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Dose Dense Doxorubucin and Cyclophosphamide Followed by Eribulin Mesylate for the Adjuvant Treatment of Early Stage Breast Cancer

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ClinicalTrials.gov Identifier: NCT01328249
Recruitment Status : Completed
First Posted : April 4, 2011
Results First Posted : September 26, 2018
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HER2-normal
Intervention Drug: eribulin mesylate
Enrollment 81
Recruitment Details  
Pre-assignment Details A total of 81 participants were enrolled out of which 2 participants did not receive eribulin mesylate and were excluded from the eribulin-treated analysis sets (79 participants made up the Eribulin-treated Analysis Set and Eribulin-treated Safety Analysis Set).
Arm/Group Title Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Hide Arm/Group Description Participants initially received doxorubicin (60 milligram per square meter [mg/m^2]) plus cyclophosphamide (600 mg/m^2) intravenously (IV) on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician’s discretion if neutropenia occurred that recovered to Grade ≤2. Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort filgrastim was used with eribulin therapy at a dose of 300 micrograms for participants ≤60 kg or 480 micrograms for participants >60 kg, administered subcutaneously on Days 3 and 4 and Days 10 and 11 of each eribulin cycle.
Period Title: Overall Study
Started 55 26
Completed 48 23
Not Completed 7 3
Reason Not Completed
Adverse Event             3             0
Disease progression             1             0
Withdrawal by Subject             1             1
Moved before end of treatment visit             1             0
Subject choice             1             1
Protocol Violation             0             1
Arm/Group Title Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim Total
Hide Arm/Group Description Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) intravenously (IV) on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician’s discretion if neutropenia occurred that recovered to Grade ≤2. Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort filgrastim was used with eribulin therapy at a dose of 300 micrograms for participants ≤60 kg or 480 micrograms for participants >60 kg, administered subcutaneously on Days 3 and 4 and Days 10 and 11 of each eribulin cycle. Total of all reporting groups
Overall Number of Baseline Participants 55 26 81
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 55 participants 26 participants 81 participants
49.4  (9.09) 50.1  (9.33) 49.6  (9.12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants 26 participants 81 participants
Female
55
 100.0%
26
 100.0%
81
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Percentage of Participants With Feasibility
Hide Description The regimen was considered feasible if the participant was able to complete the eribulin portion without dose delay or reduction. Dose delay was defined as a delay due to eribulin-related adverse event (AE) for more than 2 days for subsequent doses (cycles after the initiation of full dose of eribulin, except holidays, scheduling difficulties and nonclinical logistical issues). If a participant had more than 1 dose omission, delay or reduction due to eribulin-related AE, these events were collectively counted as one entity in the same participant. Participants were followed for approximately 3 years after the last dose of the study treatment. Feasibility rates were calculated with or without growth factor support. In both cohorts, the percentage of participants who completed the eribulin portion of the regimen without a dose omission, delay or reduction due to eribulin-related AE was estimated via the observed completion rate and an exact 90% confidence interval (CI) was constructed.
Time Frame From date of first dose, up to 3 years after the last dose of study treatment, or up to approximately 4 years 2 months
Hide Outcome Measure Data
Hide Analysis Population Description
The eribulin-treated analysis set included all participants who received at least 1 dose of eribulin mesylate at the starting dose of 1.4 mg/m^2. This was the primary analysis set for the feasibility evaluation.
Arm/Group Title Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Hide Arm/Group Description:
Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) intravenously (IV) on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician’s discretion if neutropenia occurred that recovered to Grade ≤2.
Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort filgrastim was used with eribulin therapy at a dose of 300 micrograms for participants ≤60 kg or 480 micrograms for participants >60 kg, administered subcutaneously on Days 3 and 4 and Days 10 and 11 of each eribulin cycle.
Overall Number of Participants Analyzed 54 25
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of participants
70.4
(58.5 to 80.4)
60.0
(41.7 to 76.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 1: Eribulin Mesylate With Filgrastim as Needed, Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Comments [Not Specified]
Type of Statistical Test Other
Comments Fisher’s Exact test
Statistical Test of Hypothesis P-Value 0.4422
Comments Null hypothesis: The feasibility rates of Cohort 1 and Cohort 2 are same.
