuropathy in Patients With Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Eribulin Mesylate
* Drug: Ixabepilone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 1. Female subjects with confirmed locally recurrent or metastatic carcinoma of the breast who have received prior taxane therapy and at least one prior cytotoxic chemotherapy regimen for advanced disease. Exclusion criteria: Subjects who have received prior ixabepilone therapy. Subjects with prior participation in an eribulin clinical study, even if not assigned to eribulin treatment. Subjects with pre-existing neuropathy Grade greater than or equal to 2. Subjects with a history of diabetes mellitus Type 1 or 2. Subjects with bilateral mastectomy which included bilateral axillary lymph node dissection. Subjects with missing digits required for vibration assessment. Subjects with any other concurrent diseases or conditions that would be expected to interfere with neuropathy assessments, which may include vitamin deficiency, sequelae of cerebrovascular disease, thyroid insufficiency, lumbar or cervical radiculopathy, or alcoholic or inflammatory neuropathy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Eribulin mesylate<br> | Drug: Eribulin Mesylate<br>* E7389 (eribulin mesylate) given at a dose of 1.4 mg/m^2 as a 2 to 5 minute intravenous (IV) bolus on Days 1 and 8 of a 21-day cycle. The Treatment Phase will include six cycles. Patients may enter the Extension Phase for additional cycles following the sixth cycle of treatment.<br>* Other names: E7389;|
| Active Comparator: Ixabepilone<br> | Drug: Ixabepilone<br>* Ixabepilone given at a starting dose of 32 or 40 mg/m^2 (as per approved labeling) as a 3-hour IV infusion on Day 1 of a 21-day cycle. The Treatment Phase will include six cycles. Patients may enter the Extension Phase for additional cycles following the sixth cycle of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-Emergent Neuropathy Adverse Events (AEs) | Neuropathy AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and coded according to the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Neuropathy AEs included the broad list of preferred terms (PTs) defined in the Standard MedDRA Query for Neuropathy and the following additional PTs: neuropathy, hyperesthesia, painful response to normal stimuli, pallanesthesia, and allodynia. If the post-baseline maximum CTCAE grade of the combined term neuropathy was greater than the baseline maximum CTCAE grade of the combined term, then the event was considered as treatment emergent neuropathy adverse events per CTCAE grade. For a single participant, 1) a neuropathy AE occurring more than once during the study, whether defined with the same or different MedDRA PTs, was counted only once, 2) a neuropathy AE with different CTCAE grades had only the highest grade AE counted. | From administration of first dose up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Incidence of Treatment-emergent Myalgia/Arthralgia | The incidence rate of TE myalgia/arthralgia was calculated as the percent of participants with TE myalgia/arthralgia. A participant who had an arthralgia or myalgia AE more than once over the course of the study was counted only once in the incidence calculation for myalgia/arthralgia AEs. A participant who had myalgia/arthralgia AEs with different CTCAE grades was counted with the highest CTCAE grade over the course of the evaluation period. If the post-baseline CTCAE grade of the combined term Myalgia/Arthralgia was greater than the baseline maximum CTCAE grade of the combined term, the participant had TE myalgia/arthralgia. The 2-sided 95% confidence interval (CI) for incidence rate of TE myalgia/arthralgia was calculated using the Clopper-Pearson method (i.e., the exact method) for each treatment group. | From administration of first dose up to approximately 5 years | 
| Change From Baseline in Vibration Perception Threshold (VPT) | The participant-reported questionnaire was used to compare the incidence and severity of neuropathy AEs. Sensory and motor scores were to be analyzed separately using a generalized linear model. Separate subgroup analyses were performed by each stratification variable. VPAT was measured using a Vibratron II device (Physitemp, Inc.) and a modified Two Alternative Forced Choice psychophysical algorithm. VPT was assessed on the ventral surface of the distal index finger (side opposite the nail), contralateral to the side of the mastectomy or primary disease and on the distal fleshy pad of both the right and left great toes (side opposite the nail). If the mastectomy was bilateral, the index finger on the side without axillary lymph node dissection was tested. Data ranged from 0 (invalid) to 20 vu. A lower VPT indicated a greater sensitivity. | Baseline, Treatment Phase: Cycles 2 to 6 (Day 1); Extension Phase: Cycle 9 Day 1, Cycle 12 Day 1, Cycle 15 Day 1 (Each Cycle length=21 days), End of Treatment, Post-treatment Follow-up, Worst Post-baseline result (Up to approximately 5 years) | 
| Number of Participants With Shift From Baseline to Worst Post-baseline Participant Neurotoxicity Questionnaire (PNQ) Score for Item 1 (Sensory) | The PNQ consisted of 3 parts; Item 1 (sensory) measured numbness, pain, burning or tingling in hands or feet, Item 2 (motor) measured weakness in arms or legs, and Item 3 (activities) measured activities that interfered with daily life. The participant was told that there was no right or wrong answer and their answer should reflect how they currently felt since last completing the PNQ. Sensory scores were analyzed separately. Letter scores (A= none, B=mild, C=moderate, D=moderate to severe, and E=severe) for PNQ were converted to numeric scores A (none)=0, B (mild)=1, C (moderate)=2, D (moderate to severe)=3 and E (severe)=4). Total scores ranged from 0 (minimum severity) to 10 (maximum severity). Higher scores indicated greater severity. Neuropathy AEs that were sensory were evaluated with the PNQ Item 1 (sensory). Categories where no participant showed any shift from baseline to post-baseline for both the arms were not included in the presentation. | Baseline up to approximately 5 years | 
