Mass Balance, Pharmacokinetics and Metabolism Study of Alisertib

Study Overview
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Brief Summary
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The purpose of this study is to assess the mass balance (i.e. cumulative excretion of total radioactivity [TRA] in urine and feces) of alisertib and pharmacokinetic (PK) of alisertib in plasma and urine, and of TRA in plasma and whole blood.

Detailed Description
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The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat participants who have advanced solid tumors or lymphomas. This study looked at mass balance, pharmacokinetics (PK), metabolism, elimination and safety of alisertib. The study enrolled 3 patients. The study consisted of 2 parts: Part A and Part B. Participants received: [^14C]-alisertib 35 mg in Part A alisertib 50 mg in Part B Participants were asked to take a single dose of [^14C]-alisertib oral solution containing 80-100 μCi of total radioactivity (1.19-1.48 mCi/mmol) in Part A and alisertib 50 mg, orally, twice daily for 7 days in 21-day cycles until disease progression or unacceptable toxicity in Part B. This single center trial was conducted in United States. The overall time to participate in this study was up to 117 days. Participants remained confined to clinic in Part A and made multiple visits to the clinic in Part B. Participants were contacted 30 days after last dose of alisertib in Part A (if not continuing in Part B), or were contacted by telephone or a final visit 30 days after receiving their last dose of alisertib in Part B for a follow-up assessment.

Official Title
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Mass Balance, Pharmacokinetics, and Metabolism of [^14C]-Alisertib in Patients With Advanced Solid Tumors or Lymphomas

Conditions
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Advanced Solid Tumors, Lymphoma

Intervention / Treatment
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* Drug: [^14C]-alisertib
* 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 to be enrolled in the study: 18 years or older. Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment does not exist, or is no longer effective or tolerable. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Expected survival longer than 3 months from enrollment in the study. Radiographically or clinically evaluable tumor. Suitable venous access for the conduct of blood sampling. Recovered from the reversible effects of prior antineoplastic treatment (with the exception of alopecia and Grade 1 neuropathy). Female participants who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time. Male participants who agree to practice effective barrier contraception during the entire study and through 4 months after the last dose of study drug OR agree to abstain from heterosexual intercourse. Exclusion Criteria: Participants meeting any of the following exclusion criteria are not to be enrolled in the study: Female participants who are lactating or have a positive serum pregnancy test. Treatment with any investigational products or systemic antineoplastic treatment within 21 days before the first dose of alisertib. Medical conditions requiring daily, chronic, or regular use of proton pump inhibitors(PPIs) within 7 days preceding the first dose of alisertib, or H2-receptor antagonists within 24 hours preceding the first dose of alisertib. Participants requiring systemic anticoagulation (excluding low-dose aspirin, or low-dose anticoagulation to maintain patency of venous access devices). Low molecular weight heparin, administered as preventive treatment, is allowed if the participant has tolerated treatment with a stable dose and schedule without bleeding complications for more than 1 month. Major surgery within the 14 days preceding the first dose of alisertib. Infection requiring systemic intravenous (IV) antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection. Life-threatening or uncontrolled medical illness unrelated to cancer. Ongoing nausea or vomiting that is Grade 2 or worse in intensity. Diarrhea that is Grade 2 or worse in intensity or use of an antimotility agent to control diarrhea to an intensity of Grade 1 or lower level. Known GI disease or GI procedures that could interfere with the oral absorption, excretion, or tolerance of alisertib. History of urinary and/or fecal incontinence. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease. Inability to swallow tablets, or inability or unwillingness to avoid taking anything by mouth except for water and prescribed medications for 2 hours before and 1 hour after the first dose of alisertib. Inadequate bone marrow or other organ function as specified in study protocol. Any cardiovascular condition specified in the study protocol. Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Inability to comply with study visits and procedures including required inpatient confinement (approximately 11-17 days). Please note that there are additional exclusion criteria. The study center will determine if you meet all of the criteria.

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>Part A: [^14C]-alisertib 35 mg, oral solution containing 80 - 100 microcuries (μCi) of total radioactivity (1.19 - 1.48 mCi/mmol), orally, single dose on Day 1. Part B: Alisertib 50 mg, enteric coated tablets, 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 3 Cycles). | Drug: [^14C]-alisertib<br>* [^14C]-alisertib oral solution<br>* Other names: MLN8237;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 |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for Alisertib and Drug-Related Material Following a Single Dose of [^14C]-Alisertib Oral Solution |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Tmax: Time of First Occurrence of Cmax for Alisertib and Drug-Related Material in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Plasma Concentration for Alisertib and Drug-Related Material Following a Single Dose of [^14C]-Alisertib Oral Solution |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Plasma Concentration for Alisertib and Drug-Related Material Following a Single Dose of [^14C]-Alisertib Oral Solution |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| T1/2: Terminal Half Life for Alisertib and Drug-Related Material in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Plasma Concentration for Alisertib Following a Single Dose of [^14C]-Alisertib Oral Solution |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ratio of Whole Blood Total Radioactivity (TRA) Cmax to Plasma TRA Cmax |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ratio of Alisertib Plasma Cmax to Drug-Related Material TRA Plasma Cmax |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ratio of Whole Blood TRA AUClast to Plasma TRA AUClast |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ratio of Alisertib Plasma AUClast to Drug-Related Material TRA Plasma AUClast |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ratio of Whole Blood TRA AUC∞ to Plasma TRA AUC∞ |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ratio of Alisertib Plasma AUC∞ to Drug-Related Material TRA Plasma AUC∞ |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Fe: Fraction of Administered Dose of [^14C]-Alisertib Excreted in Urine |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Fe: Fraction of Administered Dose of [^14C]-Alisertib Excreted in Feces |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ae: Amount of [^14C]-Alisertib Excreted in Urine |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ae: Amount of [^14C]-Alisertib Excreted in Feces |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Percent of Total Radioactivity (TRA) in Urine and Feces |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Fe: Fraction of Administered Dose of Alisertib Excreted in Urine |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Ae: Amount of Alisertib Excretion in Urine |  | Predose and multiple timepoints post-dose (up to 240 hours) | 
| Renal Clearance (CLR) of Alisertib |  | Predose and multiple timepoints post-dose (up to 240 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Alisertib Metabolites in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution | Total radioactive peak distributions of metabolites in 0 to 192 hours pooled plasma samples from participants. | Predose and multiple timepoints post-dose (0 to 192 hours) | 
| Percentage of Alisertib Metabolites in Urine Following a Single Dose of [^14C]-Alisertib Oral Solution | Total radioactive peak distributions of metabolites in 0 to 192 hours pooled urine samples from participants. | Predose and multiple timepoints post-dose (0 to 192 hours) | 
| Percentage of Alisertib Metabolites in Feces Following a Single Dose of [^14C]-Alisertib Oral Solution | Total radioactive peak distributions of metabolites in 0 to 192 hours pooled fecal samples from participants. | Predose and multiple timepoints post-dose (0 to 192 hours) | 
| Number of Participants With Treatment-Emergent Adverse Events and Serious Adverse Events | An Adverse Event (AE) was 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) was defined as any AE at any dose that: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in a persistent or significant disability/incapacity or resulted in congenital anomaly/birth defect. A treatment-emergent adverse event is defined as an adverse event with an onset that occurs after receiving study drug. | From first dose of study drug through 30 days after the last dose of study drug (Up to 117 days) | 
| Number of Participants With Clinically Significant Changes or Abnormalities in Clinical Laboratory Values Reported as AEs | An abnormal laboratory was assessed to be an AE if the 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. | Part A: Day 1 and End of Study (EOS) Day 31 if not continuing to Part B, Part B: Days 8 and 15 of each cycle and EOS (Up to 117 days) | 
| Number of Participants With Clinically Significant Changes or Abnormalities in Vital Sign Measurements | Vital signs included body temperature, heart rate, and sitting blood pressure. The investigator determined if the changes were clinically significant. | Part A: Day 1 and EOS (Day 31 if not continuing to Part B), Part B: Day 1 of each cycle and EOS (Up to 117 days) | 

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