Method Fisher Exact
Comments Exploratory analysis comparing primary feasibilities between 2 cohorts, based on Fisher's Exact test.
2.Secondary Outcome
Title Number of Participants With Non-serious Adverse Events and Serious Adverse Events (SAEs)
Hide Description Safety assessments consisted of monitoring and recording all AEs and SAEs, clinical laboratory results, vital signs, physical examinations, Eastern Cooperative Oncology Group (ECOG) performance status, electrocardiograms (ECGs), and left-ventricular ejection fracture (LVEF) by multigated acquisition scan (MUGA) or echocardiogram. An AE was considered a treatment emergent adverse event (TEAE) if the AE onset date was on or after the first dose of study drug and up to 30 days after receiving the last dose of study drug. Treatment-related TEAEs included TEAEs that were considered by the Investigator to be possibly or probably related to eribulin mesylate and/or doxorubicin/cyclophosphamide, or missing causality. Standardized Medical Dictionary for Regulatory Activities Queries (SMQ).
Time Frame From date of first dose up to 30 days after the last dose of study treatment, or up to approximately 4 years 2 months
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set included all participants who were enrolled, received at least 1 dose of study treatments and had at least 1 post-treatment safety assessment. This was the primary analysis set for all safety evaluations including issues related to cyclophosphamide and doxorubicin (AC) or eribulin treatments.
Arm/Group Title Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Hide Arm/Group Description:
Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician’s discretion if neutropenia occurred that recovered to Grade ≤2.
Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) intravenously IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort filgrastim was used with eribulin therapy at a dose of 300 micrograms for participants ≤60 kg or 480 micrograms for participants >60 kg, administered subcutaneously on Days 3 and 4 and Days 10 and 11 of each eribulin cycle.
Overall Number of Participants Analyzed 55 26
Measure Type: Count of Participants
Unit of Measure: Participants
All TEAEs 55 26
AC-related TEAEs 55 26
Eribulin-related TEAEs 54 23
Grade ≥3 TEAEs 31 18
SAEs 6 4
Alopecia 40 19
Neutropenia (SMQ) 20 11
Peripheral neuropathy (SMQ) 40 15
Time Frame From date of first dose up to 30 days after the last dose of study treatment, or up to approximately 4 years 2 months
Adverse Event Reporting Description Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) were reported. AEs were graded on a 5-point scale according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. All SAEs were reported, no fatal AEs, and all SAEs have CTCAE grade less than (<) 4. The safety analysis set consisted of participants who were enrolled, received at least 1 dose of study treatments, and had at least 1 post-treatment safety assessment.
 
Arm/Group Title Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Hide Arm/Group Description Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) intravenously (IV) on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort growth factors, subcutaneous pegfilgrastim (6 mg) or filgrastim, could be used with eribulin therapy at the physician’s discretion if neutropenia occurred that recovered to Grade ≤2. Participants initially received doxorubicin (60 mg/m^2) plus cyclophosphamide (600 mg/m^2) IV on Day 1, of every 14-day cycle for 4 cycles. Eribulin mesylate was administered following the doxorubicin plus cyclophosphamide regimen at a dose of 1.4 mg/m^2 IV over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle for 4 cycles (Cycles 5 to 8). In this Cohort filgrastim was used with eribulin therapy at a dose of 300 micrograms for participants ≤60 kg or 480 micrograms for participants >60 kg, administered subcutaneously on Days 3 and 4 and Days 10 and 11 of each eribulin cycle.
