Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma
Phase: Phase 2
Diagnosis: Brain/Neuro Cancer: Recurrent Glioblastoma
NCT ID: NCT01339052
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 11-033
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.
Dana-Farber Cancer Institute, Brigham and Women's Hospital, Massachusetts General Hospital
Patrick Wen, MD,
Dana-Farber Cancer Institute
Andrew Chi, MD, PhD,
Massachusetts General Hospital
Dana-Farber Cancer Institute:
Massachusetts General Hospital:
Cancer Trials Call Center, 877-789-6100
- Participants must be able to understand and be willing to sign a written informed
- 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
- 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
- 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
- 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.
- 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
- 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
- Requirement of more than 8mg of dexamethasone daily.
- Participants taking drugs with known risk to promote QT prolongation and Torsades de
- 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
- 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
- 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
- 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
- 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.