A Phase 2 Trial of MLN8237 in Adult Participants With Acute Myelogenous Leukemia and High-Grade Myelodysplastic Syndrome

This is an open-label, multicenter, phase 2 study of alisertib (MLN8237) in participants with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome (MDS). This study looked at the antitumor activity in people who received alisertib.

The study enrolled 57 patients. Participants were categorized by disease sub-types AML and MDS. Participants received:

• Alisertib 50 mg

All participants took alisertib capsules every 12 hours each day for 7 days followed by a 14-day rest period in 21-day cycles for approximately 26 cycles.

This multi-center trial was conducted in North America and France. The overall time to participate in this study was until there is evidence of disease progression or unacceptable treatment-related toxicity. The participant could continue treatment beyond 12 months if it was considered by the Sponsor and the Investigator that they would derive benefit from continued alisertib treatment. Participants had weekly blood work and clinic visits, with disease assessments every 2 cycles (ie. every 6 weeks) up to and including Cycle 16. Reduced visits (every 12 weeks) were conducted for participants tolerating treatment beyond Cycle 16 and for participants off treatment without disease progression.

Eligibility Criteria:
Inclusion Criteria:

Each participants must meet all of the following inclusion criteria:

1. Male or female participants 18 years or older
2. Eligible diagnoses:

   * Acute myelogenous leukemia (except acute promyelocytic leukemia \[APL\]) with \> 10% bone marrow or peripheral blood blasts; failed to achieve complete response (CR) or relapse after prior therapy, not candidates for potentially curative treatment. Untreated participants \> 60 are eligible if not candidates for standard induction.
   * High-grade myelodysplastic syndrome (MDS), defined by all the following features: International Prognostic Scoring System (IPSS) Intermediate-2 or High Risk; \> 10% blasts on bone marrow examination; treatment failure from, or not candidates for, standard therapies including demethylating agents, e.g. azacytidine or decitabine.
3. Eastern Cooperative Oncology Group performance status 0-2
4. Female participants:

   * Postmenopausal for at least one year
   * Surgically sterile, or
   * If childbearing potential, agree to practice two effective methods of contraception or abstain from heterosexual intercourse.
5. Male participants:

   * Practice effective barrier contraception to one month after the last dose of study drug, or
   * Abstain from heterosexual intercourse.
6. Voluntary written consent
7. Participants on hydroxyurea may be included

Exclusion Criteria:

1. Pregnant or lactating females
2. Known human immunodeficiency virus (HIV) positive or acquired immune deficiency syndrome (AIDS) - related illness
3. Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the protocol completion
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 to 5 x the ULN if reasonably ascribed to underlying hematological disorder.
6. Calculated creatinine clearance \< 30 mL/minute
7. Antineoplastic or radiotherapy within 14 days preceding the first dose
8. 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
9. Major surgery 14 days prior to the first dose
10. Clinically uncontrolled central nervous system (CNS) involvement.
11. Inability to swallow capsules
12. History of uncontrolled sleep apnea or conditions that result in excessive daytime sleepiness, such as chronic lung disease