Phase I Trial of BKM120 in Combination With Carboplatin and Pemetrexed in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Inclusion Criteria:

- Patients who have signed a written informed consent

- Patients must have a histologic or cytologic diagnosis of advanced, nonsquamous NSCLC
(stage IV by American Joint Committee on Cancer [AJCC] 7th edition [ed.])

- Patients should not have received prior systemic chemotherapy for metastatic disease
(prior epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]
therapy is allowed); prior adjuvant or neoadjuvant therapy for early stage disease is
allowed if received >= 12 months prior to study entry

- Prior radiation therapy is allowed to < 25% of the bone marrow; prior radiation must
be completed at least 2 weeks prior to day 1 of cycle 1, and patients must have
recovered from the acute toxic effects

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Patients must have at least one site of measurable disease (per Response Evaluation
Criteria in Solid Tumors [RECIST] 1.1)

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

- Platelets >= 100 x 10^9/L

- Hemoglobin (Hb) > 9 g/dL

- Total calcium (corrected for serum albumin) within normal limits (bisphosphonate 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 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)

- Serum creatinine =< 1.5 x ULN or calculated or 24-hour clearance >= 45 mL/min
(calculated creatinine clearance based on Cockcroft-Gault formula)

- 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

- International normalized ratio (INR) =< 2

Exclusion Criteria:

- Patients who have received prior treatment with a P13K inhibitor or mammalian target
of rapamycin (mTOR)-directed inhibitor

- Patients with a known hypersensitivity of 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 > 2 weeks from therapy completion (incl. radiation and/or surgery), is
clinically stable at the time of study entry; stable corticosteroids treatment (e.g.
dexamethasone 2 mg/day, prednisolone 10 mg/day) is permitted if it was initiated at
least 14 days before start of study treatment

- Patients with acute or chronic liver, renal disease or pancreatitis

- Patient has any of the following mood disorders as judged by the investigator or a
psychiatrist, or as a result of the 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 Patient Health Questionnaire (PHQ)-9 or
a cut-off of >= 15 in the Generalized Anxiety Disorder 7-item (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)

- Patients with diarrhea >= CTCAE grade 2

- Left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram
(ECHO)

- Corrected QT interval (QTc) > 480 msec on screening electrocardiogram (ECG) (using
the Fridericia correction QTc [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

- Myocardial infarction 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)

- 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 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 the lung for 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 BJM120 (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 must be able
to swallow capsules whole

- 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 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
airway 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; premedication
dexamethasone for pemetrexed is allowed

- Patients who are currently treated with drugs known to be moderate and strong
inhibitors or inducers of isoenzyme cytochrome P450 3A4 (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 and inducers of CYP3A4 is
allowed)

- Herbal preparations/medication including but are not limited to St. John's wort,
kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw
palmetto, ginseng; patients should stop using these herbal medications 7 days prior
to first dose of study drug

- Patients who have received systemic chemotherapy =< 4 weeks (4 weeks for nitrosourea,
antibodies or mitomycin-C) and prior to starting study drug toxicities 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

- 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 (Coumadin) or
any other warfarin-derivative anticoagulant

- 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; 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 follicle stimulating hormone (FSH)
levels > 40 mIU/mL (for United States [US] only: and estradiol < 20 pg/mL) or
have had surgical bilateral 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 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:

- 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 should be the sole partner for that patient

- 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
suppository

- Oral contraception, injected or implanted hormonal methods are not allowed

- Fertile males, defined as all males physiologically capable of conceiving
offspring, must use a condom during treatment, for 5 T1/2 (8 days) after
stopping treatment and for an 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
the investigator