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Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01670877
Recruitment Status : Completed
First Posted : August 22, 2012
Results First Posted : April 15, 2022
Last Update Posted : April 15, 2022
Sponsor:
Collaborators:
Puma Biotechnology, Inc.
United States Department of Defense
Information provided by (Responsible Party):
Washington University School of Medicine

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Neoplasms
Interventions Drug: Neratinib
Drug: Fulvestrant
Drug: Trastuzumab
Procedure: Tumor biopsy
Procedure: Research blood sample
Enrollment 56
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Period Title: Part I and Part 2
Started 16 5 11 24 0 0
Completed 16 4 10 21 0 0
Not Completed 0 1 1 3 0 0
Reason Not Completed
Grade 2 vomiting and progressive disease             0             1             0             0             0             0
Grade 3 diarrhea and withdrawal             0             0             1             0             0             0
Grade 2 vomiting             0             0             0             1             0             0
Grade 3 dizziness and progressive disease             0             0             0             1             0             0
Grade 3 diarrhea and duodenal ulcer             0             0             0             1             0             0
Period Title: Crossover
Started 0 0 0 0 3 5
Completed 0 0 0 0 3 5
Not Completed 0 0 0 0 0 0
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Total
Hide Arm/Group Description -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 16 5 11 24 56
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
58
(31 to 74)
63
(58 to 67)
58
(41 to 82)
64
(35 to 76)
61
(31 to 82)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
Female
16
 100.0%
5
 100.0%
10
  90.9%
24
 100.0%
55
  98.2%
Male
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
1
   1.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
2
   8.3%
2
   3.6%
Not Hispanic or Latino
16
 100.0%
5
 100.0%
9
  81.8%
17
  70.8%
47
  83.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
2
  18.2%
5
  20.8%
7
  12.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   6.3%
0
   0.0%
1
   9.1%
0
   0.0%
2
   3.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   6.3%
1
  20.0%
2
  18.2%
1
   4.2%
5
   8.9%
White
13
  81.3%
4
  80.0%
8
  72.7%
23
  95.8%
48
  85.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
Canada 2 0 0 0 0
United States 14 5 11 24 56
HER2 Status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
Activating
15
  93.8%
5
 100.0%
11
 100.0%
24
 100.0%
55
  98.2%
Novel
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.8%
Histology Subtype  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
Ductal
10
  62.5%
3
  60.0%
7
  63.6%
10
  41.7%
30
  53.6%
Lobular
5
  31.3%
2
  40.0%
2
  18.2%
12
  50.0%
21
  37.5%
Other
1
   6.3%
0
   0.0%
1
   9.1%
2
   8.3%
4
   7.1%
Unknown
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
1
   1.8%
Tumor Grade   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
I/II
8
  50.0%
0
   0.0%
5
  45.5%
12
  50.0%
25
  44.6%
II
1
   6.3%
1
  20.0%
0
   0.0%
3
  12.5%
5
   8.9%
III
7
  43.8%
4
  80.0%
2
  18.2%
3
  12.5%
16
  28.6%
Unknown
0
   0.0%
0
   0.0%
4
  36.4%
6
  25.0%
10
  17.9%
[1]
Measure Description:
  • Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.
  • A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.
  • An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.
  • A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.
Tumor Stage at Initial Diagnosis   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 5 participants 11 participants 24 participants 56 participants
I
2
  12.5%
1
  20.0%
2
  18.2%
4
  16.7%
9
  16.1%
II
6
  37.5%
2
  40.0%
3
  27.3%
9
  37.5%
20
  35.7%
IIA
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
1
   1.8%
IIB
2
  12.5%
0
   0.0%
0
   0.0%
0
   0.0%
2
   3.6%
III
4
  25.0%
1
  20.0%
0
   0.0%
4
  16.7%
9
  16.1%
IIIA
0
   0.0%
0
   0.0%
0
   0.0%
3
  12.5%
3
   5.4%
IIIC
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
1
   1.8%
IV
1
   6.3%
1
  20.0%
2
  18.2%
1
   4.2%
5
   8.9%
Unknown
1
   6.3%
0
   0.0%
3
  27.3%
2
   8.3%
6
  10.7%
[1]
Measure Description:
  • Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.