All-Cause Mortality
Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Affected / at Risk (%) Affected / at Risk (%)
Total   3/55 (5.45%)   0/26 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Affected / at Risk (%) Affected / at Risk (%)
Total   6/55 (10.91%)   4/26 (15.38%) 
Blood and lymphatic system disorders     
Febrile neutropenia  1  2/55 (3.64%)  1/26 (3.85%) 
Gastrointestinal disorders     
Nausea  1  2/55 (3.64%)  0/26 (0.00%) 
Oesophagitis  1  2/55 (3.64%)  0/26 (0.00%) 
Vomiting  1  2/55 (3.64%)  0/26 (0.00%) 
General disorders     
Mucosal inflammation  1  0/55 (0.00%)  1/26 (3.85%) 
Pyrexia  1  2/55 (3.64%)  1/26 (3.85%) 
Infections and infestations     
Breast abscess  1  0/55 (0.00%)  1/26 (3.85%) 
Catheter site cellulitis  1  0/55 (0.00%)  1/26 (3.85%) 
Genital herpes  1  1/55 (1.82%)  0/26 (0.00%) 
Lung infection  1  0/55 (0.00%)  1/26 (3.85%) 
Upper respiratory tract infection  1  1/55 (1.82%)  0/26 (0.00%) 
Investigations     
Weight decreased  1  1/55 (1.82%)  0/26 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  2/55 (3.64%)  0/26 (0.00%) 
Nervous system disorders     
Syncope  1  1/55 (1.82%)  0/26 (0.00%) 
1
Term from vocabulary, MedDRA Version 17.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cohort 1: Eribulin Mesylate With Filgrastim as Needed Cohort 2: Eribulin Mesylate With Prophylactic Filgrastim
Affected / at Risk (%) Affected / at Risk (%)
Total   55/55 (100.00%)   26/26 (100.00%) 
Blood and lymphatic system disorders     
Anemia  1  3/55 (5.45%)  1/26 (3.85%) 
Febrile neutropenia  1  3/55 (5.45%)  1/26 (3.85%) 
Leukopenia  1  17/55 (30.91%)  1/26 (3.85%) 
Neutropenia  1  20/55 (36.36%)  11/26 (42.31%) 
Lymphopenia  1  3/55 (5.45%)  1/26 (3.85%) 
Cardiac disorders     
Palpitations  1  6/55 (10.91%)  2/26 (7.69%) 
Ear and labyrinth disorders     
Tinnitus  1  2/55 (3.64%)  2/26 (7.69%) 
Eye disorders     
Dry eye  1  11/55 (20.00%)  9/26 (34.62%) 
Lacrimation increased  1  14/55 (25.45%)  12/26 (46.15%) 
Gastrointestinal disorders     
Constipation  1  32/55 (58.18%)  14/26 (53.85%) 
Diarrhea  1  19/55 (34.55%)  12/26 (46.15%) 
Dyspepsia  1  22/55 (40.00%)  11/26 (42.31%) 
Flatulence  1  0/55 (0.00%)  2/26 (7.69%) 
Gatrooesophageal reflux disease  1  1/55 (1.82%)  2/26 (7.69%) 
Hemorrhoids  1  1/55 (1.82%)  2/26 (7.69%) 
Nausea  1  39/55 (70.91%)  22/26 (84.62%) 
Stomatitis  1  13/55 (23.64%)  5/26 (19.23%) 
Vomiting  1  18/55 (32.73%)  8/26 (30.77%) 
Abdominal pain  1  3/55 (5.45%)  0/26 (0.00%) 
Gingival pain  1  0/55 (0.00%)  2/26 (7.69%) 
General disorders     
Chills  1  7/55 (12.73%)  7/26 (26.92%) 
Fatigue  1  54/55 (98.18%)  24/26 (92.31%) 
Mucosal inflammation  1  36/55 (65.45%)  6/26 (23.08%) 
Oedema peripheral  1  5/55 (9.09%)  5/26 (19.23%) 
Pain  1  1/55 (1.82%)  2/26 (7.69%) 
Pyrexia  1  12/55 (21.82%)  10/26 (38.46%) 
Infections and infestations     
Bronchitis  1  1/55 (1.82%)  2/26 (7.69%) 
Upper respiratory tract infection  1  2/55 (3.64%)  2/26 (7.69%) 
Urinary tract infection  1  4/55 (7.27%)  1/26 (3.85%) 
Vulvovaginal myotic infection  1  4/55 (7.27%)  0/26 (0.00%) 
