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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Neratinib
* Drug: Fulvestrant
* Drug: Trastuzumab
* Procedure: Tumor biopsy
* Procedure: Research blood sample


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: Neratinib Only<br>-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<br> <br> * Other names: PF-05208767;Procedure: Tumor biopsy<br>* -Optional at baseline and disease progression<br>Procedure: Research blood sample<br>* -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)<br>|
| Experimental: Part II: Neratinib Only (ER-)<br>-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<br> <br> * Other names: PF-05208767;Procedure: Tumor biopsy<br>* -Optional at baseline and disease progression<br>Procedure: Research blood sample<br>* -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)<br>|
| Experimental: Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)<br>-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<br> <br> * Other names: PF-05208767;Drug: Fulvestrant<br> <br> * Other names: Faslodex;Procedure: Tumor biopsy<br>* -Optional at baseline and disease progression<br>Procedure: Research blood sample<br>* -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)<br>|
| Experimental: Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)<br>-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<br> <br> * Other names: PF-05208767;Drug: Fulvestrant<br> <br> * Other names: Faslodex;Procedure: Tumor biopsy<br>* -Optional at baseline and disease progression<br>Procedure: Research blood sample<br>* -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)<br>|
| Experimental: Crossover: Neratinib + Trastuzumab<br>-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<br> <br> * Other names: PF-05208767;Drug: Trastuzumab<br> <br> * Other names: Herceptin;Procedure: Tumor biopsy<br>* -Optional at baseline and disease progression<br>Procedure: Research blood sample<br>* -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)<br>|
| Experimental: Crossover: Neratinib + Fulvestrant + Trastuzumab<br>-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<br> <br> * Other names: PF-05208767;Drug: Fulvestrant<br> <br> * Other names: Faslodex;Drug: Trastuzumab<br> <br> * Other names: Herceptin;Procedure: Tumor biopsy<br>* -Optional at baseline and disease progression<br>Procedure: Research blood sample<br>* -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Through completion of treatment (median treatment time of 168 days, full range 28-671 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 |  | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Through completion of treatment (median treatment time of 168 days, full range 28-671 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neratinib, fulvestrant, HER2 mutation, metastatic breast cancer, trastuzumab