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

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

Detailed Description
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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.

Official Title
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A Phase 2 Trial of MLN8237, an Oral Aurora A Kinase Inhibitor, in Adult Patients With Acute Myelogenous Leukemia and High-Grade Myelodysplastic Syndrome

Conditions
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Acute Myelogenous Leukemia, High-Grade Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Alisertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each participants must meet all of the following inclusion criteria: Male or female participants 18 years or older 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. Eastern Cooperative Oncology Group performance status 0-2 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. Male participants: Practice effective barrier contraception to one month after the last dose of study drug, or Abstain from heterosexual intercourse. Voluntary written consent Participants on hydroxyurea may be included Exclusion Criteria: Pregnant or lactating females Known human immunodeficiency virus (HIV) positive or acquired immune deficiency syndrome (AIDS) - related illness Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the protocol completion Total bilirubin > 1.5 × the upper limit of normal (ULN) 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. Calculated creatinine clearance < 30 mL/minute Antineoplastic or radiotherapy within 14 days preceding the first dose 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 Major surgery 14 days prior to the first dose Clinically uncontrolled central nervous system (CNS) involvement. Inability to swallow capsules History of uncontrolled sleep apnea or conditions that result in excessive daytime sleepiness, such as chronic lung disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib<br>Alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Drug: Alisertib<br>* Alisertib capsules<br>* Other names: MLN8237;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate (ORR) Based on Investigator's Assessment | Best ORR is defined as the number of participants with complete remission(CR) or partial remission(PR) assessed by the Investigator using modified AML/MDS International Working Group(IWG) Criteria. AML:CR=neutrophils >1x10^9/L, platelets >100x10^9/L, bone marrow blasts(BMB) <5%, transfusion independent, no extramedullary disease(EMD); CRi=BMB <5%, transfusion independent, no EMD; PR=neutrophils >1x10^9/L, platelets >100x10^9/L, BMB >50% decrease and 5% to 25%, blasts <5% with Auer rods; PRi=BMB >50% decrease and 5% to 25%. MDS:CR=bone marrow: ≤5% myeloblasts with normal maturation, peripheral blood: hemoglobin ≥11 g/dL, platelets ≥100x10^9/L, neutrophils ≥1.0x10^9/L, blasts 0%; PR=all CR criteria if abnormal before treatment except: BMB decreased by ≥50% over pretreatment but still >5%; PRi=BMB decreased by ≥50% over pretreatment but still >5%; Marrow CR=bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment, peripheral blood hematologic improvement responses noted. | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date of first study drug administration to the date of first documented progressive disease (PD) or death. | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) | 
| Duration of Response (DOR) | Duration of response is defined as the time from the date of first documentation of a response to the date of first documented PD. | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) | 
| Best Overall Hematologic Improvement (HI) Response for Myelodysplastic Syndrome Based on Investigator Assessment | Best overall HI response is defined as percentage of participants with response as assessed by Investigator based on IWG criteria: 1)Erythroid response (pretreatment,<11 g/dL): hemoglobin (Hgb) increase by ≥1.5 g/dL, relevant reduction of units of red blood cell (RBC) transfusions by absolute number of at least 4 RBC transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks. Only RBC transfusions given for Hgb of ≤9.0 g/dL pretreatment will count in RBC transfusion response evaluation. 2)Platelet response (pretreatment,<100x10^9/L):Absolute increase of ≥30x10^9/L for participants starting->20x10^9/L platelets, increase <20x10^9/L to >20x10^9/L by at least 100%. 3)Neutrophil response (pretreatment,<1.0x10^9/L):At least 100% increase and an absolute increase >0.5x10^9/L. 4)Progression or relapse after HI:At least 1 of following: 50% decrement from maximum response levels in granulocytes or platelets, or reduction in Hgb by ≥1.5 g/dL, or transfusion dependence. | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. | First dose of study drug to 30 days after last dose (Up to 18.9 months) | 
| Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events | Vital signs measurements (blood pressure, heart rate, and oral temperature) were obtained throughout the study. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | First dose of study drug to 30 days after last dose (Up to 18.9 months) | 
| Number of Participants With Abnormal Laboratory Values Reported as Treatment-Emergent Adverse Events | Abnormal Laboratory Values for Chemistry or Hematology tests that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. A treatment--emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | First dose of study drug to 30 days after last dose (Up to 18.9 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy