CompletedNCT01670877Updated Apr 15, 2022Results posted

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

A Phase 2 interventional study of Neratinib and Fulvestrant in Breast Neoplasms, sponsored by Washington University School of Medicine. Completed at 17 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-04-15.

Sponsored by Washington University School of Medicine · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 56
Allocation: Non-randomized
Ages: 18 Years and older
Sex: All

Study summary

This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.

Read the detailed description

Overexpression of HER2 due to gene amplification is an established therapeutic target in breast cancer for which multiple HER2 targeted drugs are now available. However, the majority of breast cancers are without HER2 overexpression/non-amplified and not currently eligible to receive HER2 targeted drugs. Advances in tumor genome sequencing technology led to the identification of recurrent HER2 mutations (HER2mut) in approximately 2% of HER2 non-amplified primary breast cancers, and 3-5% of metastatic tumors. Importantly, tumor cells harboring HER2mut are sensitive to the anti-tumor effects of HER2-targeted agents in preclinical models, especially neratinib, a potent irreversible pan-HER inhibitor. However, neratinib monotherapy has demonstrated only modest single agent activity in HER2mut,, non-amplified metastatic breast cancer (MBC). Based on the hypothesis that the combination of neratinib and fulvestrant will be more effective than neratinib alone in ER+/HER2mut, non-amplified MBC the investigators conducted a single arm phase II study of neratinib plus fulvestrant with 2 cohorts, fulvestrant (FUL)-treated and FUL-naïve, for patients with ER+/HER2mut, non-amplified MBC to assess the anti-tumor effects of this combination. An exploratory ER-negative (ER-) HER2mut cohort was also included for the efficacy of neratinib monotherapy.

Conditions studied

Breast Neoplasms

Browse trials for

Breast Neoplasms 12,543

Keywords

Neratinib
fulvestrant
HER2 mutation
metastatic breast cancer
trastuzumab

In context

Breast Neoplasms

12,543 studies on the registry are indexed under Breast Neoplasms; 2,892 are open to participants now.

This study's enrollment of 56 is below the median of 72 across 9,302 interventional studies indexed under Breast Neoplasms.

Browse Breast Neoplasms studies →

Lead sponsor

Washington University School of Medicine is the lead sponsor of 1,765 studies on the registry; 271 are open to participants now.

Of its 324 completed or terminated interventional studies of FDA-regulated products, 212 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility criteria

Inclusion Criteria for Pre-registration (for patients with unknown HER2 mutation status to have tumor tissue screened centrally by Washington University GPS laboratory):

Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-amplified by FISH) breast cancer that is stage IV.
Agree to provide archival tumor material for research
There is no limitation on the number of prior lines of systemic therapy.
Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except to be eligible for the Part II fulvestrant-naive ER+ cohort, at least one measurable disease by RECIST 1.1 is required.
At least 18 years of age.
ECOG performance status ≤ 2
Adequate organ function as defined below within 8 weeks of pre-registration:
- Serum creatinine ≤1.5 x ULN
- Chil-Pugh class A if with liver disease
Able to understand and willing to sign an IRB approved written informed consent document.

Note: HER2 mutation testing may be performed while the patient is receiving active systemic therapy for metastatic breast cancer so that the result can be used to determine eligibility for study drug therapy in the future.

Exclusion Criteria for Pre-registration:

Testing for LVEF is not required for pre-registration, but patient must not have a recent LVEF \< LLN or have symptoms of congestive heart failure.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment).
History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias.
Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.

Inclusion Criteria for Registration (for patients initially pre-registered and with HER2 mutation identified by Washington University GPS laboratory)

Tumor tissue tested positive for HER2 mutation. HER2 mutations detected by Guardant360 are also eligible.
Agree to provide archival tumor material for research
ECOG performance status ≤2
Adequate organ function as defined below within 2 weeks of registration:
- ANC ≥1.5 x 10\^9/L
- Platelet count ≥100 x 10\^9/L
- Serum creatinine ≤1.5 x ULN
- Child-Pugh class A if with liver disease
The patient must have completed radiation therapy and be at least 1 week from the last systemic chemotherapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib.
Presence of disease progression on the most recent disease evaluation.
Patients with known brain metastasis are eligible, but must have received radiation and be off steroids and stable (without evidence of disease progression by imaging or exam) for 3 months.
QTc interval ≤450 msec for men or \< or ≤ 470 msec for women within 2 weeks of registration.
LVEF > or = institutional ILLN within 4 weeks of registration.
Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product.
Able to understand and willing to sign an IRB approved written informed consent document.
There is no limitation on the number of prior lines of systemic therapy.
To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required.
To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required. In addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology form an earlier time point could be used and a discussion with the study chair is required.

