| Eligibility |
Inclusion Criteria:
- Written informed consent granted prior to initiation of any study-specific screening
procedures, given with the understanding that the patient has the right to withdraw
from the study at any time, without prejudice
- Histologically or cytologically confirmed diagnosis of solid malignancy; patient
should have locally advanced, inoperable or metastatic solid tumor with at least one
site of measurable disease [if applicable] (per Response Evaluation Criteria in Solid
Tumors [RECIST] for solid tumors or the appropriate disease classification/criteria
for the target population)
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Life expectancy of >= 12 weeks
- Platelet count >= 100 x 10^9/L
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Hemoglobin (Hgb) >= 9 gm/dl
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within upper
limits of normal (ULN) range (or =< 3.0 x ULN if liver metastases are present)
- Serum bilirubin within ULN range (or =< 1.5 x ULN if liver metastases are present; or
total =< 3.0 x ULN with direct bilirubin within normal range in patients with well
documented Gilbert syndrome)
- Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min
- Serum amylase =< ULN
- Serum lipase =< ULN
- Fasting plasma glucose =< 120 mg/dl
- International normalized ratio (INR) =< 2
- Magnesium >= the lower limit of normal
- Potassium within normal limits
- Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use
for malignant hypercalcemia control is not allowed)
- Women of childbearing potential must have a negative pregnancy test performed within
48 hours prior to the start of study drug
- Male and female subjects of child-bearing potential must agree to use double-barrier
contraceptive measures, oral contraception, or avoidance of intercourse during the
study and for 90 days after last investigational drug dose received
Exclusion Criteria:
- Previous anti-cancer chemotherapy, immunotherapy or investigational agents < 4 weeks
prior to the first day of study defined treatment; palliative radiation < 2 weeks;
patients who receive gamma knife radiosurgery for brain metastases are eligible if
procedure was performed > 4 weeks before treatment is started, is clinically stable
and has been on stable low dose corticosteroid treatment (e.g. dexamethasone 2 mg/day,
prednisolone 10 mg/day for at least 14 days before start of study treatment are
eligible); ongoing hormonal therapies (luteinizing hormone-releasing hormone [LHRH]
antagonists, megestrol) are allowed
- Previous treatment with a phosphatidylinositol 3-kinase (P1-3K) inhibitor
- Patients with a known hypersensitivity to BKM120 or to its excipients
- Patients with acute or chronic liver, renal disease or pancreatitis
- Patients have any of the following mood disorders as judged by the investigator or a
psychiatrist, or who meets the cut-off score of >= 12 in the Patient Health
Questionnaire (PHQ-9) or a cut-off of >= 15 in the Generalized Anxiety Disorder
(GAD-7) mood scale, respectively, or selects a positive response of '1, 2, or 3' to
questions number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent
of the total score of the PHQ-9)
- 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)
- >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety
- Patients with diarrhea >= CTCAE grade 2
- Patient has active cardiac disease including any of the following:
- Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
acquisition (MUGA) scan or echocardiogram (ECHO)
- Corrected QT interval (QTc) > 480 msec on screening electrocardiogram (ECG)
(using the QT interval corrected for Fridericia [QTcF] formula)
- Angina pectoris that requires the use of anti-anginal medication
- Ventricular arrhythmias except for benign premature ventricular contractions
- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication
- Conduction abnormality requiring a pacemaker
- Valvular disease with document compromise in cardiac function
- Symptomatic pericarditis
- Previous history of QTc prolongation as a result of other medication that
required discontinuation of that medication
- Congenital long QT syndrome or 1st degree relative with unexplained sudden death
under 40 years of age
- Patient has a history of cardiac dysfunction including any of the following:
- Myocardial infarction within the last 6 months, documents by persistent elevated
cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF
function
- History of documents congestive heart failure (New York Heart Association
functional classification III-IV)
- Documented cardiomyopathy
- Active clinically serious infections defined as >= grade 2 according to National
Cancer Institute (NCI) CTCAE, version 4.0
- Substance abuse, medical, psychological or social conditions that may, in the opinion
of the Investigator, interfere with the patient's participation in the study or
evaluation of the study results
- Any condition that is unstable or which could jeopardize the safety of the patient and
his/her protocol compliance
- Patient has poorly controlled diabetes mellitus, steroid-induced diabetes mellitus, or
glycosylated hemoglobin (HbA1c) > 7%
- Known human immunodeficiency virus (HIV) infection
- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
active or uncontrolled infection) that could cause unacceptable safety risks or
compromise compliance with the protocol
- Significant symptomatic deterioration of lung function; if clinically indicated,
pulmonary function tests including measures of predicted lung volumes, diffusion
