Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: BKM120; Surgery
Intervention description: Surgery
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BKM120; Brain tumor

Summary:

      BKM120 is a newly discovered drug that has been used in other research studies. Information
      from those other research studies suggests that BKM120 may help to slow or stop the growth of
      malignant gliomas. The purpose of this study is to see how well BKM120 works in patients with
      malignant gliomas. Patients on this study will be treated in two groups: patients who are
      going to receive surgery and those who will not receive surgery. This study is trying to
      determine how effective BKM120 is in stopping cancer cells from growing. For patients
      receiving surgery the research will also try to determine if an effective level of BKM120 can
      penetrate the brain before surgery.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must be able to understand and be willing to sign a written informed
             consent document.

          -  Subjects must be able to adhere to the dosing and visit schedules, and agree to record
             medication times accurately and consistently in a daily diary.

          -  Participants must be at least 18 years old.

          -  Participants must have a Karnofsky performance status (KPS) ≥ 60. Nature of illness
             and treatment history

          -  Participants must have histologically confirmed glioblastoma or variants. Participants
             will be eligible if the original histology was low-grade glioma and a subsequent
             histological diagnosis of glioblastoma or variants is made.

          -  Participants may have had treatment for no more than 1 prior relapse(NOTE: Relapse is
             defined as progression following initial therapy (i.e., radiation ± chemotherapy)).
             The intent therefore is that patients had no more than 2 prior therapies (initial and
             treatment for 1 relapse). If the participant had a surgical resection for relapsed
             disease and no antitumor therapy was instituted for up to 12 weeks, and the
             participant undergoes another surgical resection, this is considered as a second
             relapse. For participants who had prior therapy for a low-grade glioma, the surgical
             diagnosis of a high-grade glioma will be considered the first relapse).

          -  Participants must have shown unequivocal evidence for tumor progression by MRI or CT
             scan.

          -  For Cohort 2, CT or MRI within 14 days prior to start of study drug. MRIs should
             include vascular imaging when possible. For Cohort 2, corticosteroid dose must be
             stable or decreasing for at least 5 days prior to the scan. If steroids are added or
             the steroid dose is increased between the date of the screening MRI or CT scan and the
             start of treatment, a new baseline MRI or CT is required. For Cohort 1 subjects, CT or
             MRI should be performed ideally within 14 days prior to study registration, but
             because the screening MRI for this subset of subjects will not be used for evaluation
             of response, it is acceptable for this MRI/CT to have been performed greater than 14
             days prior to registration if unavoidable. Furthermore, for this same reason,
             fluctuation in corticosteroid dose around this MRI does not warrant repeat scan so
             long as there is documented unequivocal evidence of tumor progression available.

          -  For Cohort 2, Immunohistochemical or genetic analysis on tumor tissue from a prior
             surgery must demonstrate activation of the PI3K pathway through one of the following:
             PIK3CA mutation of PIK3R1 mutation, PTEN negativity (<10% of tumor cells staining) oh
             immunohistochemistry, PTEN mutation (any), homozygous deletion of PTEN

          -  Participants must have failed prior radiation therapy and must have an interval of at
             least 12 weeks from the completion of radiation therapy to study entry.

          -  Participants must have recovered to a grade 0 or 1 from the toxic effects of prior
             therapy (with the exception of lymphopenia which is common after therapy with
             temozolomide).

          -  From the projected start of scheduled study treatment, the following time periods must
             have elapsed: 4 weeks or 5 half-lives (whichever is shorter)from any investigational
             agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks
             from nitrosoureas), 6 weeks from antibodies, or 4 weeks or 5 half-lives (whichever is
             shorter) from other anti-tumor therapies.

          -  Participants with prior therapy that included interstitial brachytherapy or
             stereotactic radiosurgery must have confirmation of progressive disease based upon
             nuclear imaging, MR spectroscopy, perfusion imaging or histopathology.

          -  Participants having undergone recent resection of recurrent or progressive tumor will
             be eligible for Cohort 2 as long as the following conditions apply: a) They have
             recovered from the effects of surgery; b) Residual disease following resection of
             recurrent tumor is not mandated for eligibility. To best assess the extent of residual
             disease postoperatively, an MRI or CT scan should ideally been performed no later than
             96 hours following surgery or at least 28-days postoperatively, but scans performed
             outside of this window are considered acceptable if no alternative is available. In
             either case, the baseline/screening MRI must be performed within 14 days prior to
             registration. If the participant is taking corticosteroids, the dose must be stable or
             decreasing for at least 5 days prior to the scan. If steroids are added or the steroid
             dose is increased between the date of the screening MRI or CT scan and the start of
             treatment, a new baseline MRI or CT is required.

          -  Participants must have sufficient tissue from prior surgery for confirmation of
             diagnosis and correlative studies. Submission of tissue is to occur within 30 days
             after registration. The following amount of tissue is required: a) 25 unstained
             formalin fixed paraffin embedded (FFPE) sections (standard 4-5 micrometer thickness
             AND b)one of the following: i) At least 200 micrograms of frozen tissue OR ii)At least
             10 (preferably 20) unstained FFPE sections of 10 micrometer thickness OR iii) At least
             8 tissue cores from an FFPE block (200 micrometer total thickness of tissue from a
             block with a total surface area of 0.5 cm2)

          -  Clinical laboratory tests within 14 days prior to enrollment meeting the criteria
             listed in the protocol

          -  Cardiovascular assessment: baseline MUGA or Echocardiogram must demonstrate LVEF ≥ 50
             %

          -  Electrocardiogram must demonstrate QTc interval of less than 480 msec

          -  Women are considered post-menopausal and not of child bearing potential if they have
             had 12 months of natural (spontaneous) amenorrhea with appropriate clinical profile
             (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous
             amenorrhea with serum FSH levels > 40 mIU/mL 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.

          -  Women of child-bearing potential (WOCBP), defined as all women physiologically capable
             of becoming pregnant, must use highly effective contraception (defined in protocol)
             during study treatment and for 16 weeks after study discontinuation.

          -  Women of child-bearing potential must have a negative serum pregnancy test at
             screening and within 48 hours prior to dosing with the study drug.

          -  Fertile males, defined as all males physiologically capable of conceiving offspring,
             must use condom during study treatment and for 16 weeks after study discontinuation
             and should not father a child in this period.

          -  Female partner of male study subject should use highly effective contraception while
             receiving study agent and for 16 weeks after final dose of study therapy.

        Cohort 1 Inclusion Criteria (In addition to the general eligibility criteria, participants
        in the Cohort 1 preoperative portion of the study must meet the following criteria on
        screening examination to be eligible):

          -  A participant who is deemed by the site Investigator to be an appropriate candidate
             for surgical resection may be enrolled in the Cohort 1 preoperative study.

          -  There must be sufficient recurrent tumor to allow at least 400mg of tissue to be
             collected ( 2 X 0.5 cm3) for pharmacokinetic and pharmacodynamic analysis.

          -  Central Immunohistochemical analysis (by Dr. Ligon at DFCI) on tumor tissue from an
             earlier surgery must indicate pAKT positivity (1-2+ on a 0-2+ scale). [Cohort I
             patients' tissue may also demonstrate activation of the PI3K pathway via one of the
             criteria listed for Cohort 2 participants, but this is not mandatory.]

        Exclusion Criteria:

          -  Participants who have received prior treatment with a P13K inhibitor, AKT inhibitor,
             mTOR inhibitor (e.g. rapamycin, MK2206, perifosine etc.).

          -  Participants who have received anti-angiogenic or anti-VEGF targeted agents (e.g.
             bevacizumab, cediranib, aflibercept, vandetanib, XL184, sunitinib etc).

          -  Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital,
             phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine,
             rufinamide, and felbamate. Participant must be off any EIAEDs for at least two weeks
             prior to starting study drug. A list of EIAED and other inducers of CYP3A4 is provided
             in Table C-3 of Appendix C of the protocol.

          -  Participants taking a drug known to be moderate and strong inhibitors or inducers of
             isoenzyme CYP3A (protoocol Appendix C). Participant must be off CYP3A inhibitors and
             inducers for at least two weeks prior to starting study drug. NOTE: participants must
             avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice,
             grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first
             dose of study drug and during the entire study treatment period due to potential
             CYP3A4 interaction.

          -  Requirement of more than 8mg of dexamethasone daily.

          -  Participants taking drugs with known risk to promote QT prolongation and Torsades de
             Pointes (refer to protocol).

          -  Participants receiving any other investigational agents.

          -  Current use of herbal preparations/medications, including but not limited to: St.
             John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),
             yohimbe, saw palmetto, ginseng. Participants should stop using these herbal
             medications 7 days prior to first dose of study drug.

          -  Current use of warfarin sodium or any other coumadin-derivative anticoagulant.
             Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior
             to starting study drug. Low molecular weight heparin is allowed.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to BKM120.

          -  History of intratumoral or peritumoral hemorrhage if deemed significant by the
             treating physician.

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease,
             pancreatitis, chronic pulmonary disease, or psychiatric illness/social situations that
             would limit compliance with study requirements. Subjects must be free of any
             clinically relevant disease (other than glioma) that would, in the Investigator's
             opinion, interfere with the conduct of the study or study evaluations.

          -  Individuals with a history of a different malignancy except for the following
             circumstances: if they have been disease-free for at least 3 years and are deemed by
             the investigator to be at low risk for recurrence of that malignancy, individuals with
             the following cancers are eligible if diagnosed and treated within the past 3 years:
             cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

          -  Known diagnosis of human immunodeficiency virus (HIV) infection

          -  Participants with history of protocol specified mood disorders as judged by the
             Investigator or a psychiatrist, or as result of participant's screening mood
             assessment questionnaire

          -  Participants with diarrhea ≥ CTCAE grade 2

          -  Participant has active cardiac disease including any of the following: Angina pectoris
             that requires the use of anti-anginal medications; Ventricular arrhythmias except for
             benign premature ventricular contractions; Supraventricular and nodal arrythmias
             requiring a pacemaker or not controlled with medication; Conduction abnormality
             requiring a pacemaker; Valvular disease with document compromise in cardiac function;
             Symptomatic pericarditis

          -  Participant has a history of cardiac dysfunction including any of the following:
             Myocardial infraction 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; c)Documented cardiomyopathy; d) Congenital long QT
             syndrome

          -  Participants with poorly controlled diabetes mellitus (glycosylated hemoglobin > 8%)
             or poorly controlled steroid-induced diabetes mellitus (glycosylated hemoglobin > 8%)

          -  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 extensive small bowel resection).
             Participants with unresolved diarrhea will be excluded as previously indicated.

          -  Participants who have undergone major systemic surgery ≤ 2 weeks prior to starting
             study drug or who have not recovered from side effects of such therapy.