Inclusion Criteria for Registration (for patients with HER2 mutation identified at an outside CLIA certified location):

Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-amplified by FISH) breast cancer that is stage IV.
Tumor tissue or circulating tumor DNA tested positive for HER2 mutation. Mutations outside the list will be assessed on a case-by-case basis by the study team to determine eligibility.
Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except to be eligible for the Part II fulvestrant-naïve ER+ cohort, at least one measurable disease by RECIST 1.1 is required.
At least 18 years of age.
ECOG performance status \< 2 (see Appendix A).
Adequate organ function as defined below within 2 weeks of registration:
- Absolute neutrophil count: ≥1.5 × 109/L (1500/mm3)
- Platelet count: ≥100 × 109/L (100,000/mm3)
- Serum creatinine: ≤1.5 x ULN
- Child-Pugh class A if with liver disease
The patient must have completed radiation therapy and be at least 1 week from the last systemic therapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib.
Presence of disease progression on the most recent disease evaluation.
Patients with known treated brain metastasis are eligible, but must have received radiation and be off steroids and stable (without evidence of disease progression by imaging or exam) for 3 months.
QTc interval ≤ 450 msec for men or ≤ 470 msec for women within 2 weeks of registration.
LVEF > institutional LLN within 4 weeks of registration.
Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product
Able to understand and willing to sign an IRB approved written informed consent document.
There is no limitation on the number of prior lines of systemic therapy.
To be eligible for the Part II fulvestrant-naïve ER+ cohort, prior treatment with fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required.
To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required. In addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required.

Exclusion Criteria for Registration:

Currently receiving any other investigational agents or systemic cancer therapy.
Currently taking medications and herbal or dietary supplements that are strong cytochrome P450 (CYP) 3A4 inducers or inhibitors. The washout period must have been completed prior to the start of neratinib if the patient was taking any of these agents. If unavoidable, patients taking CYP3A4 inhibitors should be monitored closely.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Acute or currently active/requiring antiviral therapy hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment).
Pregnant and/or breastfeeding.
History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias.
Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.
Experiencing grade 2 or greater diarrhea.
Prior treatment with neratinib
Child-Pugh class B or C liver dysfunction

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 56 participants (actual)

Study arms

Experimental
Part I: Neratinib Only
-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.
Drug: Neratinib · Procedure: Tumor biopsy · Procedure: Research blood sample
Experimental
Part II: Neratinib Only (ER-)
-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.
Drug: Neratinib · Procedure: Tumor biopsy · Procedure: Research blood sample
Experimental
Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
-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.
Drug: Neratinib · Drug: Fulvestrant · Procedure: Tumor biopsy · Procedure: Research blood sample
Experimental
Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
-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.
Drug: Neratinib · Drug: Fulvestrant · Procedure: Tumor biopsy · Procedure: Research blood sample
Experimental
Crossover: Neratinib + Trastuzumab
-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.
Drug: Neratinib · Drug: Trastuzumab · Procedure: Tumor biopsy · Procedure: Research blood sample
Experimental
Crossover: Neratinib + Fulvestrant + Trastuzumab
-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.
Drug: Neratinib · Drug: Fulvestrant · Drug: Trastuzumab · Procedure: Tumor biopsy · Procedure: Research blood sample

Interventions

DrugNeratinib
Also known as: PF-05208767
DrugFulvestrant
Also known as: Faslodex
DrugTrastuzumab
Also known as: Herceptin
ProcedureTumor biopsy
-Optional at baseline and disease progression
ProcedureResearch blood sample
-Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)

What researchers measure

Primary outcomes

Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone
* 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)
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
* 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)
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
* 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)
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
* 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)

Secondary outcomes

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)
* 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)
Number of Participants With HER2 Mutation Subtype and Histology Subtype
Time frame: At the time of enrollment
Number of Participants With HER2 Mutation Subtype and Tumor Grade
-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
Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis
* 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
Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival
* 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)
Part II ER-cohort Only: Progression-free Survival (PFS)
* 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)
Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)
* 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)
Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)
* 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)
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
-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)
Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)
* 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)
Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)
* 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)

