Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma

• Cohort I: To evaluate PI3K pathway modulation of BKM120 in tumor tissue. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  PI3-Kinase pathway modulation will be measured using immunohistochemistry analyses of unstained tumor tissue to identify PI3-Kinase mutations including PIK3CA mutations, PTEN mutations, and PTEN deletion by immunohistochemistry. Expression of pAKT will also be analyzed using immunohistochemistry.
• Cohort II: To investigate the treatment efficacy of BKM120 in participants with recurrent GBM as measured by 6-month progression-free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Treatment efficacy will be based upon 6-month progression-free survival status. Progressive disease is defined using RANO (Response Assessment in Neuro-Oncology criteria.
• Cohort I: To evaluate BKM120 concentration in tumor tissue, plasma, and cerebrospinal fluid. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Blood will be collected over various time points prior to surgery to determine individual pharmacokinetics. During surgery, tumor tissue, plasma, and cerebrospinal fluid will be collected simultaneously. Tumor and plasma concentrations of the drug will be measured by liquid chromatography with tandem mass spectrometry to derive a tumor/plasma ratio. Descriptive statistics (mean, SD, CV% or median (range)) will be performed on all plasma concentration-time data and derived PK parameters.

• Cohort I: To evaluate effects of BKM120 on tumor cell proliferation and tumor cell death [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Modulation in pAKT scoring as measured by reduction of staining intensity of one degree or more will be reported as consistent with a positive response to drug. In addition, participants will be independently scored as a positive response if a reduction in the percentage of pAKT positive cells within a tumor is greater than 50%, and therefore less likely due to normal geographic variation in positivity patterns. All pathway modulation scores will be correlated with effects on tumor growth by measuring Ki-67 (proliferation) and cleaved caspase 3 (CC3) (apoptosis/cell death).
• Cohort I: To investigate the safety profile of BKM120 in participants with recurrent GBM [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  To assess the probability of toxicity associated with the treatment, the proportion of subjects with different grades of toxicities will be analyzed in order to further expland the safety profile for BKM120.
• Cohort I: To investigate pharmacokinetics of BKM120 in this population [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Pharmacokinetic parameters of BKM120 will be determined, either using a two-stage compartmental analysis or using a non-linear mixed-effect approach. Pharmacokinetic parameters that will be derived include, but are not limited to oral drug clearance (CL/F), central and peripheral volume of distribution (V1 and V2) and absorption rate constant (Ka). Descriptive statistics (mean, SD, CV% or median (range)) will be performed on all plasma concentration-time data and derived PK parameters.
• Cohort II: To investigate the radiographic response to BKM120 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Participants will be evaluated for radiographic response. Response rate will be the proportion of participants with measurable disease who experience complete or partial radiographic response determined by the RANO Criteria
• Cohort II: To investigate median progression free survival and overall survival of participants with recurrent GBM receiving treatment with BKM120 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Median time to progression (defined using RANO criteria) and duration of survival will be measured in months for all enrolled cohort II participants.

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.

For patients who will be having surgery, BKM will be taken orally for 8-12 days prior to surgery. Prior to surgery they will have a FDG-PET scan and during surgery a sample of tumor will be taken for research. Patients will resume oral BKM120 between 14 and 35 days after surgery.

For patients who are not having surgery and post-surgery patients, BKM120 will be taken orally for 28 days (1 cycle). Patients will continue on BKM120 as long as their brain tumor does not get worse and they do not have severe or intolerable side effects.

During each cycle patients will have a physical examination, an assessment of tumor by MRI or CT, routine blood tests, questionnaires to assess mood, and research blood samples for genetic studies and other tests that will measure any additional effect of the study drug and disease status. Participants may also be required to undergo a electrocardiogram and/or MUGA scan to monitor heart function during the study.

• Drug: BKM120
  100 mg once daily, orally, for 28 days
• Procedure: Surgery
  Surgery

• Experimental: Cohort I: Surgical subjects
  Subjects scheduled for surgery
  Interventions:

  • Drug: BKM120
  • Procedure: Surgery
• Experimental: Cohort II: Non-surgical subjects
  Subjects not candidates for surgery
  Intervention: Drug: BKM120

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 estimated life expectancy > 8 weeks in the opinion of the clinician.
• 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 must be at their first relapse. (NOTE: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy). 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.
• 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.
• 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, PTEN mutation, PTEN negative (<10% staining) on immunohistochemistry.
• 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 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 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 post-operatively, an MRI or CT scan should be done no later than 96 hours following surgery or at least 4 weeks post-operatively, in either case 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 (please see Appendix F). 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 of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant and male subjects with female partner of child-bearing potential, must agree to use highly effective contraception (as defined per protocol) during study treatment and for 12 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.

Cohort 1 Inclusion Criteria (In addition to the general eligibility criteria, participants in the Cohort 1 pre-operative 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 pre-operative study.
• There must be sufficient recurrent tumor to allow at least 200mg of tissue to be collected (0.5 cm3) for pharmacokinetic and pharmacodynamic analysis.
• Immunohistochemical analysis on tumor tissue from an earlier surgery indicating pAKT positive (1-2+ on a 0-2+ scale). An assessment guide to interpret IHC will be provided to each site's pathologist.

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, felbamate, and topiramate (only when daily dose exceeds 200 mg). 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.
• Participants taking a drug known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A (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.
• 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 seven 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 (glycosolated hemoglobin > 8%) or poorly controlled steroid-induced diabetes mellitus (glycosolated 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 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.

• Brigham and Women's Hospital
• Massachusetts General Hospital
• Novartis Pharmaceuticals
• M.D. Anderson Cancer Center
• Memorial Sloan-Kettering Cancer Center
• University of California, San Francisco
• University of California, Los Angeles
• University of Utah