Clinical Trials /

Phase II Talazoparib in BRCA1 +BRCA2 Wild-Type &Triple-Neg /HER2-Negative Breast Cancer /SolidTumors

NCT02401347

Description:

The aim of this single-arm phase 2 clinical trial is to evaluate the anti-cancer activity of Talazoparib (also known as BMN 673) in patients with advanced breast cancer with specific genetic or tumor genomic alterations. Patients with either triple-negative or HER2-negative breast cancer are eligible.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Talazoparib</span> Beyond BRCA (TBB) Trial

Title

  • Brief Title: Talazoparib Beyond BRCA (TBB) Trial
  • Official Title: A Phase II Clinical Trial of BMN 673 in BRCA1 and BRCA2 Wild-Type Patients With (i) Advanced Triple-Negative Breast Cancer and Homologous Recombination Deficiency as Assessed by the HRD Assay, and (ii) Advanced HER2-Negative Breast Cancer With Either a Germline or Somatic Mutation in Homologous Recombination Pathway Genes
  • Clinical Trial IDs

    NCT ID: NCT02401347

    ORG ID: BRS0050

    NCI ID: NCI-2015-00036

    Trial Conditions

    Advanced Breast Cancer

    HER2/Neu Negative

    Triple-Negative Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Talazoparib Tosylate BMN 673 Cohort A, Cohort B

    Trial Purpose

    The aim of this single-arm phase II clinical trial is to evaluate the anti-cancer activity
    of Talazoparib (also known as BMN 673) in patients with advanced breast cancer with specific
    genetic or tumor genomic alterations. Patients with either triple-negative or HER2-negative
    breast cancer are eligible.

    Detailed Description

    Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that potently inhibits the
    PARP enzyme and effectively traps PARP on DNA. Talazoparib has shown promising single-agent
    anti-tumor efficacy in several BRCA1/2 mutation-associated advanced cancers. The efficacy of
    PARP inhibition in BRCA1/2 wild-type TNBC with homologous recombination (HR) defects and in
    breast tumors with mutations in other non-BRCA1/2 HR pathway genes is currently unknown.

    This Phase 2 trial (TBB) explores the activity of single agent talazoparib in BRCA1/2
    wild-type BC patients using an optimal Simon two-stage design. Eligible subjects will be
    assigned to one of two parallel cohorts: 1) Cohort A: Subjects (n=29) with advanced TNBC
    with underlying HR defects as assessed by the HRD assay and, 2) Cohort B: Subjects (n=29)
    with advanced HER2-negative BC with a somatic or germline mutation in a non-BRCA1/2 HR
    pathway gene. Gene mutations of interest are: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1,
    RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes (FANCA,
    FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL).

    Trial Arms

    Name Type Description Interventions
    Cohort A Experimental Patients with advanced triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD) based on the Myriad HRD Assay. Patients receive Talazoparib 1 mg by mouth daily. Talazoparib Tosylate
    Cohort B Experimental Patients with advanced HER2-negative breast cancer with a deleterious hereditary or cancer somatic mutation in one of the following genes: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes. Patients receive Talazoparib 1 mg by mouth daily. Talazoparib Tosylate

    Eligibility Criteria

    Inclusion Criteria:

    - No deleterious germline BRCA1 or BRCA2 mutation based on full sequencing and
    comprehensive rearrangement testing at an external reference laboratory (Myriad
    Genetics); patients with variants of unknown significance will be eligible

    - Patients must have measurable disease per Response Evaluation Criteria In Solid
    Tumors (RECIST) 1.1

    - Must have progressed on at least 1 prior chemotherapy regimen for the treatment of
    advanced breast cancer; there is no upper limit on the number of prior therapies

    - An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

    - An estimated life expectancy of at least 16 weeks

    - Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
    upper limit of normal (ULN); if liver function abnormalities are due to hepatic
    metastasis, then AST and ALT =< 5 x ULN

    - Total serum bilirubin =< 1.5 x ULN (=< 3 x ULN for Gilbert's syndrome)

    - Calculated creatinine clearance >= 30 mL/min or serum creatinine =< 1.5 mg/dl

    - Hemoglobin >= 9.0 g/dL with last transfusion at least 14 days before day 1 of study
    drug

    - Absolute neutrophil count (ANC) >= 1500/mm^3

    - Platelet count >= 100,000/mm^3

    - Able to take oral medications

    - Willing and able to provide written, signed informed consent after the nature of the
    study has been explained, and prior to any research-related procedures

    - Sexually active patients of childbearing potential must be willing to use an
    acceptable method of contraception such as an intrauterine device or double barrier
    contraception during treatment and for 30 days after the last dose of study drug

    - Females of childbearing potential must have a negative serum pregnancy test at
    screening and be willing to have additional serum pregnancy tests during the study;
    females considered not of childbearing potential include those who have been in
    menopause at least 2 years, or had tubal ligation at least 1 year prior to screening,
    or who have had total hysterectomy

    - Willing and able to comply with all study procedures

    - COHORT A SPECIFIC ELIGIBILITY CRITERIA:

    - Histologically confirmed metastatic or recurrent triple-negative breast cancer
    (defined as estrogen receptor =< 5%, progesterone receptor =< 5%, HER2-negative
    via immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH])

    - An HRD score >= 42 on the Myriad HRD Assay as assessed on a tumor biopsy sample;
    in the case that obtaining an adequate metastatic tumor biopsy is not possible,
    we will assess the HRD score from the primary breast tumor

    - COHORT B SPECIFIC ELIGIBILITY CRITERIA:

    - Histologically confirmed metastatic or recurrent HER2-negative (via IHC or FISH)
    breast cancer

    - Deleterious germline or somatic mutation implicated in the homologous
    recombination (HR) pathway, excluding BRCA1 or BRCA2, based on germline
    multiplex gene testing or direct tumor next generation DNA sequencing. Genes of
    interest include: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, Rad51c,
    Rad51d, MRE11, ATR, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, plus other
    HR-related genes at the discretion of the primary investigators.

    Exclusion Criteria:

    - Any patient with a deleterious mutation in BRCA1 or BRCA2

    - Prior treatment with a platinum agent (i.e. cisplatin or carboplatin)

    - Prior treatment with a PARP inhibitor

    - Non-measurable disease only

    - Pregnant or nursing patients

    - Any anti-cancer therapy within the past 21 days of the first day of treatment

    - Brain or central nervous system (CNS) metastases that are progressive or symptomatic,
    have not been previously resected or irradiated, or are the only site of measurable
    disease

    - Other malignancy that is either active or for which patient has received treatment in
    the last five years excluding non-melanoma skin cancer and carcinoma in situ of the
    cervix

    - Radiation therapy in the last 14 days

    - Known to be human immunodeficiency virus positive

    - Known active hepatitis C virus, or known active hepatitis B virus

    - Use of any investigational product (IP) or investigational medical device within 28
    days before day 1 of study drug

    - Major surgery requiring a prolonged hospitalization or recovery within 21 days before
    day 1 of study drug

    - Concurrent disease or condition that would interfere with study participation or
    safety, such as any of the following:

    - Active, clinically significant infection either grade > 2 by National Cancer
    Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version
    4.0 or requiring the use of parenteral anti-microbial agents within 7 days
    before day 1 of study drug

    - Clinically significant bleeding diathesis or coagulopathy, including known
    platelet function disorders

    - Known hypersensitivity to any of the components of BMN 673

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Objective response rate defined as complete response or partial response per RECIST 1.1

    Secondary Outcome Measures

    Clinical benefit rate >= 24 weeks, defined as complete response, partial response or stable disease as assessed after at least 24 weeks per RECIST 1.1

    Progression-free survival

    Incidence of adverse events, graded according to CTCAE v4.0

    Trial Keywords

    PALB2 mutation

    BRIP1 mutation

    BARD1 mutation

    Rad51c mutation

    PTEN mutation

    CHEK2 mutation

    ATM mutation

    NBN mutation

    Rad51d mutation

    Rad50 mutation

    MRE11 mutation

    FANC mutation

    HRD assay score

    ATR mutation