Results

Posted Apr 15, 2022

Participant flow

Part I and Part 2

Participant flow — Part I and Part 2
Milestone	Part I: Neratinib Only	Part II: Neratinib Only (ER-)	Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)	Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
Started	16	5	11	24
Completed	16	4	10	21
Not completed	0	1	1	3
Withdrew: Grade 2 vomiting and progressive disease	0	1	0	0
Withdrew: Grade 3 diarrhea and withdrawal	0	0	1	0
Withdrew: Grade 2 vomiting	0	0	0	1
Withdrew: Grade 3 dizziness and progressive disease	0	0	0	1
Withdrew: Grade 3 diarrhea and duodenal ulcer	0	0	0	1

Crossover

Participant flow — Crossover
Milestone	Crossover: Neratinib + Trastuzumab	Crossover: Neratinib + Fulvestrant + Trastuzumab
Started	3	5
Completed	3	5
Not completed	0	0

Outcome measures

PrimaryPart I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone

* 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)
Reported as:: Count of participants · Participants

Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone
Participants	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
Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone	5	—	—	—	—	—

PrimaryPart 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

Time frame:: Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
Reported as:: Count of participants · Participants

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
Participants	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
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	—	1	—	—	—	—

PrimaryPart 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

Time frame:: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
Reported as:: Count of participants · Participants

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
Participants	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
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	—	—	3	—	—	—

PrimaryPart 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

Time frame:: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
Reported as:: Count of participants · Participants

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
Participants	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
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	—	—	—	8	—	—

SecondaryProgression-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)

* 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)
Reported as:: Number · weeks

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)
weeks	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
Activating mutation - L7L755S	—	9	—	—	—	—
Activating mutation - S310F	—	8	—	—	—	—
Activating mutation - A775_G776insYVMA	—	17	—	—	—	—

SecondaryNumber of Participants With HER2 Mutation Subtype and Histology Subtype

Time frame:: At the time of enrollment
Reported as:: Count of participants · Participants

Number of Participants With HER2 Mutation Subtype and Histology Subtype
Participants	Part I: Neratinib Only	Part II: Neratinib Only (ER-)	Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)	Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
ECD mutation : Ductal histology	3	1	1	1
ECD mutation : Other histology	0	1	1	2
Exon 20 ins mutation : Ductal histology	2	0	1	2
Exon 20 ins mutation : Other histology	2	1	0	2
KD mutation : Ductal histology	5	1	5	7
KD mutation : Other histology	4	1	3	10

SecondaryNumber of Participants With HER2 Mutation Subtype and Tumor Grade

-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
Reported as:: Count of participants · Participants

Number of Participants With HER2 Mutation Subtype and Tumor Grade
Participants	Part I: Neratinib Only	Part II: Neratinib Only (ER-)	Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)	Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
ECD mutation : Tumor grade I/II	2	0	1	2
ECD mutation : Tumor grade III	1	3	0	0
ECD mutation : Unknown	0	0	1	1
Exon 20 ins mutation : Tumor grade I/II	1	1	0	2
Exon 20 ins mutation : Tumor grade III	3	0	1	0
Exon 20 ins mutation : Unknown	0	0	0	2
KD mutation : Tumor grade I/II	6	0	4	11
KD mutation : Tumor grade III	3	2	1	3
KD mutation : Unknown	0	0	3	3

SecondaryCorrelate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis

* 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
Reported as:: Count of participants · Participants

Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis
Participants	Part I: Neratinib Only	Part II: Neratinib Only (ER-)	Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)	Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
ECD mutation : Stage I	0	0	0	1
ECD mutation : Stage II	3	1	1	2
ECD mutation : Stage III	0	0	0	0
ECD mutation : Stage IV	0	1	0	0
ECD mutation : Unknown	0	0	1	0
Exon 20 ins mutation : Stage I	0	0	0	0
Exon 20 ins mutation : Stage II	3	0	1	1
Exon 20 ins mutation : Stage III	1	1	0	2
Exon 20 ins mutation : Stage IV	0	0	0	0
Exon 20 ins mutation : Unknown	0	0	0	1
KD mutation : Stage I	2	1	2	3
KD mutation : Stage II	2	1	2	6
KD mutation : Stage III	3	0	0	6
KD mutation : Stage IV	1	0	2	1
KD mutation : Unknown	1	0	2	1

SecondaryCorrelate the Presence of HER2 Mutation Subtype With Progression-free Survival

* 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)
Reported as:: Median · weeks

Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival
weeks	Part I: Neratinib Only	Part II: Neratinib Only (ER-)	Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)	Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)
ECD mutation	11.0000 (9.0000 to 32.0000)	8.0000 (NA to NA)	48.5000 (16.0000 to 81.0000)	3.0000 (1.0000 to 24.0000)
Exon 20 ins mutation	26.0000 (8.0000 to 75.0000)	17.0000 (NA to NA)	26.000 (NA to NA)	36.5000 (9.0000 to 68.0000)
KD mutation	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)

SecondaryPart II ER-cohort Only: Progression-free Survival (PFS)

Time frame:: Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
Reported as:: Median · weeks

Part II ER-cohort Only: Progression-free Survival (PFS)
weeks	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
Part II ER-cohort Only: Progression-free Survival (PFS)	—	8.5 (8 to NA)	—	—	—	—

SecondaryPart II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)

Time frame:: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
Reported as:: Median · weeks

Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)
weeks	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
Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)	—	—	20 (8 to NA)	—	—	—

SecondaryPart II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)

Time frame:: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
Reported as:: Median · weeks

Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)
weeks	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
Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)	—	—	—	24 (15.7 to 31)	—	—

SecondarySafety 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

-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)
Reported as:: Count of participants · Participants

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
Participants	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
Anemia	2	0	1	4	0	1
LVEF Decrease	0	0	0	0	1	0
Heart failure with preserved ejection fraction	0	0	0	0	0	1
Tinnitus	1	0	0	0	0	0
Dry eye	1	0	0	1	0	0
Abdominal cramping	1	0	0	0	0	0
Abdominal pain	0	0	2	3	0	0
Bloating	0	1	0	2	0	0
Constipation	5	0	1	2	0	0
Diarrhea	15	5	8	20	0	1
Dry mouth	0	0	0	4	0	0
Dyspepsia	2	0	1	6	0	0
Flatulence	0	0	0	1	0	0
Mucositis oral	3	0	0	2	0	0
Nausea	9	3	4	11	0	1
Stomach pain	1	0	0	0	0	0
Stomatitis	0	0	0	1	0	0
Vomiting	6	1	0	6	0	2
Fatigue	6	1	5	12	0	1
Fever	0	0	0	1	0	0
Generalized weakness	1	0	0	0	0	0
Pain	0	0	0	1	0	0
Rhinitis infective	0	0	0	1	0	0
Upper respiratory infection	0	0	0	1	0	0
Urinary tract infection	1	0	2	1	0	0
Alaline aminotransferase increased	3	0	2	4	0	1
Alkaline phosphatase increased	1	0	1	3	0	0
Alkaline phosphatase decreased	0	0	0	1	0	0
Aspartate aminotransferase increased	2	0	3	7	0	1
CD4 lymphocytes decreased	1	0	0	0	0	0
Creatinine increased	3	0	0	1	0	1
Ejection fraction decreased	0	0	0	0	1	0
INR increased	0	0	1	0	0	0
Lymphocyte count decreased	0	0	2	2	0	0
Neutrophil count decreased	0	0	0	2	0	1
Platelet count decreased	0	0	0	0	1	1
Weight loss	3	1	0	4	0	1
White blood cell decreased	0	0	0	4	0	0
Anorexia	7	1	7	9	0	2
Dehydration	3	1	1	6	1	1
Hypercalcemia	0	0	0	2	0	0
Hyperglycemia	1	0	0	2	0	0
Hyperkalemia	0	0	0	1	0	1
Hypoalbuminemia	2	0	0	1	0	0
Hypocalcemia	1	0	0	2	0	0
Hypokalemia	1	0	1	1	0	0
Hyponatremia	0	0	1	1	0	0
Hypophosphatemia	2	0	0	1	0	0
Arthralgia	1	0	0	2	0	0
Back pain	2	0	0	0	0	0
Bone pain	1	0	0	0	0	0
Flank pain	1	0	0	0	0	0
Generalized muscle weakness	0	0	0	2	0	0
Joint range of motion decreased	0	0	1	0	0	0
Leg cramp	1	0	0	0	0	0
Muscle weakness left sided	0	0	0	1	0	0
Muscle weakness lower limb	0	0	0	1	0	0
Myalgia	0	0	0	1	0	0
Pain at injection site	0	0	1	0	0	0
Pain in extremity	0	0	1	0	0	0
Dizziness	1	0	2	4	0	0
Dysgeusia	0	0	1	3	0	2
Headache	1	0	2	0	0	0
Peripheral sensory neuropathy	0	1	0	1	0	0
Syncope	1	0	1	0	0	0
Depression	0	0	1	0	0	0
Insomnia	0	0	1	0	0	0
Acute kidney injury	0	0	1	0	0	0
Urinary tract obstruction	0	0	1	0	0	0
Urine discoloration	0	0	1	1	0	0
Urine odor	0	0	1	0	0	0
Cough	1	0	0	1	0	0
Dyspnea	0	0	0	1	0	0
Epistaxis	0	0	1	0	0	0
Hoarseness	0	0	0	1	0	0
Postnasal drip	0	0	1	0	0	0
Rhinorrhea	0	0	0	1	0	0
Alopecia	1	0	0	0	0	0
Dry hair	1	0	0	0	0	0
Dry skin	0	0	0	2	0	0
Nail changes	1	0	0	1	0	0
Pruritus	1	0	0	1	0	1
Rash acneiform	0	0	2	4	0	0
Rash maculopapular	1	1	1	1	0	0
Skin hyperpigmentation	1	0	0	1	0	0
Sterile abscess at subcutaneous injection site	0	0	1	0	0	0
Hot flashes	1	0	1	1	0	0
Hypotension	1	0	1	1	0	0