  • Stage I has a better outcome than Stage IV.
1.Primary Outcome
Title Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone
Hide Description
  • Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
  • Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Time Frame Through completion of treatment (median treatment time of 90 days, full range 54-716 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only Part I participants were evaluable for this outcome measure.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 16 0 0 0 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
5
  31.3%
2.Primary Outcome
Title Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation
Hide Description
  • Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
  • Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Time Frame Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 4 0 0 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
1
  25.0%
3.Primary Outcome
Title Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation
Hide Description
  • Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
  • Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Time Frame Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 0 10 0 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
3
  30.0%
4.Primary Outcome
Title Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation
Hide Description
  • Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
  • Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Time Frame Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 0 0 21 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
8
  38.1%
5.Secondary Outcome
Title Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)
Hide Description
  • Participants were followed for progressive disease from start of treatment until completion of follow-up.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time Frame Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 92 days, full range 86 days-443 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1. The data represents exact number of weeks that each participant had progression-free survival. 2 participants with Activating mutation - S310F both had 8 weeks of PFS.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 4 0 0 0 0
Measure Type: Number
Unit of Measure: weeks
Activating mutation - L7L755S Number Analyzed 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants
9
Activating mutation - S310F Number Analyzed 0 participants 2 participants 0 participants 0 participants 0 participants 0 participants
8
Activating mutation - A775_G776insYVMA Number Analyzed 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants
17
6.Secondary Outcome
Title Number of Participants With HER2 Mutation Subtype and Histology Subtype
Hide Description [Not Specified]
Time Frame At the time of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 16 5 11 24
Measure Type: Count of Participants
Unit of Measure: Participants
ECD mutation : Ductal histology
3
  18.8%
1
  20.0%
1
   9.1%
1
   4.2%
ECD mutation : Other histology
0
   0.0%
1
  20.0%
1
   9.1%
2
   8.3%
Exon 20 ins mutation : Ductal histology
2
  12.5%
0
   0.0%
1
   9.1%
2
   8.3%
Exon 20 ins mutation : Other histology
2
  12.5%
1
  20.0%
0
   0.0%
2
   8.3%
KD mutation : Ductal histology
5
  31.3%
1
  20.0%
5
  45.5%
7
  29.2%
KD mutation : Other histology
4
  25.0%
1
  20.0%
3
  27.3%
10
  41.7%
7.Secondary Outcome
Title Number of Participants With HER2 Mutation Subtype and Tumor Grade
Hide Description

-Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.

  • A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.
  • An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.
  • A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.
Time Frame A time of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 16 5 11 24
Measure Type: Count of Participants
Unit of Measure: Participants
ECD mutation : Tumor grade I/II
2
  12.5%
0
   0.0%
1
   9.1%
2
   8.3%
ECD mutation : Tumor grade III
1
   6.3%
3
  60.0%
0
   0.0%
0
   0.0%
ECD mutation : Unknown
0
   0.0%
0
   0.0%
1
   9.1%
1
   4.2%
Exon 20 ins mutation : Tumor grade I/II
1
   6.3%
1
  20.0%
0
   0.0%
2
   8.3%
Exon 20 ins mutation : Tumor grade III
3
  18.8%
0
   0.0%
1
   9.1%
0
   0.0%
Exon 20 ins mutation : Unknown
0
   0.0%
0
   0.0%
0
   0.0%
2
   8.3%
KD mutation : Tumor grade I/II
6
  37.5%
0
   0.0%
4
  36.4%
11
  45.8%
KD mutation : Tumor grade III
3
  18.8%
2
  40.0%
1
   9.1%
3
  12.5%
KD mutation : Unknown
0
   0.0%
0
   0.0%
3
  27.3%
3
  12.5%
8.Secondary Outcome
Title Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis
Hide Description
  • Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.
  • Stage I has a better outcome than Stage IV.
Time Frame At time of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 16 5 11 24
Measure Type: Count of Participants
Unit of Measure: Participants
ECD mutation : Stage I
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
ECD mutation : Stage II
3
  18.8%
1
  20.0%
1
   9.1%
2
   8.3%
ECD mutation : Stage III
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
ECD mutation : Stage IV
0
   0.0%
1
  20.0%
0
   0.0%
0
   0.0%
ECD mutation : Unknown
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
Exon 20 ins mutation : Stage I
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Exon 20 ins mutation : Stage II
3
  18.8%
0
   0.0%
1
   9.1%
1
   4.2%
Exon 20 ins mutation : Stage III
1
   6.3%
1
  20.0%
0
   0.0%
2
   8.3%
Exon 20 ins mutation : Stage IV
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Exon 20 ins mutation : Unknown
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
KD mutation : Stage I
2
  12.5%
1
  20.0%
2
  18.2%
3
  12.5%
KD mutation : Stage II
2
  12.5%
1
  20.0%
2
  18.2%
6
  25.0%
KD mutation : Stage III
3
  18.8%
0
   0.0%
0
   0.0%
6
  25.0%
KD mutation : Stage IV
1
   6.3%
0
   0.0%
2
  18.2%
1
   4.2%
KD mutation : Unknown
1
   6.3%
0
   0.0%
2
  18.2%
1
   4.2%
9.Secondary Outcome
Title Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival
Hide Description
  • Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time Frame Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 142 days, full range 54-800 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The number analyzed for each row adds up to overall total number analyzed.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 16 5 11 24
Median (95% Confidence Interval)
Unit of Measure: weeks
ECD mutation Number Analyzed 3 participants 2 participants 2 participants 3 participants
11.0000
(9.0000 to 32.0000)
8.0000 [1] 
(NA to NA)
48.5000
(16.0000 to 81.0000)
3.0000
(1.0000 to 24.0000)
Exon 20 ins mutation Number Analyzed 4 participants 1 participants 1 participants 4 participants
26.0000
(8.0000 to 75.0000)
17.0000 [1] 
(NA to NA)
26.000 [1] 
(NA to NA)
36.5000
(9.0000 to 68.0000)
KD mutation Number Analyzed 9 participants 2 participants 8 participants 17 participants
9.0000
(3.0000 to 31.0000)
6.5000
(4.0000 to 9.0000)
8.0000
(1.0000 to 24.0000)
16.0000
(9.0000 to 27.0000)
[1]
The sample size is too small to calculate the 95% confidence interval.
10.Secondary Outcome
Title Part II ER-cohort Only: Progression-free Survival (PFS)
Hide Description
  • Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time Frame Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 4 0 0 0 0
Median (95% Confidence Interval)
Unit of Measure: weeks
8.5 [1] 
(8 to NA)
[1]
There were too few participants with an event to calculate the upper limit of the confidence interval.
11.Secondary Outcome
Title Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)
Hide Description
  • Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time Frame Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 0 10 0 0 0
Median (95% Confidence Interval)
Unit of Measure: weeks
20 [1] 
(8 to NA)
[1]
There were too few participants with an event to calculate the upper limit of the confidence interval.
12.Secondary Outcome
Title Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)
Hide Description
  • Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time Frame Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 0 0 21 0 0
Median (95% Confidence Interval)
Unit of Measure: weeks
24
(15.7 to 31)
13.Secondary Outcome
Title Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events
Hide Description -CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.