capacity of carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should
be considered to exclude pneumonitis or pulmonary infiltrates
- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of BKM 120 (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with
unresolved diarrhea will be excluded as previously indicated
- Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF]) =< 2 weeks prior to starting
study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior
to enrollment, may be continued
- Patients who have taken herbal medications and certain fruits within 7 days prior to
starting study drug; herbal medications include, but are not limited to St. John's
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe,
saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A
(CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits
- Patients who have received wide field radiotherapy =< 4 weeks or limited field
radiation for palliation =< 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy
- Women who are pregnant or breast feeding or adults of reproductive potential not
employing an effective method of birth control; double barrier contraceptives must be
used through the trial by both sexes; oral, implantable, or injectable contraceptives
may be affected by cytochrome P450 interactions, and are therefore not considered
effective for this study; women of child-bearing potential, defined as sexually mature
women who have not undergone a hysterectomy or who have not been naturally
postmenopausal for at least 12 consecutive months (i.e., who has had menses any time
in the preceding 12 consecutive months), must have a negative serum pregnancy test =<
48 hours prior to initiating treatment
- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous
amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mlU/mL (for US
only: 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, defined as all women physiologically capable of
becoming pregnant, must use highly effective contraception during treatment for 4
weeks (5 T1/2) after stopping treatment; the highly effective contraception is defined
as either:
- True abstinence: when this is in line with the preferred and usual lifestyle of
the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception
- Sterilization: have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment
- Male partner sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate); for female subjects on the study, the
vasectomized male partner should be the sole partner for that patient
- Use of a combination of any two of the following (a+b):
- a) Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- b) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository
- Oral contraception, injected or implanted hormonal methods are not allowed as
BKM120 potentially decreases the effectiveness of hormonal contraceptives
- Women of child-bearing potential must have a negative serum pregnancy test =< 48
hours prior to initiating treatment
- Fertile males, defined as all males physiologically capable of conceiving
offspring must use condom during treatment, for 4 weeks (5 T1/2) after stopping
treatment and for additional 12 weeks (16 weeks in total after study drug
discontinuation) and should not father a child in this period
- Female partner of male study subject should use highly effective contraception
during dosing of any study agent and for 16 weeks after final dose of study
therapy
- Inability to swallow oral medications
- Significant gastrointestinal disorder, in the opinion of the investigator, could
interfere with the absorption of BKMI20 (e.g. significant, uncontrolled inflammatory
bowel disease, history of abdominal fistula or gastrointestinal [GI] perforation
within 6 months, extensive small bowel resection and requirement for tube feeding or
parenteral hydration/nutrition)
- Patients who are currently receiving treatment with medication with a known risk to
prolong the QT interval or inducing Torsades de Pointes and the treatment cannot
either be discontinued or switched to a different medication prior to starting study
drug
- Patients receiving chronic treatment with steroids or another immunosuppressive agent;
Note: topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intra-articular) are allowed; patients
with previously treated brain metastases, who are on stable low dose corticosteroids
treatment (e.g. dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days
before start of study treatment are eligible
- Patients who are currently treated with drugs known to be moderate and strong
inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or
switched to a different medication prior to starting study drug (please note that
co-treatment with weak inhibitors of CYP3A is allowed)
- Patients who have received chemotherapy or targeted anticancer therapy =< 4 weeks (6
weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must
recover to a grade 1 before starting the trial
- Patients who have received any continuous or intermittent small molecule therapeutics
(excluding monoclonal antibodies) =< 5 effective half-lives prior to starting study
drug or who have not recovered from side effects of such therapy
- No concurrent intake of valproic acid, rifampin, phenobarbital, phenytoin, or
carbamazepine
- Patients who are currently taking therapeutic doses of warfarin sodium or any other
Coumadin derivative anticoagulant
- Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator
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