Clinical Trials /

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

NCT01670877

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Neratinib</span> +/- <span class="go-doc-concept go-doc-intervention">Fulvestrant</span> in Metastatic <span class="go-doc-concept go-doc-biomarker">HER2</span> Non-<span class="go-doc-concept go-doc-keyword">amplified</span> But <span class="go-doc-concept go-doc-biomarker">HER2</span> <span class="go-doc-concept go-doc-keyword">Mutant</span> <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
  • Official Title: A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT01670877

    ORG ID: 201209135

    Trial Conditions

    Breast Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    Neratinib PF-05208767 Part I: met HER2- BC w/HER2 mutations, Part II: met HER2- ER- BC w/HER2 mutations, Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-naive, Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-tx
    Fulvestrant Faslodex Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-naive, Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-tx
    Trastuzumab Herceptin Part I: met HER2- BC w/HER2 mutations, Part II: met HER2- ER- BC w/HER2 mutations, Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-naive, Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-tx

    Trial 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.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Part I: met HER2- BC w/HER2 mutations Experimental 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. Neratinib, Trastuzumab
    Part II: met HER2- ER- BC w/HER2 mutations Experimental 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. Neratinib, Trastuzumab
    Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-naive Experimental 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. Neratinib, Fulvestrant, Trastuzumab
    Part II: met HER2- ER+ BC w/HER2 mutations, fulvestrant-tx Experimental 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. Neratinib, Fulvestrant, Trastuzumab

    Eligibility 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Part I only: Overall clinical activity (CR+PR+SD6months) of neratinib alone in patients with metastatic HER2- breast cancer that carry HER2 mutation

    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

    Part II fulvestrant-treated ER+ cohort only: Overall clinical activity (CR+PR+SD6months) of neratinib + fulvestrant in patients with metastatic HER2- ER+ fulvestrant-treated breast cancer that carry HER2 mutation

    Part II ER-cohort only: Overall clinical activity (CR+PR+SD6months) of neratinib in patients with metastatic HER2-, ER- breast cancer that carry HER2 mutation

    Secondary Outcome Measures

    PFS of patients with HER2- but HER2 mutated breast cancer treated with neratinib alone

    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.

    PFS of patients with HER2- ER+ HER2 mutated breast cancer who are fulvestrant-naive treated with neratinib + fulvestrant

    PFS of patients with HER2- ER+ HER2 mutated breast cancer who are fulvestrant-treated treated with neratinib + fulvestrant

    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

    Trial Keywords