Time Frame Through completion of follow-up; follow-up was through 28 days following completion of treatment (median follow-up of 140 days, full range 52-798 days)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 16 5 11 24 3 5
Measure Type: Count of Participants
Unit of Measure: Participants
Anemia
2
  12.5%
0
   0.0%
1
   9.1%
4
  16.7%
0
   0.0%
1
  20.0%
LVEF Decrease
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
Heart failure with preserved ejection fraction
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  20.0%
Tinnitus
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Dry eye
1
   6.3%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Abdominal cramping
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Abdominal pain
0
   0.0%
0
   0.0%
2
  18.2%
3
  12.5%
0
   0.0%
0
   0.0%
Bloating
0
   0.0%
1
  20.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Constipation
5
  31.3%
0
   0.0%
1
   9.1%
2
   8.3%
0
   0.0%
0
   0.0%
Diarrhea
15
  93.8%
5
 100.0%
8
  72.7%
20
  83.3%
0
   0.0%
1
  20.0%
Dry mouth
0
   0.0%
0
   0.0%
0
   0.0%
4
  16.7%
0
   0.0%
0
   0.0%
Dyspepsia
2
  12.5%
0
   0.0%
1
   9.1%
6
  25.0%
0
   0.0%
0
   0.0%
Flatulence
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Mucositis oral
3
  18.8%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Nausea
9
  56.3%
3
  60.0%
4
  36.4%
11
  45.8%
0
   0.0%
1
  20.0%
Stomach pain
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Stomatitis
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Vomiting
6
  37.5%
1
  20.0%
0
   0.0%
6
  25.0%
0
   0.0%
2
  40.0%
Fatigue
6
  37.5%
1
  20.0%
5
  45.5%
12
  50.0%
0
   0.0%
1
  20.0%
Fever
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Generalized weakness
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Pain
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Rhinitis infective
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Upper respiratory infection
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Urinary tract infection
1
   6.3%
0
   0.0%
2
  18.2%
1
   4.2%
0
   0.0%
0
   0.0%
Alaline aminotransferase increased
3
  18.8%
0
   0.0%
2
  18.2%
4
  16.7%
0
   0.0%
1
  20.0%
Alkaline phosphatase increased
1
   6.3%
0
   0.0%
1
   9.1%
3
  12.5%
0
   0.0%
0
   0.0%
Alkaline phosphatase decreased
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Aspartate aminotransferase increased
2
  12.5%
0
   0.0%
3
  27.3%
7
  29.2%
0
   0.0%
1
  20.0%
CD4 lymphocytes decreased
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Creatinine increased
3
  18.8%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
1
  20.0%
Ejection fraction decreased
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
INR increased
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Lymphocyte count decreased
0
   0.0%
0
   0.0%
2
  18.2%
2
   8.3%
0
   0.0%
0
   0.0%
Neutrophil count decreased
0
   0.0%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
1
  20.0%
Platelet count decreased
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
1
  20.0%
Weight loss
3
  18.8%
1
  20.0%
0
   0.0%
4
  16.7%
0
   0.0%
1
  20.0%
White blood cell decreased
0
   0.0%
0
   0.0%
0
   0.0%
4
  16.7%
0
   0.0%
0
   0.0%
Anorexia
7
  43.8%
1
  20.0%
7
  63.6%
9
  37.5%
0
   0.0%
2
  40.0%
Dehydration
3
  18.8%
1
  20.0%
1
   9.1%
6
  25.0%
1
  33.3%
1
  20.0%
Hypercalcemia
0
   0.0%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Hyperglycemia
1
   6.3%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Hyperkalemia
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
1
  20.0%
Hypoalbuminemia
2
  12.5%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Hypocalcemia
1
   6.3%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Hypokalemia
1
   6.3%
0
   0.0%
1
   9.1%
1
   4.2%
0
   0.0%
0
   0.0%
Hyponatremia
0
   0.0%
0
   0.0%
1
   9.1%
1
   4.2%
0
   0.0%
0
   0.0%
Hypophosphatemia
2
  12.5%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Arthralgia
1
   6.3%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Back pain
2
  12.5%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Bone pain
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Flank pain
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Generalized muscle weakness
0
   0.0%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Joint range of motion decreased
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Leg cramp
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Muscle weakness left sided
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Muscle weakness lower limb
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Myalgia
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Pain at injection site
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Pain in extremity
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Dizziness
1
   6.3%
0
   0.0%
2
  18.2%
4
  16.7%
0
   0.0%
0
   0.0%
Dysgeusia
0
   0.0%
0
   0.0%
1
   9.1%
3
  12.5%
0
   0.0%
2
  40.0%
Headache
1
   6.3%
0
   0.0%
2
  18.2%
0
   0.0%
0
   0.0%
0
   0.0%
Peripheral sensory neuropathy
0
   0.0%
1
  20.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Syncope
1
   6.3%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Depression
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Insomnia
