Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma

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.