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

Study Overview
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Brief Summary
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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.

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 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.

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

Conditions
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Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, Burkitt's Lymphoma, T-cell Lymphoma, Excluding Primary Cutaneous T-cell Lymphoma, Transformed Follicular Lymphoma With ≥ 50% Diffuse Large Cell Component

Intervention / Treatment
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* Drug: Alisertib


Participation Criteria
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Eligibility Criteria
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Each participant must meet all of the following inclusion criteria to be enrolled in the study: 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. Male or female participants 18 years or older. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Measurable disease. Exclusion criteria include the following: Pregnant or lactating females. Known human immunodeficiency virus (HIV) positive or AIDS-related illness. Any serious medical or psychiatric illness that could interfere with the completion of treatment. 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 up to 5 times the ULN if their elevation can be reasonably ascribed to their underlying hematological disorder. Absolute neutrophil count (ANC) < 1,250/mm^3. Platelet count < 75,000/mm^3. Calculated creatinine clearance < 30 mL/minute. Autologous stem cell transplant less than 6 months prior to enrollment. Participants who have undergone allogeneic stem cell or organ transplantation. 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. Participants who have received treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment, within 12 weeks prior to first dose. Participants who have received treatment with radioimmunoconjugates or within 12 weeks prior to first dose. Participants who have received radiotherapy within 21 days prior to 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 within 14 days prior to the first dose. Infection requiring systemic antibiotic therapy within 14 days prior to the first dose or other serious infection. Clinically uncontrolled central nervous system (CNS) involvement. Inability to swallow capsules. History of uncontrolled sleep apnoea syndrome and other conditions that could result in excessive daytime sleepiness (eg, Chronic obstructive pulmonary disease - COPD).

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 50 mg<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 24 months or longer with Sponsor approval). | 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 Based on Investigator's Assessment (Applying the IWG 2007 Response Criteria) | Best overall response rate is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the Investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites (as specified in the Cheson 2007, IWG response criteria). | Baseline and every 2 cycles up to Month 12 (approximately 16 cycles), from Cycle 16 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months from last dose (Up to 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | Time to progression (TTP) is defined as the time in days from the date of first study drug administration to the date of first documentation of Progressive Disease (PD) according to IWG criteria (Cheson 2007). PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. | Baseline and every 2 cycles up to Month 12, from Cycle 16 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Up to 4 years) | 
| Progression Free Survival (PFS) | PFS is defined as the time in days from the date of first study drug administration to the date of first documentation of progressive disease (PD) or death. | Baseline and every 2 cycles up to Month 12, from Cycle 16 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Up to 4 years) | 
| Duration of Response (DOR) | DOR is defined as the time from the date of first documentation of a CR, or partial response (PR) to the date of first documentation of PD according to IWG criteria. CR definition includes the complete disappearance of all evidence of disease, the definition of PR includes at least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses, and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir, as described in the IWG response criteria (Cheson 2007). | Baseline and every 2 cycles up to Month 12, from Cycle 16 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Up to 4 years) | 
| Number of Participants With Treatment-Emergent Adverse Events | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug and includes all-causality (ie, treatment-related and not treatment-related as assessed by the investigator). | First dose of study drug to 30 days after last dose (Up to 25 months) | 
| Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events | Vital signs (blood pressure, heart rate, and oral temperature) measurements 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 25 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 using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE V4). 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 25 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MLN8237, Alisertib, Drug therapy