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Acute kidney injury
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Urinary tract obstruction
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Urine discoloration
0
   0.0%
0
   0.0%
1
   9.1%
1
   4.2%
0
   0.0%
0
   0.0%
Urine odor
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Cough
1
   6.3%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Dyspnea
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Epistaxis
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Hoarseness
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Postnasal drip
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Rhinorrhea
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Alopecia
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Dry hair
1
   6.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Dry skin
0
   0.0%
0
   0.0%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
Nail changes
1
   6.3%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Pruritus
1
   6.3%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
1
  20.0%
Rash acneiform
0
   0.0%
0
   0.0%
2
  18.2%
4
  16.7%
0
   0.0%
0
   0.0%
Rash maculopapular
1
   6.3%
1
  20.0%
1
   9.1%
1
   4.2%
0
   0.0%
0
   0.0%
Skin hyperpigmentation
1
   6.3%
0
   0.0%
0
   0.0%
1
   4.2%
0
   0.0%
0
   0.0%
Sterile abscess at subcutaneous injection site
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
Hot flashes
1
   6.3%
0
   0.0%
1
   9.1%
1
   4.2%
0
   0.0%
0
   0.0%
Hypotension
1
   6.3%
0
   0.0%
1
   9.1%
1
   4.2%
0
   0.0%
0
   0.0%
14.Secondary Outcome
Title Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)
Hide Description
  • RR is defined as number of participants with complete response or partial response as best response.
  • Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 0 10 0 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
3
  30.0%
15.Secondary Outcome
Title Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)
Hide Description
  • RR is defined as number of participants with complete response or partial response as best response.
  • Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description:
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Overall Number of Participants Analyzed 0 0 0 21 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
5
  23.8%
Time Frame Adverse events were tracked from start of treatment up to 28 days following the last day of study treatment. Median follow-up was 40 days, full range 52-798 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Hide Arm/Group Description -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
All-Cause Mortality
Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/16 (62.50%)   1/5 (20.00%)   5/11 (45.45%)   9/24 (37.50%)   3/3 (100.00%)   4/5 (80.00%) 
Hide Serious Adverse Events
Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/16 (31.25%)   1/5 (20.00%)   2/11 (18.18%)   9/24 (37.50%)   2/3 (66.67%)   0/5 (0.00%) 
Cardiac disorders             
Atrial flutter  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Gastrointestinal disorders             
Duodenal hemorrhage  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Vomiting  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
General disorders             
Bell's palsy  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Fatigue  1  1/16 (6.25%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Infections and infestations             
Lung infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Urinary tract infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Investigations             
Creatinine increased  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
INR increased  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Metabolism and nutrition disorders             
Dehydration  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Death due to disease progression  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Disease progression  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Nervous system disorders             
Expressive aphasia  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Syncope  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Dyspnea  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Pneumonitis  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Vascular disorders             
Thromboembolic event  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Part I: Neratinib Only Part II: Neratinib Only (ER-) Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive) Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx) Crossover: Neratinib + Trastuzumab Crossover: Neratinib + Fulvestrant + Trastuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   16/16 (100.00%)   5/5 (100.00%)   11/11 (100.00%)   24/24 (100.00%)   3/3 (100.00%)   4/5 (80.00%) 
Blood and lymphatic system disorders             
Anemia  1  3/16 (18.75%)  0/5 (0.00%)  1/11 (9.09%)  6/24 (25.00%)  2/3 (66.67%)  1/5 (20.00%) 
Thrombotic thrombocytopenia purpura  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Cardiac disorders             
Atrial fibrillation  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Heart failure with preserved ejection fraction  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