| Number of Participants With Shift From Baseline to Worst Post-baseline Participant Neurotoxicity Questionnaire (PNQ) Score for Item 2 (Motor) | The PNQ consisted of 3 parts; Item 1 (sensory) measured numbness, pain, burning or tingling in hands or feet, Item 2 (motor) measured weakness in arms or legs, and Item 3 (activities) measured activities that interfered with daily life. The participant was told that there was no right or wrong answer and their answer should reflect how they currently felt since last completing the PNQ. Motor scores were analyzed separately. Letter scores (A= none, B=mild, C=moderate, D=moderate to severe, and E=severe) for PNQ were converted to numeric scores A (none)=0, B (mild)=1, C (moderate)=2, D (moderate to severe)=3 and E (severe)=4). Total scores ranged from 0 (minimum severity) to 10 (maximum severity). Higher scores indicated greater severity. Neuropathy AEs that were motor were evaluated with the PNQ Item 2 (motor). Categories where no participant showed any shift from baseline to post-baseline for both the arms were not included in the presentation. | Baseline up to approximately 5 years | 
| Number of Participants With Shift From Baseline to Worst Post-baseline Participant Neurotoxicity Questionnaire (PNQ) Composite Score | The PNQ consisted of 3 parts; Item 1 (sensory) measured numbness, pain, burning or tingling in hands or feet, Item 2 (motor) measured weakness in arms or legs, and Item 3 (activities) measured activities that interfered with daily life. Sensory scores, motor scores and composite scores were analyzed separately. For both item 1 and item 2, letter scores (A=none, B=mild, C=moderate, D=moderate to severe, and E=severe) for PNQ were converted to numeric scores A(none)=0, B(mild)=1, C(moderate)=2, D(moderate to severe)=3 and E (severe)=4. Total scores ranged from 0 (minimum severity) to 10 (maximum severity). Higher scores indicated greater severity. PNQ composite score was defined as the worst of Item 1 and Item 2 score. If neither Item 1 or item 2 score was D or E, but if a box was checked in Item 3, PNQ composite score would be D. Categories where no participant showed any shift from baseline to post-baseline for both the arms were not included in the presentation. | Baseline up to approximately 5 years | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 for target lesions assessed by magnetic resonance imaging and computed tomography and investigator assessment. Participants with unknown or missing responses were treated as non-responders. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. ORR=CR+PR, was presented with 2-sided 95% confidence interval (CI) by the method of Clopper-Pearson method for calculating the exact binomial intervals. | From date of treatment start until disease progression (PD) (Up to approximately 5 years) | 
| Progression-Free Survival (PFS) | PFS was defined as the time from randomization until PD or death due to any cause as determined by the investigator. Disease progression per RECIST v1.0 was defined as at least a 20% relative increase and 5 millimeter absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. The duration of PFS was calculated as the end date minus date of first drug plus 1. For participants who did not have an event (those lost to follow-up or who had not progressed at the date of data cut-off) PFS was censored. The median PFS and corresponding 95% CI was estimated for each treatment group using the Kaplan-Meier method. | From date of treatment start until the date of PD or death from any cause (Up to approximately 5 years) | 
| Clinical Benefit Rate (CBR) | CBR was defined as the number of participants (CR + PR + stable disease (SD) greater than or equal to 6 months) divided by the number of participants in the analysis population. The 95% CI was generated for the clinical benefit rate for each treatment group, and it was based on the Clopper-Pearson method for calculating the exact binomial intervals. | From date of treatment start until PD or death from any cause, whichever occurred first (Up to approximately 5 years) | 
| Duration of Response (DoR) | DoR was defined as the time from first documented CR or PR until PD or death from any cause. It was measured from the time that measurement criteria were met for CR or PR (whichever status was recorded first) until the first date that recurrent or PD was objectively documented. It was defined for participants with a confirmed CR or a confirmed PR. Participants without progressive disease or death were censored. Median duration and 95% CI of the median were estimated for each treatment group, using the Kaplan-Meier method. | From date of first CR or PR until the first documentation of PD or date of death (Up to approximately 5 years) | 
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Eribulin and Ixabepilone | General safety was assessed by monitoring all TEAEs and SAEs. TEAEs were reported at a frequency of 0% or greater in the study population. | For each participant, from the first dose till 42 days after the last dose of study treatment (Up to approximately 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Oncology