Mass Balance, Pharmacokinetics and Metabolism Study of Alisertib

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01714947
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 4.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumors; Lymphoma	Drug: [^14C]-alisertib; Drug: alisertib	Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Mass Balance, Pharmacokinetics, and Metabolism of [^14C]-Alisertib in Patients With Advanced Solid Tumors or Lymphomas
• Actual Study Start Date: Jan 24, 2013
• Actual Primary Completion Date: Apr 4, 2013
• Actual Study Completion Date: Jun 14, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Alisertib 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; [^14C]-alisertib oral solution; Other Names: MLN8237 ; Drug: alisertib; Alisertib enteric coated tablets; Other Names: MLN8237

Outcome Measures

Primary Outcome Measures

1. 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)]

2. 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)]

3. 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)]

4. 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)]

5. 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)]

6. 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)]

7. Ratio of Whole Blood Total Radioactivity (TRA) Cmax to Plasma TRA Cmax [Predose and multiple timepoints post-dose (up to 240 hours)]

8. Ratio of Alisertib Plasma Cmax to Drug-Related Material TRA Plasma Cmax [Predose and multiple timepoints post-dose (up to 240 hours)]

9. Ratio of Whole Blood TRA AUClast to Plasma TRA AUClast [Predose and multiple timepoints post-dose (up to 240 hours)]

10. Ratio of Alisertib Plasma AUClast to Drug-Related Material TRA Plasma AUClast [Predose and multiple timepoints post-dose (up to 240 hours)]

11. Ratio of Whole Blood TRA AUC∞ to Plasma TRA AUC∞ [Predose and multiple timepoints post-dose (up to 240 hours)]

12. Ratio of Alisertib Plasma AUC∞ to Drug-Related Material TRA Plasma AUC∞ [Predose and multiple timepoints post-dose (up to 240 hours)]

13. Fe: Fraction of Administered Dose of [^14C]-Alisertib Excreted in Urine [Predose and multiple timepoints post-dose (up to 240 hours)]

14. Fe: Fraction of Administered Dose of [^14C]-Alisertib Excreted in Feces [Predose and multiple timepoints post-dose (up to 240 hours)]

15. Ae: Amount of [^14C]-Alisertib Excreted in Urine [Predose and multiple timepoints post-dose (up to 240 hours)]

16. Ae: Amount of [^14C]-Alisertib Excreted in Feces [Predose and multiple timepoints post-dose (up to 240 hours)]

17. Percent of Total Radioactivity (TRA) in Urine and Feces [Predose and multiple timepoints post-dose (up to 240 hours)]

18. Fe: Fraction of Administered Dose of Alisertib Excreted in Urine [Predose and multiple timepoints post-dose (up to 240 hours)]

19. Ae: Amount of Alisertib Excretion in Urine [Predose and multiple timepoints post-dose (up to 240 hours)]

20. Renal Clearance (CLR) of Alisertib [Predose and multiple timepoints post-dose (up to 240 hours)]

Secondary Outcome Measures

1. Percentage of Alisertib Metabolites in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution [Predose and multiple timepoints post-dose (0 to 192 hours)]

   Total radioactive peak distributions of metabolites in 0 to 192 hours pooled plasma samples from participants.

2. Percentage of Alisertib Metabolites in Urine Following a Single Dose of [^14C]-Alisertib Oral Solution [Predose and multiple timepoints post-dose (0 to 192 hours)]

   Total radioactive peak distributions of metabolites in 0 to 192 hours pooled urine samples from participants.

3. Percentage of Alisertib Metabolites in Feces Following a Single Dose of [^14C]-Alisertib Oral Solution [Predose and multiple timepoints post-dose (0 to 192 hours)]

   Total radioactive peak distributions of metabolites in 0 to 192 hours pooled fecal samples from participants.

4. Number of Participants With Treatment-Emergent Adverse Events and Serious Adverse Events [From first dose of study drug through 30 days after the last dose of study drug (Up to 117 days)]

   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.

5. Number of Participants With Clinically Significant Changes or Abnormalities in Clinical Laboratory Values Reported as AEs [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)]

   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.