LVEF decrease  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Sinus tachycardia  1  0/16 (0.00%)  0/5 (0.00%)  2/11 (18.18%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Ventricular tachycardia  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Ear and labyrinth disorders             
Ear pain  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Tinnitus  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Vertigo  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Eye disorders             
Blurred vision  1  1/16 (6.25%)  1/5 (20.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Conjunctivitis  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Double vision  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Dry eye  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Floaters  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Itchy eye  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Peripheral vision change  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Styes  1  0/16 (0.00%)  1/5 (20.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Gastrointestinal disorders             
Abdominal cramping  1  2/16 (12.50%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Abdominal fullness  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Abdominal pain  1  2/16 (12.50%)  0/5 (0.00%)  2/11 (18.18%)  5/24 (20.83%)  0/3 (0.00%)  0/5 (0.00%) 
Ascites  1  2/16 (12.50%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Bloating  1  2/16 (12.50%)  1/5 (20.00%)  0/11 (0.00%)  3/24 (12.50%)  0/3 (0.00%)  0/5 (0.00%) 
Constipation  1  9/16 (56.25%)  1/5 (20.00%)  3/11 (27.27%)  9/24 (37.50%)  0/3 (0.00%)  2/5 (40.00%) 
Diarrhea  1  16/16 (100.00%)  5/5 (100.00%)  9/11 (81.82%)  22/24 (91.67%)  0/3 (0.00%)  1/5 (20.00%) 
Dry mouth  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  4/24 (16.67%)  0/3 (0.00%)  0/5 (0.00%) 
Duodenal ulcer  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Dyspepsia  1  2/16 (12.50%)  0/5 (0.00%)  2/11 (18.18%)  6/24 (25.00%)  0/3 (0.00%)  0/5 (0.00%) 
Dysphagia  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Flatulence  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Gastroesophageal reflux disease  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Gastrointestinal illness  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Hematochezia  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Mucositis oral  1  3/16 (18.75%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Nausea  1  11/16 (68.75%)  4/5 (80.00%)  4/11 (36.36%)  12/24 (50.00%)  0/3 (0.00%)  2/5 (40.00%) 
Stomach pain  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Stomatitis  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Vomiting  1  10/16 (62.50%)  1/5 (20.00%)  1/11 (9.09%)  6/24 (25.00%)  0/3 (0.00%)  3/5 (60.00%) 
General disorders             
Changes in dentition  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Chills  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  1/3 (33.33%)  0/5 (0.00%) 
Edema face  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Edema limbs  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  2/24 (8.33%)  2/3 (66.67%)  0/5 (0.00%) 
Failure-to-thrive  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Fatigue  1  6/16 (37.50%)  0/5 (0.00%)  5/11 (45.45%)  12/24 (50.00%)  0/3 (0.00%)  1/5 (20.00%) 
Fever  1  0/16 (0.00%)  0/5 (0.00%)  2/11 (18.18%)  5/24 (20.83%)  0/3 (0.00%)  0/5 (0.00%) 
Flu like symptoms  1  0/16 (0.00%)  0/5 (0.00%)  2/11 (18.18%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Generalized weakness  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Localized edema  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  1/3 (33.33%)  0/5 (0.00%) 
Pain  1  4/16 (25.00%)  0/5 (0.00%)  0/11 (0.00%)  3/24 (12.50%)  0/3 (0.00%)  0/5 (0.00%) 
Immune system disorders             
Allergic reaction  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Infections and infestations             
Bilateral breast infection  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Biliary tract infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Bladder infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  1/5 (20.00%) 
Bronchial infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Cold  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Gum infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Mucosal infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Rhinitis infective  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Sepsis  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Shingles  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Sinusitis  1  2/16 (12.50%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Skin infection  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Stomach bug  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Strep throat  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Upper respiratory infection  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Urinary tract infection  1  2/16 (12.50%)  0/5 (0.00%)  3/11 (27.27%)  4/24 (16.67%)  1/3 (33.33%)  2/5 (40.00%) 
Wound infection  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Injury, poisoning and procedural complications             
Fall  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  1/3 (33.33%)  1/5 (20.00%) 
