Buparlisib, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To describe the dose-limiting toxicities, maximally tolerated dose, and identify the
recommended Phase II dose (RP2D) of the combination of BKM120 (buparlisib), gemcitabine
(gemcitabine hydrochloride), and cisplatin in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To describe safety and tolerability of the combination of BKM120, gemcitabine, and
cisplatin in patients with advanced solid tumors.

II. To describe preliminary evidence of efficacy with this combination. III. To describe any
pharmacokinetic (PK) effect of gemcitabine and cisplatin on the plasma concentrations of
BKM120.

IV. To evaluate phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha
(PIK3CA) mutations as predictive biomarkers of efficacy for the combination.

V. To evaluate PIK3CA polymorphisms and polymorphisms in BKM120 transport and metabolism as
predictors of toxicity and/or efficacy.

OUTLINE: This is a dose-escalation study.

Patients receive buparlisib orally (PO) once daily (QD) on days 1-21, gemcitabine
hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and cisplatin IV over 2
hours on day 1. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of solid malignancy

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

- Life expectancy of >= 12 weeks

- Platelet count >= 150 x 10^9/L

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Hemoglobin (Hgb) >= 9 g/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 1.5 upper
limit normal (ULN), or < 3 x ULN if liver metastases are present

- Serum total bilirubin =< ULN or 1.5 x ULN if liver metastases are present or total 3
x ULN with direct bilirubin =< ULN in patients with well documented Gilbert syndrome

- Calculated or measured creatinine clearance >= 60 mL/min

- Fasting plasma glucose < 120 mg/dL

- Magnesium >= the lower limit of normal

- Lipase =< 1.5 ULN

- Women of childbearing potential must have a negative pregnancy test performed within
7 days 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

- Subject or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

- For dose expansion cohort, patients must have histologic or cytologic confirmed
non-small cell lung cancer that are not curable

Exclusion Criteria:

- Previous anti-cancer chemotherapy, immunotherapy or investigational agents < 4 weeks,
or palliative radiation < 2 weeks prior to the first day of study treatment, or who
have not recovered to grade 1 or better from related side effects of such therapy
(except alopecia); patients who receive gamma knife radiosurgery for brain metastases
are eligible if procedure was performed > 2 weeks before treatment is started, is
clinically stable and has been on stable low dose corticosteroid treatment (e.g.,
dexamethasone 2 mg/day, prednisolone 12 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 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

- Patient has a known hypersensitivity to any of the excipients of BKM120

- Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects

- Patient is currently receiving increasing or chronic treatment (> 5 days) with
corticosteroids or another immunosuppressive agent, as chronic administration of
corticosteroids (> 5 days) can induce cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4)

- The following uses of corticosteroids are permitted: single doses; e.g. with
standard premedication for taxanes; topical applications (e.g., rash), inhaled
sprays (e.g., obstructive airways diseases), eye drops or local injections
(e.g., intra-articular)

- Patient is being treated at start of study treatment with any of the following drugs:

- Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4
including herbal medications

- Drugs with a known risk to induce Torsades de Pointes

- Note: The patient must have discontinued strong inducers for at least one week
and must have discontinued strong inhibitors before the treatment is initiated;
switching to a different medication prior to starting study treatment is allowed

- Patient is currently receiving warfarin or other Coumarin derived anti-coagulant, for
treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight
heparin (LMWH), or fondaparinux is allowed

- Patients who have other concurrent severe and/or uncontrolled medical conditions that
would, in the investigator's judgment, contraindicate patient participation in the
clinical study (eg. active or uncontrolled severe infection, chronic active
hepatitis, immunocompromised, acute or chronic pancreatitis, uncontrolled high blood
pressure, interstitial lung disease, etc.)

- Patient has a known history of human immunodeficiency virus (HIV) infection (testing
not mandatory) infection

- Patient has any of the following cardiac abnormalities:

- Symptomatic congestive heart failure

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV), documented cardiomyopathy

- Left ventricular ejection fraction (LVEF) < 50% as determined by multiple
gated acquisition (MUGA) scan or echocardiogram (ECHO)

- Myocardial infarction =< 6 months prior to enrollment

- Unstable angina pectoris

- Serious uncontrolled cardiac arrhythmia

- Symptomatic pericarditis

- Corrected QT interval using Fridericia's formula (QTcF) > 480 msec on the
screening electrocardiogram (ECG) (using the QTcF formula)

- Currently receiving treatment with medication that has a known risk to prolong
the QT interval or inducing Torsades de Pointes, and the treatment cannot be
discontinued or switched to a different medication prior to starting study drug

- Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of study drug (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)

- Patient has a score >= 12 on the Patient Health Questionnaire (PHQ)-9 questionnaire

- Patient selects a response of "1, 2 or 3" to question number 9 on the PHQ-9
questionnaire regarding potential for suicidal thoughts or ideation (independent of
the total score of the PHQ-9)

- Patient has a General Anxiety Disorder (GAD)-7 mood scale score >= 15

- Patient has 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 (e.g. risk of doing harm to
self or others), or patients with active severe personality disorders (defined
according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
[DSM-IV]) are not eligible; Note: for patients with psychotropic treatments ongoing
at baseline, the dose and the schedule should not be modified within the previous 6
weeks prior to start of study drug

- Patient has >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety

- Patient has other prior or concurrent malignancy (except for the following:
adequately treated basal cell or squamous cell skin cancer, or other adequately
treated in situ cancer, early gastric or GI cancer resected completely by endoscopy
procedures or any other cancer from which the patient has been disease free for >= 3
years)

- Patient has a history of non-compliance to medical regimen or inability to grant
consent

- Patient is concurrently using other approved or investigational antineoplastic agent

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL); patients
with elevated hCG at baseline that is judged to be related to the tumor are eligible
if hCG levels do not show the expected doubling when repeated 5-7 days later, or
pregnancy has been ruled out by vaginal ultrasound

- Patient who does not apply highly effective contraception during the study and
through the duration as defined below after the final dose of study treatment:

- Sexually active males should use a condom during intercourse while taking drug
and for 8 weeks after the final dose of study treatment and should not father a
child in this period, but may be recommended to seek advice on conservation of
sperm; a condom is required to be used also by vasectomized men in order to
prevent delivery of the drug via seminal fluid

- Women of child-bearing potential, defined as all women physiologically capable
of becoming pregnant, must use highly effective contraception during the study
and through at least 4 weeks after the final dose of study treatment

- Highly effective contraception is defined as either:

- Total 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)

- Female sterilization: have had surgical bilateral oophorectomy (with or
without hysterectomy) or tubal ligation at least six weeks before taking
study treatment; 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 study
subjects, the vasectomized male partner should be the sole partner for that
patient)

- Use a combination of the following:

- 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
suppository

- Note: hormonal contraception methods (e.g. oral, injected, and
implanted) are not allowed

- 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 have had surgical
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; for
women with therapy-induced amenorrhea, oophorectomy or serial measurements of
follicle-stimulating hormone (FSH) and/or estradiol are needed to ensure
postmenopausal status; NOTE: ovarian radiation or treatment with a luteinizing
hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate)
is not permitted for induction of ovarian suppression