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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

Tracking Information
First Submitted Date  ICMJE August 17, 2012
First Posted Date  ICMJE August 22, 2012
Results First Submitted Date  ICMJE February 10, 2022
Results First Posted Date  ICMJE April 15, 2022
Last Update Posted Date April 15, 2022
Actual Study Start Date  ICMJE December 11, 2012
Actual Primary Completion Date February 11, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2022)
  • Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone [ Time Frame: Through completion of treatment (median treatment time of 90 days, full range 54-716 days) ]
    • 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.
  • 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 [ Time Frame: Through completion of treatment (median treatment time of 62 days, full range 56-413 days) ]
    • 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.
  • 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 [ Time Frame: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days) ]
    • 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.
  • 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 [ Time Frame: Through completion of treatment (median treatment time of 168 days, full range 28-671 days) ]
    • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 17, 2012)
Overall clinical benefit (CR+PR+SD≥6months) of neratinib in patients with metastatic HER2 breast cancer that carry HER2 mutation [ Time Frame: 6 months ]
Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eight percent confidence interval (CI) will be calculated.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2022)
  • 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) [ 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) ]
    • 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.
  • 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 [ Time Frame: A time of enrollment ]
    -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.
  • Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis [ Time Frame: At time of enrollment ]
    • 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.
  • Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival [ 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) ]
    • 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.
  • Part 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) ]
    • 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.
  • Part 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) ]
    • 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.
  • Part 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) ]
    • 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.
  • 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 [ 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) ]
    -CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.
  • Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR) [ Time Frame: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days) ]
    • 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.
  • Part 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) ]
    • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2012)
  • PFS of patients treated with neratinib [ Time Frame: 2 years ]
    The time to progression or death will be listed, and the progression-free survival (PFS) will be estimated using Kaplan-Meier product limit method. For all the enrolled patients, the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and metastatic sites will be described using contingency tables and assess by McNemar test. The association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and progression-free survival (PFS) will be assessed using Fisher's exact test, Mann-Whitney rank sum test, or log-rank test as appropriate.
  • Correlate the presence of HER2 mutation with histology subtype (invasive lobular vs. invasive ductal cancer), tumor grade (grade 1-2 vs 3), tumor staging at initial diagnosis (I vs. II or III vs. IV), disease free survival in HER2- breast cancer. [ Time Frame: Baseline ]
    Assessed using RECIST guidelines version 1.1
  • Compare the occurrence of HER2 mutation in paired primary and metastatic sites. [ Time Frame: Baseline ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
Official Title  ICMJE A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
Brief 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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Neoplasms
Intervention  ICMJE
  • Drug: Neratinib
    Other Name: PF-05208767
  • Drug: Fulvestrant
    Other Name: Faslodex
  • Drug: Trastuzumab
    Other Name: Herceptin
  • Procedure: Tumor biopsy
    -Optional at baseline and disease progression
  • Procedure: Research 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)
Study Arms  ICMJE
  • 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.
    Interventions:
    • 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.
    Interventions:
    • 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.
    Interventions:
    • 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.
    Interventions:
    • 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.
    Interventions:
    • 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.
    Interventions:
    • Drug: Neratinib
    • Drug: Fulvestrant
    • Drug: Trastuzumab
    • Procedure: Tumor biopsy
    • Procedure: Research blood sample
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 18, 2021)
56
Original Estimated Enrollment  ICMJE
 (submitted: August 17, 2012)
29
Actual Study Completion Date  ICMJE March 11, 2021
Actual Primary Completion Date February 11, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01670877
Other Study ID Numbers  ICMJE 201209135
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Washington University School of Medicine
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Washington University School of Medicine
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Puma Biotechnology, Inc.
  • United States Department of Defense
Investigators  ICMJE
Principal Investigator: Cynthia Ma, M.D., Ph.D Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date April 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP