Clinical Trials /

STAR Cape+BKM120 MBC With Brain Met

NCT02000882

Description:

This is a study to determine the safety and effectiveness of BKM120 plus capecitabine in breast cancer patients with brain metastases. Both capecitabine and BMK120 have previously shown activity in patients with breast cancer. Like capecitabine, BMK120 is also effective in crossing the blood brain barrier making it a preferred candidate for its evaluation in patients with metastatic breast cancer (MBC).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Capecitabine</span> + <span class="go-doc-concept go-doc-intervention">BKM120</span> TNBC BC Brain Met

Title

  • Brief Title: Capecitabine + BKM120 TNBC BC Brain Met
  • Official Title: Phase II Multicenter Single-arm Study of BKM120 Plus Capecitabine for Triple Negative Breast Cancer (TNBC) Patients With Brain Metastases
  • Clinical Trial IDs

    NCT ID: NCT02000882

    ORG ID: 11025

    NCI ID: CBKM120ZUS39T

    Trial Conditions

    Triple Negative Breast Cancer

    Brain Metastases

    Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    BKM120 buparlisib BKM120 plus Capecitabine
    capecitabine Xeloda BKM120 plus Capecitabine

    Trial Purpose

    This is a study to determine the safety and effectiveness of BKM120 plus capecitabine in
    triple-negative (ER-, PgR-, HER2-) breast cancer (TNBC) patients with measurable brain
    metastases.

    Both capecitabine and BMK120 have previously shown activity in patients with triple-negative
    breast cancer. Like capecitabine, BMK120 is also effective in crossing the blood brain
    barrier making it a preferred candidate for its evaluation in patients with TNBC.

    Detailed Description

    This is a Phase 2, multicenter, single-arm study to determine the safety and efficacy of
    BKM120 plus capecitabine in triple-negative (ER-, PgR-, HER2-) breast cancer patients with
    measurable brain metastases. Approximately 40 patients will be included, who have previously
    received 3 prior systemic therapies for their disease.

    The Graded Prognostic Assessment (GPA) is a recently developed, validated prognostic score
    for patients with brain metastases. A recent study utilizing GPA in patients with TNBC and
    brain metastases showed that these patients had a median survival time of 6.4 months. The
    Graded Prognostic Assessment will be utilized to evaluate efficacy in this proposed clinical
    study.

    Capecitabine is a prodrug which is enzymatically converted to 5-fluorouracil in its tumor
    target where it inhibits DNA synthesis and slows tumor growth. It is currently FDA approved
    for both colorectal and breast cancer. BMK120 is a pan phosphatidylinositol-3-kinase
    inhibitor being developed under IND# 102,823 by Novartis Corporation. As of September 2012
    over 600 patients had been enrolled in fourteen separate Novartis sponsored monotherapy or
    combination therapy clinical studies of BMK120.

    Patients with triple negative breast cancer have an increased susceptibility to the
    development of brain metastases. In one clinical study 46% of TNBC patients were found to
    have CNS metastases at some point before death. Because currently available targeted
    therapies such as endocrine or HER-2 targeted agents are ineffective against TNBC, current
    treatment options are generally limited to chemotherapy.

    Phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions
    including cell proliferation, survival, translational regulation of protein synthesis,
    glucose metabolism, cell migration, and angiogenesis. PI3K signaling also serves a central
    role in the pathogenesis of numerous cancers.

    Constitutive activation of PI3K signaling is known to be a critical step in mediating the
    transforming potential of oncogenes and tumor suppressors in many tumor types. Resistance to
    a variety of therapeutic interventions, including hormonal therapy, anti-HER2 therapies and
    chemotherapy (as is the case for TNBC patients) can also be linked to constitutive
    activation of the PI3K pathway.

    Preliminary data suggest that activation of the PI3K pathway is a predictor of a poor
    prognostic outcome in many cancer types. Thus, as a pan-PI3K inhibitor, BMK120 may provide a
    therapeutic benefit to patients with TNBC. Both capecitabine and BMK120 have previously
    shown activity in patients with TNBC. Like capecitabine, BMK120 is also effective in
    crossing the blood brain barrier making it a preferred candidate for its evaluation in
    patients with TNBC.

