Alisertib With and Without Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the efficacy of MLN8237 (alisertib) alone in patients with relapsed and
refractory non-Hodgkin lymphoma (NHL) and transformed NHL.

SECONDARY OBJECTIVES:

I. To determine the efficacy of MLN8237 when combined with rituximab in NHL patients who fail
to respond to MLN8237 alone in patients with relapsed and refractory NHL and transformed NHL.

II. To determine specific toxicities associated with MLN8237 alone and when combined with
rituximab (in NHL patients) in patients with relapsed and refractory NHL and transformed NHL.

III. To determine pharmacokinetics of MLN8237 alone and in combination with rituximab (for
NHL patients) in patients with relapsed and refractory NHL and transformed NHL.

IV. To evaluate specific molecular characteristics of the NHL for patients treated with
MLN8237 alone and with rituximab in order to correlate particular molecular markers with
response and survival.

V. To evaluate long term survival of patients treated with MLN8237 alone and with rituximab.

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

COHORT A: Patients receive alisertib orally (PO) twice daily (BID) on days 1-7. Patients
unable to achieve complete response (CR) after course 4 also receive rituximab intravenously
(IV) on day 1 of courses 5-12. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

COHORT B: Patients receive alisertib as in Cohort A. Patients achieving stable disease (SD)
or asymptomatic progressive disease after 2 courses also receive rituximab IV on day 1 of
courses 3-10. Patients unable to achieve CR by course 4, receive rituximab as in Cohort A.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Must have histologically proven relapsed or refractory B-cell NHL of the following
World Health Organization (WHO) classification subtypes: follicular lymphoma (FL),
mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia
(LPL/WM), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL),
Burkitt's lymphoma (BL), and B-cell lymphoma with features unclassifiable between
Burkitt's and large cell lymphoma; alternatively, patients with histologically proven,
newly diagnosed transformed non-Hodgkin's lymphoma (tNHL) are eligible

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

- At least one prior therapy; patients with newly diagnosed tNHL are eligible and do not
need to have received prior therapy for the transformed lymphoma or prior indolent
NHL; prior autologous stem cell transplant is allowed

- Serum creatinine =< 2.0 mg/dL

- Total bilirubin within normal limits

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x upper limit
of normal

- Absolute neutrophil count (ANC) >= 1000/μL

- Platelet count >= 75,000/μL

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

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care

- Female subject is either post-menopausal or surgically sterilized or willing to use an
acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study

- Male subject agrees to use an acceptable method for contraception during the entire
study treatment period through 4 months after the last dose of MLN8237

- Must be able to take oral medication and to maintain a fast as required for 2 hours
before and 1 hour after MLN8237 administration

Exclusion Criteria:

- Pregnant or breast-feeding women and women of childbearing age who are unwilling to
use adequate contraception

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

- Patients with known human immunodeficiency virus (HIV), hepatitis B or hepatitis C
(active or carriers) are not eligible; this includes all patients with a positive
hepatitis C antibody, hepatitis B surface antigen, or hepatitis B core antibody;
previously vaccinated patients with positive hepatitis B surface antibody are eligible

- May not have received prior therapy with an Aurora kinase inhibitor

- Patients eligible for and willing to undergo autologous stem cell transplant with
curative intent at the time of enrollment are not eligible; patients refractory to at
least 2 prior regimens may enroll and proceed to curative autologous transplant if
they respond

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

- Radiation therapy to more than 25% of the bone marrow; whole pelvic radiation is
considered to be over 25%

- Prior allogeneic bone marrow or organ transplantation

- If applicable, patient has >= grade 2 peripheral neuropathy within 14 days before
enrollment

- Known history of uncontrolled sleep apnea syndrome and other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease; requirement for supplemental oxygen

- Patients who are on daily proton pump inhibitor therapy must be able to discontinue
use or only require use of antacid or hydrogen (H2) antagonist intermittently;
patients who require daily administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes are not eligible; intermittent uses of antacids or H2 antagonists
are allowed

- Systemic infection requiring IV antibiotic therapy within 14 days preceding the first
dose of study drug, or other severe infection

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities (except asymptomatic patients with
a pacemaker with electrocardiogram (ECG) changes reflecting conduction abnormalities
secondary to the pacemaker); prior to study entry, any ECG abnormality at screening
has to be documented by the investigator as not medically relevant

- Female subject is pregnant or breast-feeding; confirmation that the subject is not
pregnant must be established by a negative serum β-human chorionic gonadotropin
(β-hCG) pregnancy test result obtained during screening; pregnancy testing is not
required for post-menopausal or surgically sterilized women

- Patient has received other investigational drugs with 14 days before enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study

- Other severe acute or chronic medical or psychiatric condition, including uncontrolled
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement
for pancreatic enzymes, any condition that would modify small bowel absorption of oral
medications, or laboratory abnormality that may increase the risk associated with
study participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for enrollment in this study

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

- Treatment with clinically significant enzyme inducers, such as the enzyme- inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin,
rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and
during the study

- Patients with a corrected QT interval (QTc) at baseline of > 450 milliseconds or other
factors that increase the risk of QT prolongation or arrhythmic events (i.e., heart
failure, hypokalemia with potassium < 3.5 despite supplementation, family history of
long QT syndrome) should be excluded

- Patients who require use of a concomitant medication that can prolong the QT interval
and who are unable to discontinue use of this medication during the study period are
excluded