Neratinib with or without Fulvestrant in Metastatic HER2-Negative but HER2 Mutant Breast Cancer

Status: Active

Description

This phase II trial studies how well neratinib with or without fulvestrant works in treating patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer that carries HER2 gene mutations and has spread to other parts of the body (metastatic). Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving neratinib with fulvestrant may provide a more effective treatment for patients with this type of breast cancer.

Eligibility Criteria

Inclusion Criteria

  • INCLUSION CRITERIA FOR PRE-REGISTRATION (PATIENTS WITH UNKNOWN HER2 MUTATION STATUS TO HAVE TUMOR TISSUE SCREENED):
  • Histologically or cytologically confirmed HER2-negative (0 or 1+ by immunohistochemistry [IHC] or non-amplified by fluorescent in situ hybridization [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 Response Evaluation Criteria in Solid Tumors (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
  • Eastern Cooperate Oncology Group (ECOG) performance status =< 2
  • Serum creatinine: =< 1.5 x upper limit of normal (ULN) within 8 weeks of pre-registration
  • Total bilirubin: =< 1.5 x ULN (in case of known Gilbert’s syndrome, < 2 x ULN is allowed) within 8 weeks of pre-registration
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN or =< 5 x ULN for patients with liver metastases within 8 weeks of pre-registration
  • Able to understand and willing to sign an Institutional Review Board (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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASHINGTON UNIVERSITY [WASH U] GENOMICS AND PATHOLOGY SERVICES [GPS] LABORATORY): Tumor tissue 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 * Note: HER2 mutations listed and detected by Guardant360 are also eligible
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Agree to provide archival tumor material for research
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): ECOG performance status =< 2
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Absolute neutrophil count: >= 1.5 x 10^9/L (1500/mm^3) within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Platelet count: >= 100 x 10^9/L (100,000/mm^3) within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Serum creatinine: =< 1.5 x ULN within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Total bilirubin: =< 1.5 x ULN (in case of known Gilbert’s syndrome, < 2 x ULN is allowed) within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): AST and ALT: =< 3 x ULN or =< 5 x ULN for patients with liver metastases within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Presence of disease progression on the most recent disease evaluation
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Corrected QT (QTc) interval =< 450 msec for men or =< 470 msec for women within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) within 4 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): Able to understand and willing to sign an IRB approved written informed consent document
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): There is no limitation on the number of prior lines of systemic therapy
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed; in addition, ER and/or progesterone receptor (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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLINICAL LABORATORY IMPROVEMENT ACT [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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Tumor tissue or circulating tumor deoxyribonucleic acid (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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): ECOG performance status =< 2
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Absolute neutrophil count: >= 1.5 x 10^9/L (1500/mm^3) within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Platelet count: >= 100 x 10^9/L (100,000/mm^3) within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Serum creatinine: =< 1.5 x ULN within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Total bilirubin: =< 1.5 x ULN (in case of known Gilbert’s syndrome, < 2 x ULN is allowed) within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): AST and ALT: =< 3 x ULN or =< 5 x ULN for patients with liver metastases within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Presence of disease progression on the most recent disease evaluation
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): QTc interval =< 450 msec for men or =< 470 msec for women within 2 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): LVEF >= institutional LLN within 4 weeks of registration
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): Able to understand and willing to sign an IRB approved written informed consent document
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): There is no limitation on the number of prior lines of systemic therapy
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): 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
  • INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): 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

  • 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
  • EXCLUSION CRITERIA FOR REGISTRATION: Currently receiving any other investigational agents or systemic cancer therapy
  • EXCLUSION CRITERIA FOR REGISTRATION: Currently taking medications and herbal or dietary supplements that are strong cytochrome P450 (CYP) family 3, subfamily A, polypeptide 4 (3A4) inducers or inhibitors; a washout period of at least 5 days is required and 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
  • EXCLUSION CRITERIA FOR REGISTRATION: 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
  • EXCLUSION CRITERIA FOR REGISTRATION: Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of patients with Gilbert’s syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)
  • EXCLUSION CRITERIA FOR REGISTRATION: Pregnant and/or breastfeeding
  • EXCLUSION CRITERIA FOR REGISTRATION: History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias
  • EXCLUSION CRITERIA FOR REGISTRATION: Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
  • EXCLUSION CRITERIA FOR REGISTRATION: Experiencing grade 2 or greater diarrhea
  • EXCLUSION CRITERIA FOR REGISTRATION: Prior treatment with neratinib

