Return to List

Study Summary
No. 2011-0307:.......Brain; CNS......W K Alfred Yung......Neuro Oncology
.
Study Summary Title
Study Summary
Number:
2011-0307
Study Title:A Phase II Study of BKM120 for Patients with Recurrent Glioblastoma and
Activated PI3K Pathway
.
Physician New Patient Referral
Name:W K Alfred YungPatients Call:800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Dept:Neuro OncologyReferring MD
Call:
800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Phone:713-792-2883
Contact us about clinical trials
.
General Information
Disease Group:Brain
CNS
Supported By:Dana-Farber/Partners CancerCare.Inc
Novartis Pharmaceuticals.
Phase of Study:Phase IIReturn
Visit:
Treatment
Agents:
BKM120Home Care:
Treatment Loc:Both at MDACC & and Other Sites
Estimated
Length of Stay
in Houston:
Description/
Intervention:
The goal of this clinical research study is to learn if BKM120 can help to
control glioblastoma and/or gliosarcoma. Researchers also want to learn more
about how much study drug is in different areas of the body at different time
points. The safety of this drug will also be studied.

BKM120 is designed to block a protein that is important to the growth and
division of cancer cells, which may cause the cells to die.
.
Study Objectives / Outcomes
1 Cohort 1
    1.1 Primary Objectives
        • To evaluate Phosphatidylinositol 3'-kinase(PI3K) pathway modulation due to BKM120 in tumor tissue
        • To evaluate BKM120 concentration in tumor tissue, plasma, and cerebrospinal fluid

    1.2 Secondary Objectives
        • To evaluate effects of BKM120 on tumor cell proliferation and tumor cell death
        • To investigate the safety profile of BKM120 in this population
        • To investigate pharmacokinetics of BKM120 in this population
      1.3 Exploratory Objectives
          • Correlation of FDG-Positron Emission Tomography (PET) and FLT-PET with pharmacodynamic effects and 6 month progression-free survival(PFS6).
          • To determine the effects of BKM120 on primary Glioblastoma(GBM) cell lines derived from participants and correlate with participant benefit from BKM120 treatment.

      2 Cohort 2
        2.1 Primary Objective
            • To investigate the treatment efficacy of BKM120 in participants with recurrent GBM as measured by 6-month progressive-free survival (PFS6).
          2.2 Secondary Objectives
              • To investigate the radiographic response to BKM120.
              • To investigate median progression free survival and overall survival of participants with recurrent GBM receiving treatment with BKM120.
              • To investigate the safety profile of BKM120 in participants with recurrent GBM.

          2.3 Exploratory Objectives
              • To correlate benefit from BKM120 treatment with molecular genotype of tumor (using immunohistochemistry, mutation analysis and RNA expression profiling), and whole blood proteomics.
              • To correlate benefit from BKM120 treatment with circulating angiogenic biomarkers
              • Use of advance MRI (perfusion, permeability, diffusion imaging) to determine the effects of BKM120 on tumor vasculature and to correlate with benefit from BKM120 treatment
          .
          Study Status Information
          Study Activation / Registration Date:07/26/2011
          IRB Review and Approval Date:07/26/2011
          Study Type:Phase Ii Or Phase I/Ii
          Recruitment Status:Open
          Projected Accrual:65
          .
          Enrollment Eligibility
          If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

          Inclusion Criteria:1) Participants must be able to understand and willing to sign a written informed consent document.

          2) 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.

          3) Participants must be at least 18 years old.

          4) Participants must have a Karnofsky performance status (KPS) >/= 60

          5) 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.

          6) Patients may have had treatment for no more than 1 prior relapse. Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 2 prior therapies (initial and treatment for 1 relapse). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute 1 relapse. For patients who had prior therapy for a lower-grade glioma, the surgical diagnosis of higher grade will be considered the first relapse.

          7) Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.

          8) a) For Cohort 2, CT or MRI within 14 days prior to study registration. MRIs should include advanced physiologic 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. b) 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.

          9) Immunohistochemical or genetic analysis on tumor tissue from a prior surgery must demonstrate activation of the PI3K pathway through at least one of the following assays: a) PIK3CA or PIK3R1 mutation. b) Or Loss of PTEN activity confirmed via one or more of the following: PTEN negativity (<10% of tumor cells staining) on immunohistochemistry ¡V determinable for the purpose of this trial only by Dr. Ligon at DFCI; PTEN mutation (any); homozygous deletion of PTEN.

          10) (9. continued) Of note, ideally 30 (minimum of 20) of the 50 subjects enrolled onto Cohort II of the study will have tumor which demonstrates loss of PTEN activation (any mutation, homozygous deletion of PTEN or PTEN negativity as defined above). Additionally, ideally 20 (minimum of 10) of the 50 subjects enrolled onto Cohort II of this study will have tumor which demonstrates either PIK3CA or PIK3R1 mutation. The Sponsor Coordination Center will communicate on an ongoing basis accrual numbers based on loss of PTEN activity and PIK3CA/PIK3R1 mutations, and will inform sites if - in the interest of enriching the study for subjects with PTEN activity and PIK3CA and PIK3R1 mutations - a decision is made to restrict new potential Cohort II subjects to either patients whose tumor demonstrates loss of PTEN activity or PIK3CA or PIK3R1 mutation.

          11) (10. continued) NOTE: Participants must have sufficient tissue from prior surgery confirmed and available for trial purposes per Eligibility criterion #17. For eligibility review, the following submission of slides is required prior to registration of study subjects: a. Minimum of 2 unstained slides of 4-5 micron thickness should be sent to Keith Ligon, MD, PhD prior to registration for immunohistochemistry review (If an alternative PI3K pathway activation for eligibility as outlined above has been confirmed via another method of genetic analysis in a CLIA environment, please notify the coordinating center and Dr. Ligon of this result (provide a copy of results report) in order to have requirement for upfront IHC waived; b. Minimum of 1 unstained or 1 H&E stained slide to be sent to Keith Ligon, MD, PhD prior to registration for confirmation of diagnosis.

          12) 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.

          13) 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).

          14) 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), 6 weeks from nitrosoureas, 6 weeks from antibodies, 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies.

          15) 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.

          16) 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 ideally have been performed no later than 96 hours following surgery or at least 28 days post-operatively, 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.

          17) 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: 25 unstained formalin fixed paraffin embedded (FFPE) sections (standard 4-5 micrometer thickness AND one of the following: At least 200 mg of frozen tissue OR At least 10 (preferably 20) unstained FFPE sections of 10 micrometer thickness OR 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).

          18) Hematology: Absolute neutrophil count (ANC) >/= 1.0 x 10^9/L, Platelet count >/= 100 x 10^9/L, Hemoglobin >/= 9.0 g/dL

          19) Biochemistry: Total serum calcium (corrected for serum albumin as needed) or ionized calcium within institution's normal range; Magnesium within institution's normal range; Serum potassium within institution's normal range; AST (SGOT) and ALT (SGPT) </= institutionþes ULN; Serum bilirubin </= 1.5 x institutionþes ULN; Serum creatinine </= 1.5 x ULN or calculated 24-hour creatinine clearance >/= 50 mL/min; Serum amylase < ULN; Serum lipase < ULN; Fasting plasma glucose < 120mg/dL (6.7 mmol/L).

          20) Coagulation studies: INR < 2.0; PTT </= institution's ULN, unless receiving therapeutic low molecular weight heparin.

          21) Cardiovascular Assessment: Baseline MUGA or Echocardiogram must demonstrate LVEF >/= 50 %; QTc < 480 msec on screening ECG (using the QTcF formula)

          ....

          Criteria truncated, please contact Prinicipal Investigator's office for full criteria

          Exclusion Criteria:1) Participants who have received prior treatment with a P13K inhibitor, AKT inhibitor, mTOR inhibitor (e.g. rapamycin, MK2206, perifosine etc.).

          2) Participants who have received anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL184, sunitinib etc).

          3) 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.

          4) Participants taking a drug known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A. 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.

          5) Requirement of more than 8mg of dexamethasone daily.

          6) Participants taking drugs with known risk to promote QT prolongation and Torsades de Pointes.

          7) Participants receiving any other investigational agents.

          8) 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.

          9) 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.

          10) History of allergic reactions attributed to compounds of similar chemical or biologic composition to BKM120.

          11) History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician. If there are questions, the treating physician should contact the study Overall principal investigator.

          12) 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.

          13) 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.

          14) Known diagnosis of human immunodeficiency virus (HIV) infection

          15) Participants with the following mood disorders as judged by the Investigator or a psychiatrist, or as result of participant's mood assessment questionnaire: a. 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) b. Score of >/= 12 in the PHQ-9 c. 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) d. Score of >/= 15 in the GAD-7 mood scale e. >/= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety. Note: If participant is ineligible due to PHQ-9 or GAD-7 scores including Q9 on PHQ-9, treating investigator is to be informed immediately and will determine appropriate actions regarding referrals.

          16) Participants with diarrhea >/= CTCAE grade 2

          17) 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.

          18) Participant has a history of cardiac dysfunction including any of the following: Myocardial infraction within the last 6 months, documents by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of Left Ventricular Ejection fraction(LVEF) function; History of documents congestive heart failure (New York Heart Association functional classification III-IV); Documented cardiomyopathy; Congenital long QT syndrome.

          19) Participants with poorly controlled diabetes mellitus (glycosolated hemoglobin > 8%) or poorly controlled steroid-induced diabetes mellitus (glycosolated hemoglobin > 8%)

          20) 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.

          21) 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.

          .
          Links
          Registration Number: NCT01339052
          Study Information on Clinical Trials Registry (clinicaltrials.gov)

          Other Links:
          .
          Results


          Return to Clinical Trials at M.D. Anderson Cancer Center