    Current clinical experience with BMK120 has shown that its most frequent adverse events
    (AEs) include fatigue, decreased appetite, diarrhea, hyperglycemia, nausea, rash and mood
    alteration disorders. Therefore patients will be closely monitored for fasting plasma
    glucose (FPG) HbA1c, and insulin C-peptide. Patients will also be frequently and routinely
    evaluated for mood disorders and disturbances. The remaining most frequent AEs will be
    detected by regular, frequent monitoring with symptomatic treatment to be provided as
    required.

    Trial Arms

    Name Type Description Interventions
    BKM120 plus Capecitabine Experimental BKM120 will be administered at a dose of 100 mg orally (PO) daily. Capecitabine will be administered at a dose of 1000 mg/m2 orally (PO) twice a day (rounded down to the nearest 500 mg pill) 14 days on and 7 days off. BKM120, capecitabine

    Eligibility Criteria

    Inclusion Criteria:

    1. Age 18 years

    2. Female

    3. Histologically and/or cytologically confirmed diagnosis of inoperable metastatic
    breast cancer

    4. Triple-negative breast cancer, assessed as ER-, PgR-, and HER2-negative by local
    laboratory testing; HER2 negative status (based on most recently analyzed biopsy) is
    defined as IHC status of 0, 1+ or 2+ (if IHC 2+, a negative FISH test is required,
    ie, HER2 FISH ratio < 2.0); ER-negative and PR-negative status is defined as ER and
    PgR <10% nuclei positive by IHC

    5. At least one CNS lesion that can be accurately measured in at least one dimension as
    per RECIST 1.1

    - Prior WBRT is allowed, but clear evidence of CNS progression by MRI is required

    - Prior SRS is allowed, but previous treatment of the measurable target CNS lesion
    with SRS is not permitted

    - Previously untreated brain metastases are allowed

    6. ECOG performance status 2

    7. Adequate bone marrow function as shown by: ANC 1.5 x 109/L, Platelets 100 x
    109/L, Hb >9 g/dL

    8. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use
    for malignant hypercalcemia control is not allowed)

    9. Magnesium the lower limit of normal

    10. Potassium within normal limits for the institution

    11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal
    range (or 3.0 x upper limit of normal (ULN) if liver metastases are present)

    12. Serum bilirubin within normal range (or 1.5 x ULN if liver metastases are present;
    or total bilirubin 3.0 x ULN with direct bilirubin within normal range in patients
    with well documented Gilbert Syndrome)

    13. Serum creatinine 1.5 x ULN or 24-hour clearance 50 mL/min

    14. Serum amylase ULN

    15. Serum lipase ULN

    16. Fasting plasma glucose 120 mg/dL (6.7 mmol/L)

    17. Negative serum pregnancy test within 72 hours before starting study treatment in
    women with childbearing potential

    18. INR 2

    19. Life expectancy > 12 weeks

    20. Available tissue (blocks and/or slides) samples

    21. Patient is able to swallow and retain oral medication

    22. Signed most recent patient informed consent form

    23. Signed Patient Authorization Form

    Exclusion Criteria:

    1. Patient received prior treatment with a P13K inhibitor.

    2. Patient received prior treatment with capecitabine for metastatic disease (prior
    treatment with capecitabine as neoadjuvant or adjuvant therapy is allowed).