Investigations     
Alanine immunotransferase increased  1  1/55 (1.82%)  2/26 (7.69%) 
Weight decreased  1  6/55 (10.91%)  2/26 (7.69%) 
Metabolism and nutrition disorders     
Decreased appetite  1  16/55 (29.09%)  9/26 (34.62%) 
Hyperglycemia  1  3/55 (5.45%)  3/26 (11.54%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  25/55 (45.45%)  13/26 (50.00%) 
Back pain  1  13/55 (23.64%)  3/26 (11.54%) 
Bone pain  1  12/55 (21.82%)  6/26 (23.08%) 
Joint stiffness  1  8/55 (14.55%)  8/26 (30.77%) 
Musculoskeletal chest pain  1  3/55 (5.45%)  1/26 (3.85%) 
Musculoskeletal pain  1  3/55 (5.45%)  4/26 (15.38%) 
Myalgia  1  5/55 (9.09%)  1/26 (3.85%) 
Pain in extremity  1  13/55 (23.64%)  3/26 (11.54%) 
Nervous system disorders     
Cognitive disorder  1  7/55 (12.73%)  1/26 (3.85%) 
Dizziness  1  13/55 (23.64%)  12/26 (46.15%) 
Dysgeusia  1  8/55 (14.55%)  4/26 (15.38%) 
Headache  1  17/55 (30.91%)  10/26 (38.46%) 
Neuropathy peripheral  1  38/55 (69.09%)  14/26 (53.85%) 
Psychiatric disorders     
Anxiety  1  4/55 (7.27%)  6/26 (23.08%) 
Depression  1  4/55 (7.27%)  2/26 (7.69%) 
Insomnia  1  2/55 (3.64%)  5/26 (19.23%) 
Mood altered  1  0/55 (0.00%)  4/26 (15.38%) 
Renal and urinary disorders     
Dysuria  1  4/55 (7.27%)  0/26 (0.00%) 
Nocturia  1  2/55 (3.64%)  2/26 (7.69%) 
Reproductive system and breast disorders     
Breast pain  1  7/55 (12.73%)  1/26 (3.85%) 
Menstruation irregular  1  10/55 (18.18%)  9/26 (34.62%) 
Vaginal discharge  1  4/55 (7.27%)  1/26 (3.85%) 
Vulvovaginal dryness  1  11/55 (20.00%)  5/26 (19.23%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  28/55 (50.91%)  12/26 (46.15%) 
Dyspnoea  1  16/55 (29.09%)  8/26 (30.77%) 
Epistaxis  1  3/55 (5.45%)  5/26 (19.23%) 
Nasal congestion  1  0/55 (0.00%)  2/26 (7.69%) 
Oropharyngeal pain  1  4/55 (7.27%)  4/26 (15.38%) 
Rhinorrhea  1  3/55 (5.45%)  2/26 (7.69%) 
Upper airway cough syndrome  1  3/55 (5.45%)  2/26 (7.69%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  40/55 (72.73%)  19/26 (73.08%) 
Dry skin  1  14/55 (25.45%)  13/26 (50.00%) 
Nail discoloration  1  3/55 (5.45%)  2/26 (7.69%) 
Nail disorder  1  3/55 (5.45%)  4/26 (15.38%) 
Nail ridging  1  3/55 (5.45%)  1/26 (3.85%) 
Onychalgia  1  0/55 (0.00%)  2/26 (7.69%) 
Onychomadesis  1  3/55 (5.45%)  0/26 (0.00%) 
Palmar-plantar erythrodysaethesia syndrome  1  2/55 (3.64%)  3/26 (11.54%) 
Pruritis  1  1/55 (1.82%)  2/26 (7.69%) 
Rash  1  19/55 (34.55%)  9/26 (34.62%) 
Skin hyperpigmentation  1  4/55 (7.27%)  2/26 (7.69%) 
Vascular disorders     
Hot flush  1  34/55 (61.82%)  17/26 (65.38%) 
Hypertension  1  6/55 (10.91%)  4/26 (15.38%) 
1
Term from vocabulary, MedDRA Version 17.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Name/Title: Eisai Medical Information
Organization: Eisai Inc.
Phone: 1-888-422-4743
Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01328249     History of Changes
Other Study ID Numbers: E7389-A001-210
First Submitted: March 22, 2011
First Posted: April 4, 2011
Results First Submitted: March 2, 2018
Results First Posted: September 26, 2018
Last Update Posted: August 20, 2019