Finger pad cut off  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Spinal fracture  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Investigations             
Alanine aminotransferase increased  1  4/16 (25.00%)  1/5 (20.00%)  3/11 (27.27%)  5/24 (20.83%)  0/3 (0.00%)  1/5 (20.00%) 
Alkaline phosphatase increased  1  1/16 (6.25%)  1/5 (20.00%)  2/11 (18.18%)  6/24 (25.00%)  1/3 (33.33%)  1/5 (20.00%) 
Aspartate aminotransferase increased  1  4/16 (25.00%)  0/5 (0.00%)  5/11 (45.45%)  8/24 (33.33%)  1/3 (33.33%)  1/5 (20.00%) 
Blood bilirubin increased  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
CD4 lymphocytes decreased  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Cardiac troponin increased  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Creatinine increased  1  3/16 (18.75%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  1/5 (20.00%) 
Ejection fraction decreased  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Lymphocyte count decreased  1  2/16 (12.50%)  1/5 (20.00%)  2/11 (18.18%)  3/24 (12.50%)  0/3 (0.00%)  0/5 (0.00%) 
Neutrophil count decreased  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  1/5 (20.00%) 
Platelet count decreased  1  1/16 (6.25%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  1/5 (20.00%) 
Weight loss  1  5/16 (31.25%)  1/5 (20.00%)  0/11 (0.00%)  4/24 (16.67%)  1/3 (33.33%)  2/5 (40.00%) 
White blood cell decreased  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  4/24 (16.67%)  0/3 (0.00%)  0/5 (0.00%) 
Metabolism and nutrition disorders             
Anorexia  1  10/16 (62.50%)  1/5 (20.00%)  7/11 (63.64%)  10/24 (41.67%)  0/3 (0.00%)  2/5 (40.00%) 
Dehydration  1  3/16 (18.75%)  1/5 (20.00%)  1/11 (9.09%)  5/24 (20.83%)  1/3 (33.33%)  1/5 (20.00%) 
Hypercalcemia  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  2/24 (8.33%)  0/3 (0.00%)  1/5 (20.00%) 
Hyperglycemia  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  3/24 (12.50%)  0/3 (0.00%)  0/5 (0.00%) 
Hyperkalemia  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Hyperphosphatemia  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Hypoalbuminemia  1  4/16 (25.00%)  1/5 (20.00%)  1/11 (9.09%)  3/24 (12.50%)  1/3 (33.33%)  0/5 (0.00%) 
Hypocalcemia  1  5/16 (31.25%)  1/5 (20.00%)  1/11 (9.09%)  5/24 (20.83%)  0/3 (0.00%)  0/5 (0.00%) 
Hypokalemia  1  3/16 (18.75%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  2/5 (40.00%) 
Hyponatremia  1  4/16 (25.00%)  0/5 (0.00%)  1/11 (9.09%)  2/24 (8.33%)  1/3 (33.33%)  1/5 (20.00%) 
Hypophosphatemia  1  3/16 (18.75%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Hypoproteinemia  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Type 2 Diabetes  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Back pain  1  2/16 (12.50%)  0/5 (0.00%)  3/11 (27.27%)  4/24 (16.67%)  0/3 (0.00%)  0/5 (0.00%) 
Bone pain  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  3/24 (12.50%)  0/3 (0.00%)  1/5 (20.00%) 
Finger pain  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Flank pain  1  1/16 (6.25%)  1/5 (20.00%)  1/11 (9.09%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Gait disturbance  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Generalized muscle weakness  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  3/24 (12.50%)  1/3 (33.33%)  0/5 (0.00%) 
Joint range of motion decreased  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Leg cramp  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Muscle weakness left-sided  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Muscle weakness lower limb  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Myalgia  1  2/16 (12.50%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Myositis  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Neck pain  1  1/16 (6.25%)  1/5 (20.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Pain at injection site  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Pain in extremity  1  3/16 (18.75%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Shoulder tendonitis  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
New brain metastases  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Nervous system disorders             
Dizziness  1  3/16 (18.75%)  1/5 (20.00%)  3/11 (27.27%)  5/24 (20.83%)  1/3 (33.33%)  2/5 (40.00%) 
Dysarthria  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Dysgeusia  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  3/24 (12.50%)  0/3 (0.00%)  2/5 (40.00%) 
Expressive aphasia  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Extrapyramidal disorder  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Facial muscle weakness  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Headache  1  4/16 (25.00%)  0/5 (0.00%)  2/11 (18.18%)  2/24 (8.33%)  0/3 (0.00%)  2/5 (40.00%) 
Memory impairment  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Peripheral motor neuropathy  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  1/3 (33.33%)  0/5 (0.00%) 
Peripheral sensory neuropathy  1  3/16 (18.75%)  2/5 (40.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Presyncope  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Seizure  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Sinus pain  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Syncope  1  2/16 (12.50%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Psychiatric disorders             