6. Number of Participants With Clinically Significant Changes or Abnormalities in Vital Sign Measurements [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)]

   Vital signs included body temperature, heart rate, and sitting blood pressure. The investigator determined if the changes were clinically significant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Comprehensive Clinical Development	Tacoma	Washington	United States	98418

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01714947
• Other Study ID Numbers: C14014; U1111-1187-6760
• First Posted: Oct 26, 2012
• Last Update Posted: Oct 31, 2018
• Last Verified: Feb 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug Therapy
• Additional relevant MeSH terms: Lymphoma

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in the United States from 24 January 2013 to 14 June 2013.
Pre-assignment Detail	Participants with a diagnosis of advanced solid tumors or lymphomas received [^14C]-alisertib 35 mg oral solution single dose in Part A and alisertib 50 mg for 7 days in 21-day cycles in Part B.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Period Title: Part A
STARTED	3
COMPLETED	3
NOT COMPLETED	0
Period Title: Part A
STARTED	3
COMPLETED	0
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Alisertib
Arm/Group Description	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).
Overall Participants	3
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.0 (13.11)
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Race/Ethnicity, Customized (participants) [Number]
Not Hispanic or Latino	3 100%
Race/Ethnicity, Customized (participants) [Number]
White	2 66.7%
Black or African American	1 33.3%
Region of Enrollment (participants) [Number]
United States	3 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	173.5 (7.15)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	80.27 (20.760)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.91 (8.346)

Outcome Measures

1. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Alisertib and Drug-Related Material Following a Single Dose of [^14C]-Alisertib Oral Solution
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Alisertib	2183.3 (161.97)
Drug-Related Material	2606.7 (228.98)

2. Primary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib and Drug-Related Material in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Alisertib	1.00 (161.97)
Drug-Related Material	1.00 (228.98)

3. Primary Outcome

Title	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
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Alisertib	16800.0 (4936.60)
Drug-Related Material	37033.3 (20545.15)

4. Primary Outcome

Title	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
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Alisertib	17266.7 (5138.42)
Drug-Related Material	42233.3 (23302.43)

5. Primary Outcome

Title	T1/2: Terminal Half Life for Alisertib and Drug-Related Material in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Alisertib	23.40 (7.041)
Drug-Related Material	42.03 (25.255)

6. Primary Outcome

Title	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
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	4.06 (25.6)

7. Primary Outcome

Title	Ratio of Whole Blood Total Radioactivity (TRA) Cmax to Plasma TRA Cmax
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ratio]	0.6550 (0.0671)

8. Primary Outcome

Title	Ratio of Alisertib Plasma Cmax to Drug-Related Material TRA Plasma Cmax
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ratio]	0.8397 (0.0589)

9. Primary Outcome

Title	Ratio of Whole Blood TRA AUClast to Plasma TRA AUClast
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ratio]	0.5950 (0.1010)

10. Primary Outcome

Title	Ratio of Alisertib Plasma AUClast to Drug-Related Material TRA Plasma AUClast
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ratio]	0.4997 (0.1364)

11. Primary Outcome

Title	Ratio of Whole Blood TRA AUC∞ to Plasma TRA AUC∞
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ratio]	0.6750 (0.0170)

12. Primary Outcome

Title	Ratio of Alisertib Plasma AUC∞ to Drug-Related Material TRA Plasma AUC∞
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ratio]	0.4490 (0.1204)

13. Primary Outcome

Title	Fe: Fraction of Administered Dose of [^14C]-Alisertib Excreted in Urine
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [percent of dose]	2.650 (1.7935)

14. Primary Outcome

Title	Fe: Fraction of Administered Dose of [^14C]-Alisertib Excreted in Feces
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [percent of dose]	87.833 (2.2898)

15. Primary Outcome

Title	Ae: Amount of [^14C]-Alisertib Excreted in Urine
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [nanogram equivalent [ng(eq)]]	939420.7 (632770.92)

16. Primary Outcome

Title	Ae: Amount of [^14C]-Alisertib Excreted in Feces
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [ng(eq)]	31156703.0 (764243.97)

17. Primary Outcome

Title	Percent of Total Radioactivity (TRA) in Urine and Feces
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

PK population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Mean (Standard Deviation) [percent of TRA]	90.500 (1.3115)

