Clinical Trials /

Onalespib and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer

NCT02474173

Description:

This phase Ib trial studies the side effects and best dose onalespib when given together with paclitaxel in treating patients with triple negative breast cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Onalespib works by blocking proper processing of proteins that are important for cancer growth. This results in inability of these proteins to work properly. Paclitaxel kills breast cancer cells by interfering with their ability to divide. Giving onalespib together with paclitaxel may be better than giving either one alone in treating patients with breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

HSP90 Inhibitor AT13387 and <span class="go-doc-concept go-doc-intervention">Paclitaxel</span> in Treating Patients With Advanced <span class="go-doc-concept go-doc-keyword">Triple Negative</span> <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: HSP90 Inhibitor AT13387 and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer
  • Official Title: Phase 1b Study of HSP90 Inhibitor, AT13387 in Combination With Paclitaxel in Patients With Advanced, Triple Negative Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02474173

    ORG ID: NCI-2015-00866

    NCI ID: NCI-2015-00866

    Trial Conditions

    Estrogen Receptor Negative

    HER2/Neu Negative

    Progesterone Receptor Negative

    Recurrent Breast Carcinoma

    Stage IIIA Breast Cancer

    Stage IIIB Breast Cancer

    Stage IIIC Breast Cancer

    Stage IV Breast Cancer

    Triple-Negative Breast Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Hsp90 Inhibitor AT13387 AT13387 Treatment (HSP90 inhibitor AT13887, paclitaxel)
    Paclitaxel Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat Treatment (HSP90 inhibitor AT13887, paclitaxel)

    Trial Purpose

    This phase Ib trial studies the side effects and best dose of heat shock protein (HSP)90
    inhibitor AT13387 when given together with paclitaxel in treating patients with triple
    negative breast cancer that has spread to other places in the body and usually cannot be
    cured or controlled with treatment (advanced). HSP90 inhibitor AT13387 works by blocking
    proper processing of proteins that are important for cancer growth. This results in
    inability of these proteins to work properly. Paclitaxel kills breast cancer cells by
    interfering with their ability to divide. Giving HSP90 inhibitor AT13387 together with
    paclitaxel may be better in treating patients with breast cancer.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the recommended phase 2 dose (RP2D) of AT13387 (HSP90 inhibitor AT13387) in
    combination with paclitaxel in patients with advanced triple negative breast cancer (TNBC).

    II. To determine the toxicity profile (based on Common Terminology Criteria for Adverse
    Events [CTCAE] version [v.]4.03) of the combination of AT13387 in combination with
    paclitaxel in patients with advanced TNBC.

    SECONDARY OBJECTIVES:

    I. To determine the effect of AT13387 on pharmacokinetics of paclitaxel in the study patient
    population.

    II. To determine the effect of paclitaxel on pharmacokinetics of AT13387 in the study
    patient population.

    III. To observe anti-tumor activity by determining the overall response rate (partial
    response + complete response), response duration and progression-free survival.

    TERTIARY OBJECTIVES:

    I. To explore the association between response and molecular subtype of triple negative
    breast cancer (basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem
    cell-like and androgen luminal type).

    OUTLINE: This is a dose-escalation study of HSP90 inhibitor AT13387.

    SAFETY RUN-IN: Patients receive HSP90 inhibitor AT13387 intravenously (IV) over 1 hour on
    day -7.

    TREATMENT: Patients receive paclitaxel IV over 60 minutes on day 1 of course 1 only.
    Patients receive HSP90 inhibitor AT13387 IV over 1 hour beginning on day 8 of course 1 and
    on days 1, 8, and 15 of subsequent courses. Courses repeat every 28 days in the absence of
    disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up for 8 weeks.

    Trial Arms

    Name Type Description Interventions
    Treatment (HSP90 inhibitor AT13887, paclitaxel) Experimental SAFETY RUN-IN: Patients receive HSP90 inhibitor AT13387 IV over 1 hour on day -7. TREATMENT: Patients receive paclitaxel IV over 60 minutes on day 1 of course 1 only. Patients receive HSP90 inhibitor AT13387 IV over 1 hour beginning on day 8 of course 1 and on days 1, 8, and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Hsp90 Inhibitor AT13387, Paclitaxel

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histologically confirmed measurable or unmeasurable advanced or
    metastatic breast cancer for which standard curative measures do not exist or are no
    longer effective

    - Measurable disease is defined as at least one lesion that can be accurately
    measured in at least one dimension (longest diameter to be recorded for
    non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
    conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography
    (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

    - Primary and/or metastatic breast tumor must be negative for over-expression of
    estrogen and progesterone receptors; patients with weak estrogen receptor and/or
    expression (< 10% on immunohistochemistry [IHC]) will be eligible

