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



Status:Recruiting
Conditions:Breast Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:1/16/2019
Start Date:December 11, 2012
End Date:December 31, 2021
Contact:Cynthia Ma, M.D., Ph.D.
Email:cynthiaxma@wustl.edu
Phone:314-362-9383

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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

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.


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

- Total bilirubin ≤1.5 × ULN (in case of known Gilbert's syndrome, < 2 x ULN is
allowed)

- AST and ALT ≤3× ULN or < 5 ULN for patients with liver metastases

- 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

- Total bilirubin ≤1.5 x ULN (in case of known Gilbert's syndrome, < 2 x ULN is
allowed)

- AST and ALT ≤3× ULN or ≤ 5 x ULN for patients with liver metastases.

- 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

- Total bilirubin: ≤1.5 × ULN (in case of known Gilbert's syndrome, <2 x ULN is
allowed)

- AST and ALT: ≤3× ULN or ≤ 5 x ULN for patients with liver metastases.

- 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
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Principal Investigator: Marc E Lippman, M.D.
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1200 Moursund Street
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(713) 798-4951
Principal Investigator: Julie Nangia, M.D.
Phone: 713-798-1999
Baylor College of Medicine Baylor College of Medicine in Houston, the only private medical school...
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3900 W Avera Drive
Sioux Falls, South Dakota 57108
(605) 322-4700
Principal Investigator: Amy Krie, M.D.
Phone: 605-322-6900
Avera Cancer Institute Avera, the health ministry of the Benedictine and Presentation Sisters, is a...
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500 S State St
Ann Arbor, Michigan 48109
(734) 764-1817
University of Michigan The University of Michigan was founded in 1817 as one of the...
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Birmingham, Alabama 35294
Principal Investigator: Andres Forero, M.D.
Phone: 205-975-2837
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Boston, Massachusetts
Principal Investigator: Rachel Freedman, M.D.
Phone: 617-632-6876
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Chapel Hill, North Carolina 27599
Principal Investigator: Carey Anders, M.D.
Phone: 919-966-4431
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(312) 942-5000
Principal Investigator: Melody Cobleigh, M.D.
Rush University Medical Center Rush University Medical Center encompasses a 664-bed hospital serving adults and...
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303 E Chicago Ave
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Phone: 312-695-6180
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Durham, North Carolina 27710
Principal Investigator: Kimberly Blackwell, M.D.
Phone: 919-681-0874
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Kansas City, Missouri 64111
Principal Investigator: Timothy J Pluard, M.D.
Phone: 816-932-6005
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Los Angeles, California 90033
Principal Investigator: Janice Lu, M.D., Ph.D.
Phone: 323-865-3000
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Principal Investigator: Matthew P. Goetz, M.D.
Phone: 507-293-1605
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660 S Euclid Ave
Saint Louis, Missouri 63110
(314) 362-5000
Principal Investigator: Cynthia X Ma, M.D., Ph.D.
Phone: 314-362-9383
Washington University School of Medicine Washington University Physicians is the clinical practice of the School...
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Phone: 650-723-5801
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Vancouver, British Columbia
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