A Study of BKM120 as a Single Agent in First Line Therapy in Advanced, Metastatic, or Recurrent Endometrial Cancers
- Patients must have advanced, metastatic, recurrent, or persistent endometrial or
ovarian, fallopian tube, or primary peritoneal cancer.
- Tumor must demonstrate PI3 Kinase pathway activation: defined as PIK3CA gene
mutation, PTEN gene mutation, or PTEN null/low protein expression.
- Prior therapy:
- Patients must not have had cytotoxic therapy directed at metastatic disease.
Adjuvant chemotherapy is permitted.
- Patients must NOT have received any non-cytotoxic therapy for metastatic or
recurrent disease, except for hormonal therapy or immunologic therapy.
- Patients with persistent or refractory disease after upfront surgery and
adjuvant chemotherapy are eligible.
- Age ≥ 18 years
- ECOG performance status ≤ 2
- Patients must have at least one site of measurable disease per Response Evaluation
Criteria In Solid Tumors (RECIST) 1.1 for solid tumors or the appropriate disease
classification/criteria for the target population)
- Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x
109/L, Hb >9 g/dL
- Total calcium (corrected for serum albumin) within normal limits (biphosphonate use
for malignant hypercalcemia control is not allowed)
- Magnesium ≥ the lower limit of normal
- Potassium within normal limits for the institution
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal
range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present)
- Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present;
or total bilirubin ≤ 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 (6.7 mmol/L)
- Negative serum pregnancy test within 72 hours before starting study treatment in
women with childbearing potential
- INR ≤ 2
- Able to provide informed consent & have signed an approved consent form that conforms
to federal & institutional guidelines.
- Patients who have received prior treatment with a P13K inhibitor.
- Patients with a known hypersensitivity to BKM120 or to its excipients.
- Patients with untreated brain metastases are excluded. However, patients with
metastatic Central Nervous System (CNS) tumors may participate in this trial, if the
patient is > 4 weeks from therapy completion (including radiation and/or surgery), is
clinically stable at the time of study entry and is not receiving corticosteroid
therapy (other than stable low dose corticosteroid therapy as outlined in exclusion
- Patients with acute or chronic liver, renal disease or pancreatitis
- Patients with the following mood disorders as judged by the Investigator or a
psychiatrist, or as a result of patient's mood assessment questionnaire:
- 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
- Meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7
mood scale, respectively, or 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) will be excluded from the study
unless overruled by the psychiatric assessment
- Patients with diarrhea ≥ CTCAE grade 2
• If patient is treated for diarrhea and it resolves to grade 1, patient may be
- Patient has active cardiac disease including any of the following:
- Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated
acquisition (MUGA) scan or echocardiogram (ECHO)
- QTc > 480 msec on screening ECG (using the 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
- Conduction abnormality requiring a pacemaker
- Valvular disease with document compromise in cardiac function
- Symptomatic pericarditis
- Patient 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 LVEF
- History of documents congestive heart failure (New York Heart Association
functional classification III-IV)
- Documented cardiomyopathy
- Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus
- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
active or uncontrolled infection) that, in the opinion of the investigator, 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, DLco, O2
saturation at rest on room air should be considered to exclude pneumonitis or
- 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). Patients with
unresolved diarrhea will be excluded as previously indicated
- Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin
or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be
- 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. Please refer to table 4-8 for a list of prohibited QT prolonging drugs with
risk of Torsades de Pointes.
- Patients receiving chronic treatment with steroids or another immunosuppressive
• Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intr-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 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 CYP3A inhibitors Seville
oranges, grapefruit, pummelos, or exotic citrus fruits.
- 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 refer to
Table 4-0 for a list of prohibited inhibitors and inducers of CYP3A (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 or
whose side effects have not recovered 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
- 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
- Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or
who have not recovered from side effects of such therapy.
- Patients who are currently taking therapeutic doses of warfarin sodium or any other
- 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 ≤
72 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 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, defined as all women physiologically capable
of becoming pregnant, must use highly effective contraception during the
treatment for 5 T1/2 (8 days) after stopping treatment and for additional 12
weeks (3 months in total after study drug discontinuation). The highly effective
contraception is defined as either:
1. 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.
2. 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.
3. Male partner sterilization (with the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate). For female
subjects on the study, the vasectomised male partner should be the sole
partner for that patient.
4. Use of a combination of any two of the following (a+b):
- Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- Barrier methods of contraception: Condom or Occlusive cap (diaphragm
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
- Oral contraception, injected or implanted hormonal methods are not allowed as
BKM120 potentially decreases the effectiveness of hormonal contraceptives.
- Fertile males, defined as all males physiologically capable of conceiving
offspring must use condom during treatment, for 5 T1/2 (8 days) after stopping
treatment and for additional 12 weeks (3 months in total after study drug
discontinuation) and should not father a child in this period.
- Known diagnosis of human immunodeficiency virus (HIV) infection
- History of another malignancy within 3 years, except cured basal cell carcinoma of
the skin or excised carcinoma in situ of the cervix
- Patient is unable or unwilling to abide by the study protocol or cooperate fully with