Locations & Contacts

California

Pasadena
Keck Medical Center of USC Pasadena
Status: Active
Contact: Janice Lu
Phone: 323-865-3000

Florida

Miami
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: Active
Contact: Marc Estes Lippman
Email: mlippman@med.miami.edu

Illinois

Chicago
Rush University Medical Center
Status: Active
Contact: Melody Ann Cobleigh
Email: melody_cobleigh@rush.edu

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: Active
Contact: Rachel A. Freedman
Phone: 617-632-6876
Email: rachel_freedman@dcfi.harvard.edu

Minnesota

Rochester
Mayo Clinic
Status: Active
Contact: Matthew P. Goetz
Phone: 507-293-1605
Email: goetz.matthew@mayo.edu

Missouri

Kansas City
Saint Luke's Hospital of Kansas City
Status: Active
Contact: Timothy Joseph Pluard
Phone: 816-932-6005
Email: tpluard@saint-lukes.org
Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Contact: Cynthia Xiuguang Ma
Phone: 314-362-9383
Email: cynthiaxma@wustl.edu

North Carolina

Durham
Duke University Medical Center
Status: Active
Contact: Kimberly Lynn Blackwell
Phone: 919-681-0874
Email: kimberly.blackwell@duke.edu

South Dakota

Sioux Falls
Avera Cancer Institute
Status: Active
Contact: Amy K. Krie
Phone: 605-322-6900

Texas

Houston
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: Active
Contact: Matthew James Clifford Ellis
Email: matthew.ellis@bcm.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the clinical benefit (complete response [CR] + partial response [PR] + stable disease [SD] >= 6 months) of neratinib alone in patients with metastatic HER2- breast cancer that carry HER2 mutations. (Part I)

II. To examine the clinical benefit (CR + PR + SD >= 6 months) of neratinib in combination with fulvestrant in patients with fulvestrant-naive metastatic HER2-, estrogen receptor (ER)+ breast cancer carrying activating HER2 mutations. (Part II fulvestrant-naive ER+ cohort)

III. To examine the clinical benefit (CR + PR + SD >= 6 months) of neratinib in combination with fulvestrant in patients with metastatic HER2-, ER+ breast cancer carrying activating HER2 mutations previously treated with fulvestrant. (Part II fulvestrant-treated ER+ cohort)

IV. To determine the clinical benefit rate of neratinib alone in patients with metastatic HER2-, ER- breast cancer carrying activating HER2 mutations. (Part II ER- cohort)

SECONDARY OBJECTIVES:

I. To determine the 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 [vs.] unknown significance).

II. To assess the PFS and response rate of neratinib in combination with fulvestrant in patients with fulvestrant-naive metastatic ER+ HER2- breast cancer carrying activating HER2 mutations.

III. To assess the PFS and response rate of neratinib in combination with fulvestrant in patients with metastatic ER+ HER2- breast cancer carrying activating HER2 mutations previously treated with fulvestrant.

IV. To assess the safety profile and tolerability of neratinib in combination with fulvestrant in patients with metastatic ER+ HER2- breast cancer carrying activating HER2 mutations.

V. To 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.

EXPLORATORY OBJECTIVES:

I. To compare the occurrence of HER2 mutation in paired primary and metastatic sites.

II. To collect peripheral blood plasma samples for circulating HER2 mutation analysis.

III. To investigate other potential therapeutic targets in HER2- breast cancer.

IV. To explore potential mechanisms of treatment resistance.

V. To explore anti-tumor response after adding trastuzumab to neratinib or neratinib plus fulvestrant when tumor progresses on single agent neratinib or neratinib in combination with fulvestrant.

OUTLINE:

Patients receive neratinib orally (PO) once daily (QD) on days 1-28. Patients with ER+ disease also receive fulvestrant intramuscularly (IM) on days 1 and 15 of course 1 and day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression on single-agent neratinib may begin to receive trastuzumab intravenously (IV) every 2 weeks.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Cynthia Xiuguang Ma

Trial IDs

Primary ID 201209135
Secondary IDs NCI-2012-01513
Clinicaltrials.gov ID NCT01670877