SecondaryPart II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)

* 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)
Reported as:: Count of participants · Participants

Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)
Participants	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
Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)	—	—	3	—	—	—

SecondaryPart II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)

Time frame:: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
Reported as:: Count of participants · Participants

Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)
Participants	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
Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)	—	—	—	5	—	—

Adverse events

Collected over 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.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Part I: Neratinib Only	10/16 (62.5%)	5/16 (31.3%)	16/16 (100%)
Part II: Neratinib Only (ER-)	1/5 (20%)	1/5 (20%)	5/5 (100%)
Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)	5/11 (45.5%)	2/11 (18.2%)	11/11 (100%)
Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)	9/24 (37.5%)	9/24 (37.5%)	24/24 (100%)
Crossover: Neratinib + Trastuzumab	3/3 (100%)	2/3 (66.7%)	3/3 (100%)
Crossover: Neratinib + Fulvestrant + Trastuzumab	4/5 (80%)	0/5 (0%)	4/5 (80%)

Most frequent serious events

Showing 10 of 17

Most frequent serious events
Event	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
Lung infectionInfections and infestations	0/16	0/5	0/11	0/24	1/3	0/5
Disease progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)	0/16	0/5	0/11	0/24	1/3	0/5
FatigueGeneral disorders	1/16	1/5	0/11	2/24	0/3	0/5
PneumonitisRespiratory, thoracic and mediastinal disorders	0/16	1/5	0/11	0/24	0/3	0/5
INR increasedInvestigations	0/16	0/5	1/11	0/24	0/3	0/5
Death due to disease progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)	1/16	0/5	1/11	2/24	0/3	0/5
SyncopeNervous system disorders	1/16	0/5	1/11	0/24	0/3	0/5
Urinary tract infectionInfections and infestations	0/16	0/5	0/11	2/24	0/3	0/5
Atrial flutterCardiac disorders	1/16	0/5	0/11	0/24	0/3	0/5
Thromboembolic eventVascular disorders	1/16	0/5	0/11	0/24	0/3	0/5

Most frequent other events

Showing 10 of 182

Most frequent other events
Event	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
DiarrheaGastrointestinal disorders	16/16	5/5	9/11	22/24	0/3	1/5
NauseaGastrointestinal disorders	11/16	4/5	4/11	12/24	0/3	2/5
AnemiaBlood and lymphatic system disorders	3/16	0/5	1/11	6/24	2/3	1/5
Edema limbsGeneral disorders	1/16	0/5	1/11	2/24	2/3	0/5
AnorexiaMetabolism and nutrition disorders	10/16	1/5	7/11	10/24	0/3	2/5
VomitingGastrointestinal disorders	10/16	1/5	1/11	6/24	0/3	3/5
ConstipationGastrointestinal disorders	9/16	1/5	3/11	9/24	0/3	2/5
FatigueGeneral disorders	6/16	0/5	5/11	12/24	0/3	1/5
Aspartate aminotransferase increasedInvestigations	4/16	0/5	5/11	8/24	1/3	1/5
Urinary tract infectionInfections and infestations	2/16	0/5	3/11	4/24	1/3	2/5

Baseline characteristics

Age, Continuous
Age, Continuous(years)	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
Median	58 (31 to 74)	63 (58 to 67)	58 (41 to 82)	64 (35 to 76)	61 (31 to 82)

