A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas

Study Overview
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Brief Summary
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The purpose of this study was to determine the safety profile, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetic (PK) profile of alisertib twice daily (BID) dosing for 7 days in East Asian participants with advanced solid tumors or lymphomas. The secondary objective was to describe any antitumor activity that may have been observed with alisertib treatment.

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 advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment did not exist or was no longer effective or tolerable. This study evaluated the safety and pharmacokinetic (PK) profile, and maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of alisertib, as well as any antitumor activity. The study enrolled 36 patients. Participants were assigned to one of the two treatment groups and received: Alisertib 30 mg Alisertib 40 mg All participants took two enteric-coated tablets every 12 hours each day for 7 days followed by a 14-day rest period in a 21-day cycle for up to 16 cycles. This multi-center trial is conducted in East Asia. The overall time to participate in this study was 24 months, unless it was determined that a participant would derive benefit from continued therapy beyond 24 months. Participants made multiple visits to the clinic, and were contacted up to a maximum of 30 days after last dose of study drug for a follow-up assessment.

Official Title
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A Phase 1 Dose Escalation and Pharmacokinetic Study of Alisertib (MLN8237), an Aurora A Kinase Inhibitor, in Adult East Asian Patients With Advanced Solid Tumors or Lymphomas

Conditions
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Advanced Solid Tumors, Lymphomas

Intervention / Treatment
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* Drug: Alisertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female East Asian participants 18 years or older Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas for which no effective standard treatment is available Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Expected survival longer than 3 months from study enrollment Radiographically or clinically evaluable tumor Female participants 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 study drug or agree to abstain from heterosexual intercourse Male participants who agree to practice effective barrier contraception through 6 months after the last dose of alisertib or agree to abstain from heterosexual intercourse Voluntary written consent Exclusion Criteria: Female participants who are lactating or pregnant Treatment with any investigational products, systemic antineoplastic treatment, or antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of alisertib Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease) Medical conditions requiring daily, chronic, or regular use of proton pump inhibitors or H2-receptor antagonists Treatment with radioimmunoconjugates such as ibritumomab tiuxetan or tositumomab within 56 days preceding first alisertib dose Major surgery within the 14 days preceding the first dose of alisertib Life-threatening or uncontrolled medical illness unrelated to cancer Known gastrointestinal (GI) disease or procedures that could interfere with the oral absorption or tolerance of alisertib Inability to swallow capsules Inadequate bone marrow or other organ function Diagnosed or treated for another malignancy within 2 years of first dose of alisertib, or previously diagnosed with another malignancy and have any radiographic or biochemical marker evidence of active disease. In the case of prior prostate cancer treated with radiotherapy, the prostate specific antigen (PSA) may be detectable, but must be < 1 ng/mL. Participants with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy of any type are not excluded Other severe acute or chronic medical or psychiatric conditions, including uncontrolled diabetes, or laboratory abnormality Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib 30 mg<br>Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2. | Drug: Alisertib<br>* Alisertib enteric-coated tablets<br>* Other names: MLN8237;|
| Experimental: Alisertib 40 mg<br>Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2. | Drug: Alisertib<br>* Alisertib enteric-coated tablets<br>* Other names: MLN8237;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | MTD was defined as highest dose at which <2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets <25,000/mm^3) for >7 days; 4. Platelet count <10,000 cells/mm^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by >7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting <1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment. | Treatment Cycle 1 | 
| Number of Participants With Adverse Events and Serious 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 Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. | First dose to 30 days past last dose (Up to 12.1 Months) | 
| Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | First dose to 30 days past last dose (Up to 12.1 Months) | 
| Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study. | First dose to 30 days past last dose (Up to 12.1 Months) | 
| Cmax: Maximum Observed Concentration for Alisertib |  | Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose | 
| Tmax: Time to First Occurrence of Cmax for Alisertib |  | Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose | 
| AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib |  | Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose | 
| Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib | Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams. | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | 
| T1/2: Terminal Half-Life for Alisertib |  | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | 
| Rac: Accumulation Ratio for Alisertib |  | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | 
| PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib |  | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | 
| CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib |  | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate Based on Investigator Assessment | Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions. | Baseline and every 2 cycles for up to 24 months or until progressive disease | 
| Duration of Response | DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions. | First documented response until disease progression; approximately 12 months | 
| Concentrations of Relevant Tumor Markers |  | Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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East Asian Patients, Advanced solid tumors, Lymphomas, MLN8237, Alisertib, Aurora A Kinase Inhibitor, Drug therapy