Alisertib in Treating Patients With Relapsed or Refractory Peripheral T-Cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To estimate the objective response rate (complete responses + partial responses) after
treatment with alisertib (MLN8237) in patients with relapsed or refractory peripheral T-cell
non-Hodgkin lymphoma.

II. To assess overall survival (OS) and progression-free survival (PFS) in this patient
population.

III. To evaluate the safety and tolerability of MLN8237 treatment for this patient
population.

IV. To explore the association between pre-treatment aurora kinase A expression in tumor
biopsies as measured by fluorescence in situ hybridization (FISH) and objective response
rate in patients with peripheral T-cell lymphomas (PTCL) treated with MLN8237.

IV. To investigate the copy number, mutational status, expression of aurora kinase (A, B,
and C) and associated signaling pathways in PTCL utilizing tissue microarray analysis (TMA)
before and after treatment with MLN8237.

V. To investigate changes in the serum cytokine profile pre- and post- aurora kinase
Inhibitor treatment.

VI. To evaluate serum markers of apoptosis pre- and post- aurora kinase inhibitor treatment
as pharmacodynamic markers of efficacy.

OUTLINE:

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7. Treatment repeats
every 21 days for 17 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed relapsed/refractory
non-Hodgkin lymphoma (NHL) having progressed after a minimum of one systemic therapy
with any of the following T-cell histologies:

- Peripheral T-cell NHL (PTCL) not otherwise specified (NOS)

- Anaplastic large cell T-cell lymphoma (ALCL) that is anaplastic lymphoma kinase
either positive or negative

- Angioimmunoblastic T-cell NHL

- Subcutaneous panniculitis-like T-cell lymphoma

- Enteropathy-associated T-cell NHL

- Hepatosplenic T-cell lymphomas

- Extranodal natural killer (NK)/T-cell lymphoma, nasal type

- Adult T-cell leukemia/lymphoma

- Unclassifiable PTCL

- Transformed cutaneous T-cell lymphoma (CTCL) to PTCL with systemic involvement
(not local skin transformation)

- No other histologies are eligible; examples of ineligible histologies include:
T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia,
NK-cell leukemia, mycosis fungoides, Sezary syndrome, lymphomatoid papulosis,
and primary CTCL

- Patients must have received at least one course of prior systemic therapy which may
include chemotherapy, antibody therapy, or immunotherapy; for all forms of systemic
therapy, patients must have completed therapy at least 21 days prior to registration;
patients must not be within 84 days of radioimmunotherapy; steroids at a low dose for
control of itching (up to the equivalent of 20 mg of prednisone daily) are allowed

- Patients may have received prior radiation in combination with systemic therapy;
patients must not be within 21 days of external beam radiation therapy

- Patients must not have received a previous allogeneic stem cell transplant or be
within 90 days of an autologous stem cell transplant

- Adequate sections and a paraffin block from the relapsed/refractory specimen must be
submitted for review by the lymphoma pathology group; an adequate biopsy requires
sufficient tissue to establish the architecture and a Revised European American
Lymphoma (REAL) or World Health Organization (WHO) histologic subtype with certainty;
thus, core biopsies, especially multiple core biopsies MAY be adequate; whereas,
needle aspirations or cytologies are not adequate

- Patients must have bidimensionally measurable disease within 28 days prior to
registration; a diagnostic quality computed tomography (CT) scan of the chest
abdomen, pelvis, neck and positron emission tomography (PET)/CT must be performed
within 28 days of registration (PET/CT scan can be done instead of separate PET and
CT scans only if the CT component is a diagnostic CT with contrast); patients who
also have non-measurable disease in addition to measurable disease must have all
non-measurable disease assessed within 42 days prior to registration

- Patients must have a bilateral or unilateral bone marrow aspirate and biopsy
performed within 42 days prior to registration

- Patients must not have clinical evidence of central nervous system involvement by
lymphoma; any laboratory tests that are performed to assess clinical signs of central
nervous system involvement must have been performed within 42 days prior to
registration, and the results must be negative

- Patients must be able to swallow tablets

- Patients known to be human immunodeficiency virus (HIV)-positive must not have
multi-drug resistant HIV infection, CD4 counts < 150/mcL, or other concurrent
acquired immunodeficiency syndrome (AIDS)-defining conditions

- Patients must be offered the opportunity to consent to the banking of specimens for
future use

- Absolute granulocyte count >= 1,500 cells/mcL; patients with documented marrow
involvement may be transfused to this value

- Platelet count >= 75,000 cells/mcL; patients with documented marrow involvement may
be transfused to this value

- Serum creatinine (mg/dL) =< institutional upper limit of normal (IULN) obtained
within 14 days prior to registration

- Calculated creatinine clearance > 50 ml/min; the serum creatinine value used in the
calculation must have been obtained within 14 days prior to registration

- Serum bilirubin =< 2 times institutional upper limit of normal

- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 2.5
x IULN

- Serum lactate dehydrogenase (LDH) obtained within 14 days prior to registration

- Patients must have a Zubrod performance status of 0, 1, or 2

- Patients must NOT have New York Heart Association (NYHA) class II-IV heart failure

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease free for five years

- Pregnant or nursing women are not eligible; women/men of reproductive potential must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation and for
4 months after completion of MLN8237 administration; should a woman become pregnant
or suspect she is pregnant while she or her partner is participating in this study,
the patient should inform the treating physician immediately

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines