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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2015 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01670877
First received: August 17, 2012
Last updated: July 2, 2015
Last verified: July 2015
  Purpose

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.


Condition Intervention Phase
Breast Neoplasms
Drug: Neratinib
Drug: Fulvestrant
Drug: Trastuzumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Part I only: Overall clinical activity (CR+PR+SD≥6months) of neratinib alone in patients with metastatic HER2- breast cancer that carry HER2 mutation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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. Eighty percent confidence interval (CI) will be calculated.

  • Part II fulvestrant-naive ER+ cohort only: Response rate (CR+PR) of neratinib + fulvestrant in patients with metastatic HER2- ER+ fulvestrant-naive breast cancer that carry HER2 mutation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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. Eighty percent confidence interval (CI) will be calculated.

  • Part II fulvestrant-treated ER+ cohort only: Overall clinical activity (CR+PR+SD≥6months) of neratinib + fulvestrant in patients with metastatic HER2- ER+ fulvestrant-treated breast cancer that carry HER2 mutation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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. Eighty percent confidence interval (CI) will be calculated.

  • Part II ER-cohort only: Overall clinical activity (CR+PR+SD≥6months) of neratinib in patients with metastatic HER2-, ER- breast cancer that carry HER2 mutation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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. Eighty percent confidence interval (CI) will be calculated.


Secondary Outcome Measures:
  • PFS of patients with HER2- but HER2 mutated breast cancer treated with neratinib alone [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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: 2 years ] [ Designated as safety issue: No ]
  • PFS of patients with HER2- ER+ HER2 mutated breast cancer who are fulvestrant-naive treated with neratinib + fulvestrant [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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.

  • PFS of patients with HER2- ER+ HER2 mutated breast cancer who are fulvestrant-treated treated with neratinib + fulvestrant [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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.

  • Safety and tolerability of neratinib in combination with fulvestrant in patients with HER2- ER+ HER2 mutated breast cancer as measured by grade and frequency of adverse events [ Time Frame: 5 months ] [ Designated as safety issue: Yes ]
    CTCAE v 4.0 will be used to record AEs


Estimated Enrollment: 70
Study Start Date: December 2012
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part I: met HER2- BC w/HER2 mutations
  • 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.
  • If a participant experiences disease progression following neratinib, trastuzumab 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.
Drug: Neratinib
Other Name: PF-05208767
Drug: Trastuzumab
Other Name: Herceptin
Experimental: Part II: met HER2- ER- BC w/HER2 mutations
  • 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.
  • If a participant experiences disease progression following neratinib, trastuzumab 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.
Drug: Neratinib
Other Name: PF-05208767
Drug: Trastuzumab
Other Name: Herceptin
Experimental: Part II: met HER2- ER+ BC w/HER2 mutations, 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.
  • If a participant experiences disease progression following neratinib, trastuzumab 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.
Drug: Neratinib
Other Name: PF-05208767
Drug: Fulvestrant
Other Name: Faslodex
Drug: Trastuzumab
Other Name: Herceptin
Experimental: Part II: met HER2- ER+ BC w/HER2 mutations, 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.
  • If a participant experiences disease progression following neratinib, trastuzumab 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.
Drug: Neratinib
Other Name: PF-05208767
Drug: Fulvestrant
Other Name: Faslodex
Drug: Trastuzumab
Other Name: Herceptin

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Pre-registration:

  • Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-amplified by FISH) breast cancer that is stage IV.
  • 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
  • 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

  • Tumor tissue tested positive for HER2 mutation.
  • 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.
  • To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01670877