    3. Patient with known hypersensitivity to BKM120, capecitabine, or their excipients.

    4. Patient has received more than three lines of chemotherapy for metastatic disease

    - A chemotherapy line in advanced disease is an anticancer regimen(s) that
    contains at least 1 cytotoxic chemotherapy agent and was discontinued due to
    progression. If a cytotoxic chemotherapy regimen was discontinued for a reason
    other than disease progression then this regimen does not count as a "prior line
    of chemotherapy"

    - Adjuvant/neo-adjuvant therapy will be counted as prior line of therapy for
    metastatic/recurrent disease if the patient had a progression/recurrence within
    6 months after completion of the therapy (12 months for taxane-based therapy)

    - Endocrine or biologic treatments, without a cytotoxic agent, are not counted as
    a line of therapy

    5. Patient has evidence of impending herniation on baseline brain imaging.

    6. Patient has evidence of diffuse leptomeningeal disease on brain MRI or by previously
    documented CSF.

    7. Patients has acute or chronic liver, renal disease or pancreatitis (liver metastases
    are allowed)

    8. Patients has a mood disorder as judged by the Investigator or a psychiatrist, or as a
    result of patient's mood assessment questionnaire (PHQ-9 and/or GAD-7):

    - Medically documented history of or active major depressive episode, bipolar
    disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
    suicidal attempt or ideation, or homicidal ideation (immediate risk of doing
    harm to others) or patients with active severe personality disorders (defined
    according to DSM- IV) are not eligible. Note: for patients with psychotropic
    treatments ongoing at baseline, the dose and the schedule should not be modified
    within the previous 6 weeks prior to start of study drug.

    - CTCAE grade 3 anxiety

    - Meets the cut-off score of 12 in the PHQ-9 or a cut-off of 15 in the GAD-7
    mood scale, respectively, or selects a positive response of "1, 2, or 3" to
    question number 9 regarding potential for suicidal thoughts in the PHQ-9
    (independent of the total score of the PHQ-9)

    9. Patients has diarrhea CTCAE grade 2

    10. Patients with uncontrolled hypertension defined as systolic blood pressure 170 or
    greater or diastolic blood pressure over 100.

    11. Patient has active cardiac disease including any of the following:

    - Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Gated
    acquisition (MUGA) scan or echocardiogram (ECHO)

    - QTc > 480 msec on screening ECG (using the QTcF formula)

    - Angina pectoris that requires the use of anti-anginal medication

    - Ventricular arrhythmias except for benign premature ventricular contractions

    - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
    with medication

    - Conduction abnormality requiring a pacemaker

    - Valvular disease with document compromise in cardiac function

    - Symptomatic pericarditis

    12. Patient has a history of cardiac dysfunction including any of the following:

    - Myocardial infarction within the last 6 months, documented by persistent
    elevated cardiac enzymes or persistent regional wall abnormalities on assessment
    of LVEF function

    - History of documented congestive heart failure (New York Heart Association
    functional classification III-IV)

    - Documented cardiomyopathy

    13. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus

    14. Patient has other concurrent severe and/or uncontrolled concomitant medical
    conditions (e.g., active or uncontrolled infection) that could cause unacceptable
    safety risks or compromise compliance with the protocol

    - Significant symptomatic deterioration of lung function. If clinically indicated,
    pulmonary function tests including measures of predicted lung volumes, DLco, O2
    saturation at rest on room air should be considered to exclude pneumonitis or
    pulmonary infiltrates.

    15. Impairment of gastrointestinal (GI) function or GI disease that may significantly
    alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea,
    vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with
    unresolved diarrhea will be excluded as previously indicated

    16. Patient was treated with any hematopoietic colony-stimulating growth factors (e.g.,
    G-CSF, GM-CSF) 2 weeks prior to starting study drug. Erythropoietin or darbepoetin
    therapy, if initiated at least 2 weeks prior to enrollment, may be continued

    17. Patient is currently receiving treatment with medication with a known risk to prolong
    the QT interval or inducing Torsades de Pointes and the treatment cannot either be
    discontinued or switched to a different medication prior to starting study drug.

    18. Patients receiving chronic treatment with steroids or another immunosuppressive
    agent. Patients must have been off all corticosteroids (except for physiologic doses
    of hydrocortisone as replacement therapy) for at least 2 weeks prior to study entry.

    - Note: Single doses, or topical applications (e.g. rash), inhaled sprays (e.g.
    obstructive airways diseases), eye drops or local injections (e.g.
    intra-articular) are allowed.

