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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2016 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: April 14, 2016
Last verified: April 2016

August 17, 2012
April 14, 2016
December 2012
December 2018   (final data collection date for primary outcome measure)
  • 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.
Overall clinical benefit (CR+PR+SD≥6months) of neratinib 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. Eight percent confidence interval (CI) will be calculated.
Complete list of historical versions of study NCT01670877 on ClinicalTrials.gov Archive Site
  • 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
  • PFS of patients treated with neratinib [ 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: Baseline ] [ Designated as safety issue: No ]
    Assessed using RECIST guidelines version 1.1
  • Compare the occurrence of HER2 mutation in paired primary and metastatic sites. [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
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.
Not Provided
Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Breast Neoplasms
  • Drug: Neratinib
    Other Name: PF-05208767
  • Drug: Fulvestrant
    Other Name: Faslodex
  • Drug: Trastuzumab
    Other Name: Herceptin
  • 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.
    Interventions:
    • Drug: Neratinib
    • Drug: Trastuzumab
  • 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.
    Interventions:
    • Drug: Neratinib
    • Drug: Trastuzumab
  • 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.
    Interventions:
    • Drug: Neratinib
    • Drug: Fulvestrant
    • Drug: Trastuzumab
  • 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.
    Interventions:
    • Drug: Neratinib
    • Drug: Fulvestrant
    • Drug: Trastuzumab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
70
November 2020
December 2018   (final data collection date for primary outcome measure)

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.
Both
18 Years and older   (Adult, Senior)
No
Contact: Cynthia Ma, M.D., Ph.D. 314-362-9383 cma@dom.wustl.edu
United States,   Canada
 
NCT01670877
201209135
No
Not Provided
Not Provided
Washington University School of Medicine
Washington University School of Medicine
Not Provided
Principal Investigator: Cynthia Ma, M.D., Ph.D Washington University School of Medicine
Washington University School of Medicine
April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP