Clinical Trials /

Galunisertib and Paclitaxel in Treating Patients With Metastatic Androgen Receptor Negative (AR-) Triple Negative Breast Cancer

NCT02672475

Description:

This phase I trial studies the side effects and best dose of Galunisertib when given together with paclitaxel in treating patients with androgen receptor negative or triple negative breast cancer that has spread to other places in the body. Some tumors need growth factors, which are made by the body's white blood cells, to keep growing. Galunisertib may interfere with growth factors and help cause tumor cells to die. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving Galunisertib together with paclitaxel may kill more tumor cells.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Galunisertib and <span class="go-doc-concept go-doc-intervention">Paclitaxel</span> in Treating Patients With Metastatic Androgen Receptor Negative (<span class="go-doc-concept go-doc-biomarker">AR</span>-) <span class="go-doc-concept go-doc-keyword">Triple Negative</span> Breast Cancer

Title

  • Brief Title: Galunisertib and Paclitaxel in Treating Patients With Metastatic Androgen Receptor Negative (AR-) Triple Negative Breast Cancer
  • Official Title: A Phase Ib Trial of LY2157299 (TGFR1 Kinase Inhibitor) With Paclitaxel in Patients With Triple Negative Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02672475

    ORG ID: VICC BRE 1557

    NCI ID: NCI-2015-02055

    Trial Conditions

    Estrogen Receptor Negative

    HER2/Neu Negative

    Progesterone Receptor Negative

    Recurrent Breast Carcinoma

    Stage IV Breast Cancer

    Triple-Negative Breast Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Galunisertib LY-2157299, LY2157299 Treatment (paclitaxel, galunisertib)
    Paclitaxel Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat Treatment (paclitaxel, galunisertib)

    Trial Purpose

    This phase I trial studies the side effects and best dose of galunisertib when given
    together with paclitaxel in treating patients with androgen receptor negative or triple
    negative breast cancer that has spread to other places in the body. Some tumors need growth
    factors, which are made by the body's white blood cells, to keep growing. Galunisertib may
    interfere with growth factors and help cause tumor cells to die. Drugs used in chemotherapy,
    such as paclitaxel, work in different ways to stop the growth of tumor cells, either by
    killing the cells, by stopping them from dividing, or by stopping them from spreading.
    Giving glunisertib together with paclitaxel may kill more tumor cells.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To assess the safety and tolerability of paclitaxel when administered with LY2157299
    (galunisertib).

    II. To determine the maximally tolerated dose (MTD) of paclitaxel + LY2157299. III. To
    determine the recommended dose of paclitaxel with LY2157299 for phase II studies.

    SECONDARY OBJECTIVES:

    I. To evaluate the efficacy, as measured by median progression free survival (PFS), of
    paclitaxel + LY2157299 in patients with metastatic androgen receptor negative triple
    negative metastatic breast cancer.

    II. To evaluate the efficacy, as measured by clinical benefit rate (CBR), of paclitaxel +
    LY2157299 in patients with androgen receptor negative metastatic triple negative metastatic
    breast cancer.

    III. To determine the overall response rate (ORR) of paclitaxel + LY2157299 in patients with
    androgen receptor negative metastatic triple negative breast cancer.

    TERTIARY OBJECTIVES:

    I. To interrogate the entire coding sequence of 236 cancer-related genes (3,769 exons) plus
    47 introns from 19 genes often rearranged or altered in cancer.

    II. Nanostring analysis of established gene expression signatures. III. Determine breast
    cancer subtype by PAM50 testing and correlate with response.

    IV. To measure changes in circulating plasma transforming growth factor beta 1 (TGFB1),
    interleukin (IL)-6, and cluster of differentiation 34 (CD34) positive (+), peripheral blood
    mononuclear cells (PBMCs) induced by LY2157299.

    OUTLINE: This is a dose-escalation study of galunisertib.

    Patients receive paclitaxel intravenously (IV) on days 1, 8, and 15. Patients also receive
    galunisertib orally (PO) twice daily (BID) on days 1-14. Courses repeat every 28 days in the
    absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up periodically.

    Trial Arms

    Name Type Description Interventions
    Treatment (paclitaxel, galunisertib) Experimental Patients receive paclitaxel IV on days 1, 8, and 15. Patients also receive galunisertib PO BID on days 1-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Galunisertib, Paclitaxel

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must provide informed written consent

    - Eastern Cooperative Oncology Group (ECOG) performance status 0-1

    - Clinical stage IV invasive mammary carcinoma that is estrogen receptor (ER),
    progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) negative
    (triple negative) previously documented by conventional methods (immunohistochemistry
    [ISH], fluorescence in situ hybridization [FISH]); ER negative is defined as
    expression of ER in =< 5% cells, PR negative is defined as expression of PR in =< 5%
    cells, HER2 negative (acceptable methods of HER2 analysis include IHC [0, 1+],
    fluorescence in situ hybridization [FISH] with HER2/chromosome 17 centromere [CEN-17]
    ratio < 2, and/or chromogenic in situ hybridization [CISH] with HER2/CEN-17 ratio <
    2), as previously documented by histological analysis

    - Androgen receptor negativity, defined as =< 10% of tumor cell nuclei with
    immunoreactivity for androgen receptor (AR) on central review at Vanderbilt

    - Measurable disease, defined as at least one lesion that can be accurately measured in
    at least one dimension by Response Evaluation Criteria in Solid Tumors (RECIST)
    criteria 1.1

    - Patients must have available tissue (archived formalin-fixed paraffin embedded blocks
    [FFPB] or fresh frozen tissue from original diagnosis or metastatic setting) for
    correlative studies; patients will not be able to start study drugs without tumor
    tissue availability; patients without available tumor tissue can still participate if
    willing to have a fresh biopsy of a metastatic lesion that is deemed to be medically
    safe (except for bone metastases)

    - Any number of prior therapies as long as patients have adequate performance status
    and meet all other eligibility criteria

    - Absolute neutrophil count (ANC) >= 1000/mm^3

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

    - Hemoglobin >= 9 g/dL

    - Creatinine =< 1.5 X upper limits of normal

    - International normalized ratio (INR) =< 2

    - Total serum bilirubin =< 1.5 x upper limit of normal (ULN) unless attributable to
    Gilbert's syndrome

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (or
    =< 4.0 x ULN if hepatic metastases are present)

    - Patients must be able to swallow and retain oral medication

    - Patients who have received prior radiotherapy must have recovered from toxicity
    induced by this treatment

    - Pre-menopausal patients must have a negative pregnancy test and agree to use birth
    control methods while participating in the study; women of childbearing age and their
    male counterparts should use a barrier method of contraception during and for 3
    months following protocol therapy

    - Patients must complete all screening assessments as outlined in the protocol

    Exclusion Criteria:

    - Locally recurrent resectable breast cancer

    - Pregnant or lactating women

    - Patients with untreated or symptomatic metastatic central nervous system (CNS)
    disease; however patients with CNS involvement may participate if:

    - Clinically stable with respect to the CNS tumor at the time of screening and > 2
    weeks from prior therapy completion (including radiation and/or surgery) to the
    start of study treatment

    - Not on steroid therapy

    - Not receiving enzyme inducing anti-epileptic medications that were started for
    brain metastases (these include carbamazepine, phenytoin, phenobarbital,
    primidone, oxcarbazepine, topiramate, and vigabatrin)

    - Patient has a history of another malignancy within 2 years prior to starting study
    treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in
    situ of the cervix

    - Patient who has not recovered to grade 1 or better (except alopecia) from related
    side effects of any prior antineoplastic therapy

    - Patient who has had systemic therapy within 2 weeks (6 weeks for nitrosoureas or
    mitomycin C) prior to study entry

    - Patient who has received radiotherapy =< 2 weeks prior to starting study drugs, who
    has not recovered from side effects of such therapy to baseline or grade =< 1

    - Patient who has undergone major surgery =< 4 weeks prior to starting study treatment
    or who has not recovered from side effects of such procedure

    - Patient has a clinically significant cardiac disease or impaired cardiac function,
    such as:

    - The presence of cardiac disease, including a myocardial infarction within 6
    months prior to study entry, unstable angina pectoris, New York Heart
    Association class III/IV congestive heart failure, or uncontrolled hypertension

    - Documented major electrocardiogram (ECG) abnormalities (not responding to
    medical treatments)

    - Major abnormalities documented by echocardiography (ECHO) with Doppler (for
    example, moderate or severe heart valve function defect and/or left ventricular
    [LV] ejection fraction < 50%, evaluation based on the institutional lower limit
    of normal)

    - Predisposing conditions that are consistent with development of aneurysms of the
    ascending aorta or aortic stress (for example, family history of aneurysms,
    Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels
    of the heart documented by computed tomography [CT] scan/magnetic resonance
    imaging [MRI] with contrast)

    - Patient who has any severe and/or uncontrolled medical conditions such as:

    - Active or uncontrolled severe infection,

    - Liver disease such as cirrhosis, decompensated liver disease, and chronic
    hepatitis (i.e. quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid
    [DNA]) and/or positive hepatitis B virus surface antigen [HbsAg], quantifiable
    hepatitis C virus [HCV]-ribonucleic acid [RNA])

    - Known severely impaired lung function (spirometry and diffusing capacity of the
    lung for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation
    88% or less at rest on room air)

    - Active bleeding diathesis

    - Uncontrolled arterial hypertension defined by blood pressure > 170/100 mm Hg at
    rest (average of 3 consecutive readings 5 min apart)

    - Psychiatric illness/social situations that would compromise patient safety or
    limit compliance with study requirements including maintenance of a
    compliance/pill diary

    - Chronic treatment with corticosteroids or other immunosuppressive agents

    - Patient with impaired gastrointestinal (GI) function or GI disease that may
    significantly alter the absorption of oral drug (e.g. ulcerative disease,
    uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
    resection)

    - Patient with known positive serology for human immunodeficiency virus (HIV)

    - Patient who does not apply highly effective contraception during the study and
    through the duration as defined below after the final dose of study treatment:

    - Sexually active males should use a condom during intercourse while taking drug
    and for 8 weeks after the final dose of study treatment and should not father a
    child in this period; a condom is required to be used also by vasectomized men
    in order to prevent delivery of the drug via seminal fluid

    - Women of child-bearing potential, defined as all women physiologically capable
    of becoming pregnant, unless they are using highly effective methods of
    contraception during dosing and for 3 months following the discontinuation of
    study treatment; highly effective contraception methods include:

    - Total abstinence (when this is in line with the preferred and usual
    lifestyle of the subject; periodic abstinence [e.g., calendar, ovulation,
    symptothermal, post-ovulation methods]) and withdrawal are not acceptable
    methods of contraception

    - Female sterilization (have had surgical bilateral oophorectomy with or
    without hysterectomy) or tubal ligation at least six weeks before taking
    study treatment; in case of oophorectomy alone, only when the reproductive
    status of the woman has been confirmed by follow up hormone level
    assessment

    - Male sterilization (at least 6 months prior to screening); for female
    subjects on the study the vasectomized male partner should be the sole
    partner for that subject

    - Combination of the following (a+b):

    - a. Placement of an intrauterine device (IUD) or intrauterine system
    (IUS)

    - b. Barrier methods of contraception: condom or occlusive cap
    (diaphragm or cervical/vault caps) with spermicidal
    foam/gel/film/cream/vaginal suppository

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of adverse events

    Maximum Tolerated Dose (MTD) of paclitaxel + LY2157299

    Secondary Outcome Measures

    Overall Response Rate (ORR)

    Progression-Free Survival (PFS)

    Trial Keywords