    19. Patient has taken herbal medications and certain fruits within 7 days prior to
    starting study drug. Herbal medications include, but are not limited to St. John's
    wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),
    yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville
    oranges, grapefruit, pummelos, or exotic citrus fruits. Regular orange juice is
    permitted.

    20. Patient is currently treated with drugs known to be moderate and strong inhibitors or
    inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to
    a different medication prior to starting study drug. Please refer to Table 4-8 for a
    list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment
    with weak inhibitors of CYP3A is allowed).

    21. Patient received chemotherapy or targeted anticancer therapy 3 weeks (6 weeks for
    nitrosourea, antibodies or mitomycin-C) prior to starting study drug, and have
    related side effects must recover to a grade 1 or less before starting the trial

    22. Patient received any continuous or intermittent small molecule therapeutics
    (excluding monoclonal antibodies) with 5 effective half lives prior to starting
    study drug or who have not recovered from side effects of such therapy

    23. Patient received wide field radiotherapy 4 weeks or limited field radiation for
    palliation 2 weeks prior to starting study drug or who have not recovered from side
    effects of such therapy

    24. Patient underwent major surgery 2 weeks prior to starting study drug or who have
    not recovered from side effects of such therapy.

    25. Patient is currently taking therapeutic doses of warfarin sodium or any other
    coumadin-derivative anticoagulant.

    26. Patient is pregnant or breast feeding or is of reproductive potential and not
    employing an effective method of birth control.

    - Note: Double barrier contraceptives must be used through the trial by both
    sexes. Oral, implantable, or injectable contraceptives may be affected by
    cytochrome P450 interactions, and are therefore not considered effective for
    this study. Women of child-bearing potential, defined as sexually mature women
    who have not undergone a hysterectomy or who have not been naturally
    postmenopausal for at least 12 consecutive months (i.e., who has had menses any
    time in the preceding 12 consecutive months), must have a negative serum
    pregnancy test 72 hours prior to initiating treatment.

    - Note: Women are considered post-menopausal and not of child bearing potential if
    they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
    clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six
    months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only:
    and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or
    without hysterectomy) at least six weeks ago. In the case of oophorectomy alone,
    only when the reproductive status of the woman has been confirmed by follow up
    hormone level assessment is she considered not of child bearing potential.

    - Note: Women of child-bearing potential, defined as all women physiologically
    capable of becoming pregnant, must use highly effective contraception during
    treatment for 4 weeks (5 T1/2) after stopping treatment. The highly effective
    contraception is defined as either:

    i. True 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.

    ii. Sterilization: have had surgical bilateral oophorectomy (with or without
    hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy
    alone, only when the reproductive status of the woman has been confirmed by follow up
    hormone level assessment.

    iii. Male partner sterilization (with the appropriate post-vasectomy documentation of
    the absence of sperm in the ejaculate). For female subjects on the study, the
    vasectomised male partner should be the sole partner for that patient.

    iv. Use of a combination of any two of the following (a+b):

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

    2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
    cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

    - Oral contraception, injected or implanted hormonal methods are not allowed
    as BKM120 potentially decreases the effectiveness of hormonal
    contraceptives.

    27. Patient has known diagnosis of human immunodeficiency virus (HIV) infection

    28. Patient has history of another malignancy within 3 years, except cured basal cell
    carcinoma of the skin or excised carcinoma in situ of the cervix

    29. Patient is unable or unwilling to abide by the study protocol or cooperate fully with
    the investigator

    30. Patient is concurrently using other approved or investigational antineoplastic agent.

    31. Patient taking or needing enzyme-inducing anti-epileptic medication.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    clinical benefit rate (CBR)

    Secondary Outcome Measures

    Objective Response Rate (ORR)

    Median time to progression

    Median Overall Survival

    Number of Adverse Events

    Median time to deterioration of neurologic function

    Trial Keywords

    Breast Cancer

    Triple Negative Breast Cancer

    Brain Metastases

    Capecitabine