Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
NCT ID: NCT01670877
Last Updated: 2022-04-15
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
56 participants
INTERVENTIONAL
2012-12-11
2021-03-11
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
Neratinib
Tumor biopsy
-Optional at baseline and disease progression
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)
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.
Neratinib
Tumor biopsy
-Optional at baseline and disease progression
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)
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.
Neratinib
Fulvestrant
Tumor biopsy
-Optional at baseline and disease progression
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)
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.
Neratinib
Fulvestrant
Tumor biopsy
-Optional at baseline and disease progression
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)
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.
Neratinib
Trastuzumab
Tumor biopsy
-Optional at baseline and disease progression
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)
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.
Neratinib
Fulvestrant
Trastuzumab
Tumor biopsy
-Optional at baseline and disease progression
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)
Interventions
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Neratinib
Fulvestrant
Trastuzumab
Tumor biopsy
-Optional at baseline and disease progression
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)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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.
* 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.
* 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
* 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.
* 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
18 Years
ALL
No
Sponsors
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Puma Biotechnology, Inc.
INDUSTRY
United States Department of Defense
FED
Washington University School of Medicine
OTHER
Responsible Party
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Principal Investigators
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Cynthia Ma, M.D., Ph.D
Role: PRINCIPAL_INVESTIGATOR
Washington University School of Medicine
Locations
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University of Alabama Cancer Center
Birmingham, Alabama, United States
Mayo Clinic
Phoenix, Arizona, United States
University of Southern California Keck School of Medicine
Los Angeles, California, United States
Stanford Medicine Cancer Institute
Stanford, California, United States
University of Miami Hospital and Clinics
Miami, Florida, United States
Northwestern University - Feinberg School of Medicine
Chicago, Illinois, United States
Rush University Medical Center
Chicago, Illinois, United States
Dana-Farber Cancer Institute, Harvard University
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
St. Luke's Cancer Institute
Kansas City, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center)
Chapel Hill, North Carolina, United States
Duke Cancer Institute at Duke University Medical Center
Durham, North Carolina, United States
Avera Cancer Institute
Sioux Falls, South Dakota, United States
Baylor College of Medicine
Houston, Texas, United States
BC Cancer Agency
Vancouver, British Columbia, Canada
Princess Margaret Cancer Centre
Toronto, Ontario, Canada
Countries
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References
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Jhaveri K, Eli LD, Wildiers H, Hurvitz SA, Guerrero-Zotano A, Unni N, Brufsky A, Park H, Waisman J, Yang ES, Spanggaard I, Reid S, Burkard ME, Vinayak S, Prat A, Arnedos M, Bidard FC, Loi S, Crown J, Bhave M, Piha-Paul SA, Suga JM, Chia S, Saura C, Garcia-Saenz JA, Gambardella V, de Miguel MJ, Gal-Yam EN, Rapael A, Stemmer SM, Ma C, Hanker AB, Ye D, Goldman JW, Bose R, Peterson L, Bell JSK, Frazier A, DiPrimeo D, Wong A, Arteaga CL, Solit DB. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol. 2023 Oct;34(10):885-898. doi: 10.1016/j.annonc.2023.08.003. Epub 2023 Aug 18.
Shishido SN, Masson R, Xu L, Welter L, Prabakar RK, D' Souza A, Spicer D, Kang I, Jayachandran P, Hicks J, Lu J, Kuhn P. Disease characterization in liquid biopsy from HER2-mutated, non-amplified metastatic breast cancer patients treated with neratinib. NPJ Breast Cancer. 2022 Feb 18;8(1):22. doi: 10.1038/s41523-022-00390-5.
Exman P, Garrido-Castro AC, Hughes ME, Freedman RA, Li T, Trippa L, Bychkovsky BL, Barroso-Sousa R, Di Lascio S, Mackichan C, Lloyd MR, Krevalin M, Cerami E, Merrill MS, Santiago R, Crowley L, Kuhnly N, Files J, Lindeman NI, MacConaill LE, Kumari P, Tolaney SM, Krop IE, Bose R, Johnson BE, Ma CX, Dillon DA, Winer EP, Wagle N, Lin NU. Identifying ERBB2 Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials. JCO Precis Oncol. 2019 Nov 15;3:PO.19.00087. doi: 10.1200/PO.19.00087. eCollection 2019.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Related Links
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Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
Other Identifiers
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201209135
Identifier Type: -
Identifier Source: org_study_id
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