    - Primary and/or metastatic breast tumor must be negative for human epidermal growth
    factor receptor (HER-2/neu) over-expression based on immunohistochemistry (IHC) (0 or
    1+, 2+ if fluorescence in-situ hybridization [FISH] test is negative) or FISH
    (HER2/copy number of centromere of chromosome 17 [CEP17] ratio < 2.0 or < 4 Her-2/neu
    signals per nucleus)

    - Any number of prior therapies for metastatic breast cancer is allowed; patients with
    weakly estrogen receptor positive breast cancer who received any number of endocrine
    agents for metastatic breast cancer will also be eligible

    - Prior taxane is allowed (as long as the patient is not experiencing grade > 1
    neuropathy and had no history of disease progression on a taxane therapy within 6
    months prior to study enrollment)

    - Patients who consent to pre-treatment tumor biopsy must have at least 1 tumor site
    that is amenable to a biopsy

    - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

    - Life expectancy of greater than 12 weeks

    - Leukocytes >= 2,000/uL

    - Absolute neutrophil count >= 1,500/uL

    - Platelets >= 100,000/uL

    - Total bilirubin within normal institutional limits

    - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
    [SGOT])/alanine aninotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
    =< 2.5 institutional upper limit of normal (except for patients with liver
    metastases in whom AST/ALT can be < 5 x institutional upper limit of normal)

    - Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min
    for patients with creatinine levels above institutional normal

    - Left ventricular ejection fraction of > 50% on baseline echocardiography or
    multi-gated acquisition (MUGA) scan

    - Corrected QT interval (QTc) of < 480 milliseconds

    - Female subjects with child bearing potential must have a negative pregnancy test at
    screening; child bearing potential is defined as sexually active patients with menses
    less than 1 year prior to enrollment, < 65 years of age, have no history of
    oophorectomy or hysterectomy

    - Women of child-bearing potential and men must agree to use adequate contraception
    prior to study entry, for the duration of study participation and 4 months after
    completion of study treatment administration; adequate contraception includes methods
    such as oral contraceptives, double barrier method (condom plus spermicide or
    diaphragm), or abstaining from sexual intercourse; should a woman become pregnant or
    suspect she is pregnant while she or her partner is participating in this study, she
    should inform her treating physician immediately

    - Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:

    - Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
    nitrosoureas or mitomycin C) prior to entering the study

    - Patients who are receiving any other investigational agents within 4 weeks or 5
    half-lives (whichever is later) prior to the first dose of the study regimen

    - Prior radiation therapy within 2 weeks prior to the first dose of the study regimen

    - Patients in whom prior treatment related toxicities have not recovered to grade 1 or
    less (except for alopecia)

    - Recent initiation of bone modifying therapy with a bisphosphonate or denosumab unless
    it has been started more than 2 weeks prior to the first dose of the study regimen

    - Prior therapy with AT13387 or another HSP90 inhibitor

    - Patients with known brain metastases should be excluded from this clinical trial;
    however, patients with previously treated and stable brain metastases are eligible as
    long as they are no longer requiring steroids, completed radiation therapy more than
    2 weeks prior to the first dose of study regimen and have no seizures or worsening
    neurologic symptoms

    - History of grade 3-4 immediate hypersensitivity reaction to paclitaxel

    - History of clinically significant allergic reactions attributed to compounds of
    similar chemical or biologic composition to AT13387 or paclitaxel

    - The use of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and
    cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors/inducers
    while not prohibited in this study, is discouraged whenever feasible; concurrent use
    of strong CYP2C8 and CYP3A4 inhibitors/inducers should be documented and the
    principal investigator (PI) of the study shall be notified prior to dosing; as part
    of the enrollment/informed consent procedures, the patients will be counseled on the
    risk of interactions with other agents, and what to do if new medications need to be
    prescribed or if the patient is considering a new over-the-counter medicine or herbal
    product

    - 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

    - Pregnant women are excluded from this study; breastfeeding should be discontinued if
    the mother is treated with AT13387 and paclitaxel

    - Patients who are human immunodeficiency virus (HIV) positive will be excluded from
    the study

    - Inability to understand and sign informed consent

    - Any other medical or psychiatric condition that in the opinion of the investigator
    would make the study therapy unsafe for the patient

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    R2PD or maximum tolerated dose of HSP90 inhibitor AT13387 in combination with paclitaxel defined as the dose level at which no more than 1 of 3-6 patients experiences a dose limiting toxicity

    Toxicity profile of HSP90 inhibitor AT13387 in combination with paclitaxel, based on the CTCAE v.4.03

    Secondary Outcome Measures

    Molecular subtype of triple negative breast cancer (basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem cell-like and androgen luminal type)

    Overall response rate (partial response [PR]+ complete response [CR]) based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

    Pharmacokinetic (PK) parameters of HSP90 inhibitor AT13387

    PK parameters of paclitaxel

    Progression-free survival

    Response duration, based on RECIST 1.1 criteria

    Trial Keywords