18. Primary Outcome

Title	Fe: Fraction of Administered Dose of Alisertib Excreted in Urine
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

Participant from the PK Population, all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance, with data available for Fe.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	2
Mean (Standard Deviation) [percent of dose]	0.009045 (0.000714)

19. Primary Outcome

Title	Ae: Amount of Alisertib Excretion in Urine
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

Participants from the PK Population, all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance, with data available for Ae.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	2
Mean (Standard Deviation) [ng]	3215.0 (219.20)

20. Primary Outcome

Title	Renal Clearance (CLR) of Alisertib
Time Frame	Predose and multiple timepoints post-dose (up to 240 hours)

Outcome Measure Data

Analysis Population Description

Participants from the PK Population, all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance, with data for CLR.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	2
Mean (Standard Deviation) [L/hr]	0.000687 (0.000013)

21. Secondary Outcome

Title	Percentage of Alisertib Metabolites in Plasma Following a Single Dose of [^14C]-Alisertib Oral Solution
Description	Total radioactive peak distributions of metabolites in 0 to 192 hours pooled plasma samples from participants.
Time Frame	Predose and multiple timepoints post-dose (0 to 192 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Metabolite M1	12.0
Metabolite M2	34.6
Metabolite M3	5.6

22. Secondary Outcome

Title	Percentage of Alisertib Metabolites in Urine Following a Single Dose of [^14C]-Alisertib Oral Solution
Description	Total radioactive peak distributions of metabolites in 0 to 192 hours pooled urine samples from participants.
Time Frame	Predose and multiple timepoints post-dose (0 to 192 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Unknown	0.24
M8a	0.28
M9	0.66
M536	0.14
M1	0.84
M8	0.37
Others	0.05

23. Secondary Outcome

Title	Percentage of Alisertib Metabolites in Feces Following a Single Dose of [^14C]-Alisertib Oral Solution
Description	Total radioactive peak distributions of metabolites in 0 to 192 hours pooled fecal samples from participants.
Time Frame	Predose and multiple timepoints post-dose (0 to 192 hours)

Outcome Measure Data

Analysis Population Description

PK Population included all participants with sufficient dosing and PK concentration-time data to reliably estimate PK parameters and mass balance.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
M536	4.45
M520a	1.19
M3a	2.22
M550	2.96
M537	9.17
M520b	1.72
M3	20.82
M520c	5.94
Alisertib	26.27
M2	8.62
Others	0

24. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events and Serious Adverse Events
Description	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.
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (Up to 117 days)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Any AE	3 100%
SAE	0 0%

25. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes or Abnormalities in Clinical Laboratory Values Reported as AEs
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Neutrophil Count Decreased	1 33.3%
Neutropenia	1 33.3%
Blood Magnesium Decreased	1 33.3%

26. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes or Abnormalities in Vital Sign Measurements
Description	Vital signs included body temperature, heart rate, and sitting blood pressure. The investigator determined if the changes were clinically significant.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Alisertib
Arm/Group Description	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).
Measure Participants	3
Number [Participants]	0 0%

Adverse Events

Time Frame	From first dose of study drug through 30 days after the last dose of study drug (Up to 117 days)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Alisertib
Arm/Group Description	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).
All Cause Mortality
	Alisertib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alisertib
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Alisertib
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Neutropenia	1/3 (33.3%)
Gastrointestinal disorders
Nausea	1/3 (33.3%)
Vomiting	1/3 (33.3%)
Glossodynia	1/3 (33.3%)
General disorders
Fatigue	2/3 (66.7%)
Pyrexia	1/3 (33.3%)
Chills	1/3 (33.3%)
Oedema peripheral	1/3 (33.3%)
Injury, poisoning and procedural complications
Ligament sprain	1/3 (33.3%)
Investigations
Blood magnesium decreased	1/3 (33.3%)
Neutrophil count decreased	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/3 (33.3%)
Musculoskeletal pain	1/3 (33.3%)
Pain in extremity	1/3 (33.3%)
Nervous system disorders
Headache	1/3 (33.3%)
Reproductive system and breast disorders
Scrotal swelling	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)
Respiratory tract congestion	1/3 (33.3%)
Skin and subcutaneous tissue disorders
Alopecia	2/3 (66.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.