Study of BKM120 & Rituximab in Patients With Relapsed or Refractory Indolent B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of
combined rituximab and BKM120 (PI3k inhibitor BKM120) in patients with previously treated
indolent non-Hodgkin lymphoma (NHL) (including follicular lymphoma (FL), marginal zone
lymphoma, and lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia), and mantle cell
lymphoma (MCL).

SECONDARY OBJECTIVES:

I. To determine specific toxicities associated with combined BKM120 and rituximab.

II. Evaluate for efficacy of BKM120 in combination with rituximab in these diseases.

OUTLINE: This is a dose-escalation study of PI3K inhibitor BKM120.

Patients receive PI3K inhibitor BKM120 orally (PO) daily on days 1-28 and rituximab
intravenously (IV) on days 2, 8, 15, and 22 of course 1 and on day 1 of courses 3, 5, 7, 9,
and 11. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity. Patients with asymptomatic progression may continue treatment for up to 12 months.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have histologically confirmed indolent B-cell NHL or mantle cell
lymphoma; acceptable subtypes of indolent B-cell NHL include follicular lymphoma
(grades 1, 2, or 3a), marginal zone lymphoma, or lymphoplasmacytic
lymphoma/Waldenstrom's macroglobulinemia; patients with mantle cell lymphoma must have
a documented t(11;14) or overexpression of cyclin D1 by immunohistochemical
evaluation; patients with active large cell transformation are not eligible; however,
patients with a history of large cell transformation are eligible provided that there
is no current clinical evidence of active transformed lymphoma

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- At least one prior therapy; prior autologous or allogeneic stem cell transplant is
allowed; patients may not be on chronic immunosuppressive therapy for
graft-versus-host disease (GVHD); patients who have received prior treatment with a
pan-selective PI3K inhibitor are not eligible; however, prior therapy with a selective
PI3K inhibitor, Bruton's tyrosine kinase inhibitor, or other B-cell receptor targeting
agents is allowed

- Serum creatinine =< 2.0 mg/dL

- Total bilirubin =< upper limit of normal

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.0 x upper limit
of normal

- Absolute neutrophil count (ANC) >= 750/mm^3

- Platelets >= 50,000/ mm^3

- Serum lipase =< upper limit of normal

- Serum amylase =< upper limit of normal

- International normalized ratio (INR) =< 2.0

- Fasting glucose < 120mg/dL

- Recovery to =< grade 1 toxicities associated with prior therapy

- Negative serum pregnancy test; if, on cycle 1 day 1, greater than 72 hours has elapsed
since the last negative result, a serum pregnancy test must be repeated and be
negative on cycle 1 day 1 (C1D1) for the patient to remain eligible

- Patient has the ability and willingness to provide informed consent and has signed the
informed consent document

Exclusion Criteria:

- Pregnant or breast-feeding women and women of childbearing age or men who are
unwilling to use adequate contraception; females of childbearing age and potential
(i.e., not surgically sterilized) must use a second form of contraception, including
total abstinence, intra-uterine device, double-barrier contraception, or other
non-hormonal form of contraception

- Patients with a history of central nervous system involvement by lymphoma

- The presence of co-existing medical conditions that would limit compliance with study
medications, including, but not limited to active infection, active or untreated
cardiac or pulmonary disease, or malignancy

- Patients with significant, symptomatic deterioration of lung function confirmed by
spirometry, diffusion capacity of carbon monoxide (DLCO), or resting oxygen (O2)
saturation

- Patients with impairment of gastrointestinal function that may alter the absorption of
BKM120

- Patients currently being actively treated or who have been treated within the past 3
years for an unrelated malignancy (except non-melanoma skin cancer, cervical carcinoma
in-situ, and low risk prostate cancer)

- Patients who have undergone major surgery within 2 weeks prior to study enrollment or
who have not recovered from a major surgery

- Patients with known human immunodeficiency virus (HIV), hepatitis B or hepatitis C
(active or carriers)

- Patients with a fasting blood glucose >= 120 mg/dL (6.7mmol/L); patients with diabetes
mellitus are eligible if they require oral agents only and have a fasting blood
glucose =< 120 mg/dL; patients with a history of diabetes mellitus who require daily
long-acting or mealtime insulin are not eligible; patients who have previously
required treatment for hyperglycemia due to steroids or other medications are eligible
as long as they have not required insulin or any other oral agent within 2 months
prior to study enrollment

- Patients who are on chronic steroids for unrelated conditions (i.e. rheumatologic
conditions) are not eligible if their total daily dose of steroids is >= 10mg
prednisone

- Patients with a known hypersensitivity to BKM120 or its excipients

- Patients with active moderate or severe major mood or psychiatric disorder as judged
by the investigator, primary care physician, counselor, psychiatrist, or as a result
of the patient's mood assessment questionnaire that may interfere with the ability to
comply with the trial; in addition, given the prior mood-associated toxicities,
patients with a history of psychiatric hospitalization within the past 5 years,
electroconvulsive therapy (ECT) within the past 5 years, or whose psychiatric
condition has been unstable within 2 months prior to study enrollment requiring
addition or change of psychotropic medications are not eligible; examples include, but
are not limited to:

- Medically documented history of or active major depressive episode requiring
inpatient or intensive outpatient therapy, bipolar disorder (I or II),
obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or
active ideation, or homicidal ideation (immediate risk of doing harm to others);
patients under the care of a primary care physician who are treated with one oral
agent and who have not required dose adjustments or new medications within 2
months prior to study enrollment and who otherwise meet eligibility requirements
may be enrolled

- >= Common Terminology for Adverse Events (CTCAE) version 4.0 grade 3 anxiety

- Patients meeting the cutoff score of >= 12 in the Patient Health Questionnaire-9
(PHQ-9) or a cut-off of >= 15 in the Generalized Anxiety Disorder-7 (GAD-7) mood
scale, respectively, or who select 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) are not eligible

- Patients with diarrhea >= CTCAE grade 2

- Patients with active cardiac disease including any of the following:

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

- Corrected QT interval (QTc) > 480 msec on screening ECG (using the QTcF formula)

- Active angina pectoris

- Ventricular arrhythmias except for benign premature ventricular contractions

- Supraventricular or nodal arrhythmias or any conduction abnormality requiring a
pacemaker or automatic implantable cardioverter defibrillator (AICD)

- Valvular disease with documented compromise in cardiac function

- Symptomatic pericarditis

- Myocardial infarction within the past 6 months

- Congestive heart failure (New York Heart Association [NYHA] functional
classification III-IV)

- Patients who are currently receiving treatment with medications 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 study enrollment

- Patients who have taken herbal medications and certain fruits within 7 days prior to
study enrollment are not eligible; 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; exclusionary fruits include the cytochrome
P450 family 3, subfamily A, polypeptide 4 (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 study enrollment; (please note that
co-treatment with weak inhibitors of CYP3A is allowed)

- Patients who have received oral or IV chemotherapy, targeted anticancer therapy or
radiation therapy =< 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C)
prior to study enrollment

- Patients who are currently taking therapeutic doses of warfarin sodium or any other
Coumadin-derivative anticoagulant; patients who can be safely changed to enoxaparin or
other non-warfarin derived anti-coagulant and who otherwise meet eligibility
requirements may be enrolled