Contacts
Contact: Cynthia Ma, M.D., Ph.D. 314-362-9383 cma@dom.wustl.edu

Locations
United States, Alabama
University of Alabama Cancer Center Recruiting
Birmingham, Alabama, United States, 35294
Contact: Andres Forero-Torres, M.D.    205-975-2837    aforero@uab.edu   
Principal Investigator: Andres Forero, M.D.         
United States, California
University of Southern California Keck School of Medicine Recruiting
Los Angeles, California, United States, 90033
Contact: Augustin A. Garcia, M.D.    323-865-0832    aagarcia@usc.edu   
Principal Investigator: Augustin A. Garcia, M.D.         
Stanford Medicine Cancer Institute Recruiting
Stanford, California, United States, 94305
Contact: Mark Pegram, M.D.    650-723-5801    mpegram@stanford.edu   
Principal Investigator: Mark Pegram, M.D.         
United States, Florida
University of Miami Not yet recruiting
Miami, Florida, United States, 33136
Contact: Marc E Lippman, M.D.       mlippman@med.miami.edu   
Principal Investigator: Marc E Lippman, M.D.         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Melody Cobleigh, M.D.       melody_cobleigh@rush.edu   
Principal Investigator: Melody Cobleigh, M.D.         
United States, Massachusetts
Dana-Farber Cancer Institute, Harvard University Recruiting
Boston, Massachusetts, United States, 02215
Contact: Rachel Freedman, M.D.    617-632-6876    rachel_freedman@dfci.harvard.edu   
Principal Investigator: Rachel Freedman, M.D.         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Daniel Hayes, M.D.    734-615-6725    hayesdf@umich.edu   
Principal Investigator: Daniel Hayes, M.D.         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Matthew P. Goetz, M.D.    507-293-1605    Goetz.Matthew@mayo.edu   
Principal Investigator: Matthew P. Goetz, M.D.         
United States, Missouri
St. Luke's Cancer Institute Recruiting
Kansas City, Missouri, United States, 64111
Contact: Timothy J Pluard, M.D.    816-932-6005    tpluard@saint-lukes.org   
Principal Investigator: Timothy J Pluard, M.D.         
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Cynthia Ma, M.D., Ph.D.    314-362-9383    cma@dom.wustl.edu   
Sub-Investigator: Ron Bose, M.D., Ph.D.         
Sub-Investigator: Michael Naughton, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sub-Investigator: Foluso Ademuyiwa, M.D.         
Sub-Investigator: Hussam Al-Kateb, Ph.D., FACMG         
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Shanu Modi, M.D.    646-888-4554    modis@mskcc.org   
Principal Investigator: Shanu Modi, M.D.         
United States, North Carolina
University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center) Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Carey Anders, M.D.    919-966-4431    canders@med.unc.edu   
Sub-Investigator: Charles Perou, Ph.D.         
Principal Investigator: Carey Anders, M.D.         
Sub-Investigator: E. Claire Dees, M.D.         
Sub-Investigator: Francis A. Collichio, M.D.         
Sub-Investigator: Trevor A. Jolly, M.D.         
Sub-Investigator: Katherine Reeder-Hays, M.D.         
Duke Cancer Institute at Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Kimberly Blackwell, M.D.    919-681-0874    kimberly.blackwell@duke.edu   
Principal Investigator: Kimberly Blackwell, M.D.         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Matthew JC Ellis, MB, Ph.D.       matthew.ellis@bcm.edu   
Sub-Investigator: Matthew JC Ellis, MB, Ph.D.         
Principal Investigator: Polly Ann Niravath, M.D.         
Canada, British Columbia
BC Cancer Agency Not yet recruiting
Vancouver, British Columbia, Canada, V5Z 1L3
Contact: Karen Gelmon, M.D.       kgelmon@bccancer.bc.ca   
Principal Investigator: Karen Gelmon, M.D.         
Canada, Ontario
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Philippe Bedard, M.D.    416-946-4534    philippe.bedard@uhn.ca   
Principal Investigator: Philippe Bedard, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Cynthia Ma, M.D., Ph.D Washington University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01670877     History of Changes
Other Study ID Numbers: 201209135
Study First Received: August 17, 2012
Last Updated: July 2, 2015
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Estradiol
Fulvestrant
Trastuzumab
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Estrogen Antagonists
Estrogen Receptor Modulators
Estrogens
Hormone Antagonists
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on August 03, 2015