Altered mental status  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Anxiety  1  3/16 (18.75%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Confusion  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Depression  1  2/16 (12.50%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  1/3 (33.33%)  0/5 (0.00%) 
Insomnia  1  1/16 (6.25%)  0/5 (0.00%)  3/11 (27.27%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Renal and urinary disorders             
Acute kidney injury  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Bilateral ureteral stent placement  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Cystitis noninfective  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Urge incontinence  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Urinary frequency  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Urinary retention  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Urinary tract obstruction  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Urinary tract pain  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Urine discoloration  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Urine odor  1  0/16 (0.00%)  0/5 (0.00%)  2/11 (18.18%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Reproductive system and breast disorders             
Breast pain  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Pelvic pain  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Vaginal dryness  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Chest tightness  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Cough  1  3/16 (18.75%)  0/5 (0.00%)  2/11 (18.18%)  4/24 (16.67%)  1/3 (33.33%)  0/5 (0.00%) 
Dyspnea  1  3/16 (18.75%)  1/5 (20.00%)  1/11 (9.09%)  6/24 (25.00%)  1/3 (33.33%)  1/5 (20.00%) 
Epistaxis  1  0/16 (0.00%)  0/5 (0.00%)  3/11 (27.27%)  1/24 (4.17%)  1/3 (33.33%)  1/5 (20.00%) 
Hoarseness  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  3/24 (12.50%)  0/3 (0.00%)  0/5 (0.00%) 
Hypoxia  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  1/5 (20.00%) 
Nasal congestion  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  1/5 (20.00%) 
Nose irritation  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Pleural effusion  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Pneumonia  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  1/3 (33.33%)  0/5 (0.00%) 
Pneumothorax  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Postnasal drip  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Pulmonary edema  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Rhinorrhea  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Sneezing  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Sore throat  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Skin and subcutaneous tissue disorders             
Alopecia  1  2/16 (12.50%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  1/5 (20.00%) 
Bug bite  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Dry hair  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Dry skin  1  1/16 (6.25%)  1/5 (20.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Erythema  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Hyperhidrosis  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Nail changes  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
New skin lesion  1  0/16 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Pruritus  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  1/5 (20.00%) 
Rash acneiform  1  1/16 (6.25%)  0/5 (0.00%)  2/11 (18.18%)  4/24 (16.67%)  0/3 (0.00%)  0/5 (0.00%) 
Rash maculopapular  1  2/16 (12.50%)  1/5 (20.00%)  2/11 (18.18%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Skin hyperpigmentation  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Sterile abscess at subcutaneous injection site  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
Surgical and medical procedures             
Bilateral percutaneous nephrostomy tubes placement  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Chest wall port placement  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Nephrostomy tubes exchange  1  0/16 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Vascular disorders             
Hot flashes  1  1/16 (6.25%)  0/5 (0.00%)  2/11 (18.18%)  1/24 (4.17%)  1/3 (33.33%)  0/5 (0.00%) 
Hypertension  1  0/16 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  1/24 (4.17%)  0/3 (0.00%)  0/5 (0.00%) 
Hypotension  1  1/16 (6.25%)  0/5 (0.00%)  1/11 (9.09%)  2/24 (8.33%)  0/3 (0.00%)  0/5 (0.00%) 
Thromboembolic event  1  1/16 (6.25%)  0/5 (0.00%)  0/11 (0.00%)  0/24 (0.00%)  0/3 (0.00%)  0/5 (0.00%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Cynthia Ma, M.D., Ph.D.
Organization: Washington University School of Medicine
Phone: 314-362-9383
EMail: cynthiaxma@wustl.edu
Layout table for additonal information
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01670877    
Other Study ID Numbers: 201209135
First Submitted: August 17, 2012
First Posted: August 22, 2012
Results First Submitted: February 10, 2022
Results First Posted: April 15, 2022
Last Update Posted: April 15, 2022