Sex: Female, Male
Sex: Female, Male(Participants)	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
Female	16	5	10	24	55
Male	0	0	1	0	1

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	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
Hispanic or Latino	0	0	0	2	2
Not Hispanic or Latino	16	5	9	17	47
Unknown or Not Reported	0	0	2	5	7

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	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
American Indian or Alaska Native	0	0	0	0	0
Asian	1	0	1	0	2
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	1	1	2	1	5
White	13	4	8	23	48
More than one race	0	0	0	0	0
Unknown or Not Reported	1	0	0	0	1

Region of Enrollment
Region of Enrollment(participants)	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
Canada	2	0	0	0	0
United States	14	5	11	24	56

HER2 Status
HER2 Status(Participants)	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
Activating	15	5	11	24	55
Novel	1	0	0	0	1

Histology Subtype
Histology Subtype(Participants)	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
Ductal	10	3	7	10	30
Lobular	5	2	2	12	21
Other	1	0	1	2	4
Unknown	0	0	1	0	1

Tumor Grade
Tumor Grade(Participants)	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
I/II	8	0	5	12	25
II	1	1	0	3	5
III	7	4	2	3	16
Unknown	0	0	4	6	10

1 further baseline measures are reported on the registry.

Study locations

17 sites

University of Alabama Cancer Center
Birmingham, Alabama 35294, United States
Mayo Clinic
Phoenix, Arizona 85054, United States
University of Southern California Keck School of Medicine
Los Angeles, California 90033, United States
Stanford Medicine Cancer Institute
Stanford, California 94305, United States
University of Miami Hospital and Clinics
Miami, Florida 33136, United States
Northwestern University - Feinberg School of Medicine
Chicago, Illinois 60611, United States
Rush University Medical Center
Chicago, Illinois 60612, United States
Dana-Farber Cancer Institute, Harvard University
Boston, Massachusetts 02215, United States
University of Michigan
Ann Arbor, Michigan 48109, United States
St. Luke's Cancer Institute
Kansas City, Missouri 64111, United States
Washington University School of Medicine
Saint Louis, Missouri 63110, United States
University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center)
Chapel Hill, North Carolina 27514, United States
Duke Cancer Institute at Duke University Medical Center
Durham, North Carolina 27710, United States
Avera Cancer Institute
Sioux Falls, South Dakota 57105, United States
Baylor College of Medicine
Houston, Texas 77030, United States
BC Cancer Agency
Vancouver, British Columbia V5Z 1L3, Canada
Princess Margaret Cancer Centre
Toronto, Ontario M5G 2M9, Canada

References and documents

Publications

Shishido SN, Masson R, Xu L, Welter L, Prabakar RK, D' Souza A, Spicer D, Kang I, Jayachandran P, Hicks J, Lu J, Kuhn P. Disease characterization in liquid biopsy from HER2-mutated, non-amplified metastatic breast cancer patients treated with neratinib. NPJ Breast Cancer. 2022 Feb 18;8(1):22. doi: 10.1038/s41523-022-00390-5. PubMed 35181666 ↗
Exman P, Garrido-Castro AC, Hughes ME, Freedman RA, Li T, Trippa L, Bychkovsky BL, Barroso-Sousa R, Di Lascio S, Mackichan C, Lloyd MR, Krevalin M, Cerami E, Merrill MS, Santiago R, Crowley L, Kuhnly N, Files J, Lindeman NI, MacConaill LE, Kumari P, Tolaney SM, Krop IE, Bose R, Johnson BE, Ma CX, Dillon DA, Winer EP, Wagle N, Lin NU. Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials. JCO Precis Oncol. 2019 Nov 15;3:PO.19.00087. doi: 10.1200/PO.19.00087. eCollection 2019. PubMed 32923853 ↗

Study documents

Protocol and statistical analysis plan · Mar 16, 2020
Informed consent form · Jan 14, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Apr 15, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01670877
Lead sponsor: Washington University School of Medicine
Collaborators: Puma Biotechnology, Inc., United States Department of Defense
Responsible party: Sponsor
First posted: Aug 22, 2012
Start date: Dec 11, 2012
Primary completion: Feb 11, 2021
Completion: Mar 11, 2021
Results posted: Apr 15, 2022
Last update: Apr 15, 2022

Study contacts

Cynthia Ma, M.D., Ph.D

principal investigator · Washington University School of Medicine

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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