MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine

The drug tested in this study was called alisertib. Alisertib was tested to treat people who
have relapsed or refractory diffuse large B-cell lymphoma or other aggressive B-cell
lymphomas. This study looked at safety, any anti-tumor effect, and it also determined a
recommended dose of alisertib plus rituximab and alisertib plus rituximab and vincristine to
take into further studies. Pharmacokinetic blood samples were studied to characterize any
effects on the concentration of each of the drugs when administered together .

The study enrolled 45 patients. Participants received the following treatments:

Phase 1

- Alisertib 50 mg + rituximab in the Safety Lead-in

- Alisertib 30 mg + rituximab + vincristine in the Dose Escalation

- Alisertib 40 mg + rituximab + vincristine in the Dose Escalation

- Alisertib 50 mg + rituximab + vincristine in the Dose Escalation

All participants were asked to take one alisertib table twice a day for 7 days in each cycle
for up to 8 cycles along with rituximab on Day 1 of each cycle; some patients also received
vincristine on Day 1 and Day 8 of each cycle. All participants with documented disease
response or stabilization could continue with alisertib single-agent therapy for an
additional 2 years or more.

This multi-center trial was conducted in the USA. The overall time to participate in this
study was up to 5.2 years. Participants made multiple visits to the clinic, plus a final
visit 30 days after receiving their last dose of study drug for a follow-up assessment.

Inclusion Criteria:

- Histologically confirmed diagnosis of diffuse large B-cell lymphoma
(DLBCL)/transformed follicular lymphoma (TFL). Note: Patients with Mantle Cell or
Burkitt's lymphoma may be eligible for enrollment to the safety lead-in and dose
escalation cohorts, parts 1 & 2 only

- Relapsed or refractory after at least 1 prior systemic treatment for aggressive
lymphoma (including anthracycline unless contra-indicated). Relapse following an
autologous stem cell transplant is allowed.

- Relapsed after autologous stem cell transplantation or not be eligible for autologous
stem cell transplantation or refuse autologous stem cell transplantation. Patients
enrolled to the phase 2 part must have received prior rituximab.

- Measurable disease as specified in study protocol

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

- Female patients who are post menopausal for at least 1 year, surgically sterile, or
agree to practice 2 effective methods of contraception through 30 days after the last
dose of alisertib (MLN8237) or agree to abstain from heterosexual intercourse.
Patients should also use effective contraception for 12 months following the last dose
of rituximab and 1 month following the last dose of alisertib (MLN8237.

- Male patients who agree to practice effective barrier contraception through 4 months
after the last dose of MLN8237 or agree to abstain from heterosexual intercourse

- Voluntary written consent

Exclusion Criteria

- Received more than 4 prior systemic treatment regimens for lymphoma

- Known human immunodeficiency virus (HIV) positive or acquired immunodeficiency
syndrome (AIDS)-related illness; hepatitis B virus, or hepatitis C virus; known
history of Charcot-Marie-Tooth disease or polio

- Autologous stem cell transplant less than 3 months prior to enrollment

- Patients who have undergone allogeneic stem cell or organ transplantation any time

- Systemic antineoplastic therapy, including glucocorticoids or treatment with an
investigational agent within 14 days preceding the first dose of study drug treatment.
Steroids are permitted for administration with rituximab to prevent or treat infusion
reaction

- Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other
unconjugated antibody treatment within 42 days (21 days if clear evidence of
progressive disease) prior to the first day of study drug treatment

- Treatment with radioimmunoconjugates or toxin immunoconjugates, such as
ibritumomab-tiuxetan, or tositumomab, within 12 weeks prior to the first day of study
drug treatment

- Radiotherapy within 21 days prior to the first dose of study drug treatment

- Treatment with enzyme-inducing antiepileptic drugs, such as phenytoin, carbamazepine,
or phenobarbital, or with rifampin, rifabutin, rifapentine, or St. John's wort, within
14 days prior to the first dose of alisertib (MLN8237) also not permitted during study

- Cardiac status as described in protocol

- Major surgery, serious infection, or infection requiring systemic antibiotic therapy
within 14 days prior to the first dose of study treatment

- History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months

- Clinically uncontrolled central nervous system involvement

- Inability to receive IV rituximab or vincristine, or to swallow tablets or inability
or unwillingness to avoid taking anything by mouth except for water and prescribed
medications for 2 hours before and 1 hour after each dose of alisertib (MLN8237)

- History of uncontrolled sleep apnea syndrome and other conditions that could result in
excessive daytime sleepiness

- Female patients who are lactating or pregnant

- Serious medical or psychiatric illness or laboratory abnormality that could, in the
investigator's opinion, potentially interfere with the completion of treatment
according to the protocol

- Clinically apparent ≥ Grade 2 neuropathy due to any cause in the 3 months prior to
enrollment, or history of ≥ Grade 3 neuropathy related to vincristine at any time

- Prior treatment with Aurora A-targeted agents, including alisertib (MLN8237)

- Patients who have received myeloid growth factors or platelet transfusion within 14
days prior to the first dose of study treatment

- Patients with known hypersensitivity to rituximab, vincristine (or vinca alkaloids),
or their diluents