Study of Alisertib (MLN8237) in Adults With Aggressive Non-Hodgkin's Lymphoma

A Phase 2 Trial of MLN8237, an Oral Aurora A Kinase Inhibitor, in Adult Patients With Aggressive Non-Hodgkin's Lymphoma

The purpose of this study is to evaluate the anti-tumor activity of alisertib (MLN8237) in participants with relapsed or refractory non-hodgkin's lymphoma.

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have relapsed or refractory non-Hodgkin's lymphoma (NHL). The study looked at anti-tumor activity in participants who received alisertib.

The study enrolled 48 patients. Participants were categorized as per disease subtypes into five subtypes: Large B-Cell lymphoma, mantle cell lymphoma, transformed follicular lymphoma, Burkitts lymphoma and aggressive T-Cell lymphoma (Note: There were no participants enrolled with Precursor B-lymphoblastic Leukemia/Lymphoma). Participants received:

• Alisertib 50 mg BID on Days 1 to 7

All participants took alisertib capsules approximately every 12 hours each day for 7 days followed by a 14-day rest period in a 21-days cycle. MLN8237 was supplied in capsules of 5 or 25 mg strength.

This multi-center trial was conducted in United States. The overall time to participate in this study was until there is evidence of disease progression or unacceptable treatment-related toxicity. If the participant would derive benefit from continued alisertib treatment beyond 24 months, the Sponsor was consulted for approval of further treatment. Participants made multiple visits to the clinic, with imaging assessments every 12 weeks. Participants discontinuing treatment prior to disease progression continue with clinic visits, chemistry and hematology lab testing, and tumor assessments every 12 weeks up to 12 months after last dose of study drug for follow-up assessments.

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

1. Participant must have histological or cytological diagnosis of a hematological malignancy of the following types that has relapsed or was refractory to prior therapy:

   • Diffuse large B-cell lymphoma
   • Mantle cell lymphoma
   • Burkitt's lymphoma
   • Precursor B-lymphoblastic leukemia/lymphoma
   • T-cell lymphoma, excluding primary cutaneous T-cell lymphoma
   • Transformed follicular lymphoma with ≥ 50% diffuse large cell component.

2. Male or female participants 18 years or older.

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

4. Measurable disease.

Exclusion criteria include the following:

1. Pregnant or lactating females.
2. Known human immunodeficiency virus (HIV) positive or AIDS-related illness.
3. Any serious medical or psychiatric illness that could interfere with the completion of treatment.
4. Total bilirubin ≥ 1.5 × the upper limit of normal (ULN).
5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 2.5 × the ULN. AST, ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to their underlying hematological disorder.
6. Absolute neutrophil count (ANC) < 1,250/mm^3.
7. Platelet count < 75,000/mm^3.
8. Calculated creatinine clearance < 30 mL/minute.
9. Autologous stem cell transplant less than 6 months prior to enrollment.
10. Participants who have undergone allogeneic stem cell or organ transplantation.
11. Systemic antineoplastic therapy including glucocorticoids (> 15 mg prednisone/day or equivalent), or treatment with an investigational agent within 14 days preceding the first dose of study drug treatment.
12. Participants who have received treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment, within 12 weeks prior to first dose.
13. Participants who have received treatment with radioimmunoconjugates or within 12 weeks prior to first dose.
14. Participants who have received radiotherapy within 21 days prior to first dose.
15. Myocardial infarction within 6 months of enrollment or current history of New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
16. Major surgery within 14 days prior to the first dose.
17. Infection requiring systemic antibiotic therapy within 14 days prior to the first dose or other serious infection.
18. Clinically uncontrolled central nervous system (CNS) involvement.
19. Inability to swallow capsules.
20. History of uncontrolled sleep apnoea syndrome and other conditions that could result in excessive daytime sleepiness (eg, Chronic obstructive pulmonary disease - COPD).