Pharmacokinetics of Alisertib in Adults With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Function

• ClinicalTrials.gov Identifier: NCT02214147
• Recruitment Status: Completed
• First Posted: August 12, 2014
• Results First Posted: November 15, 2018
• Last Update Posted: November 15, 2018
• Sponsor: Millennium Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Takeda ( Millennium Pharmaceuticals, Inc. )

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Advanced Solid Tumors; Relapsed/Refractory Lymphoma
• Intervention: Drug: Alisertib
• Enrollment: 36

Participant Flow

Recruitment Details	Participants took part in the study at 6 investigative sites in the United States from 21 August 2014 to 18 July 2016.
Pre-assignment Details	Participants with a diagnosis of advanced solid tumors or relapsed/refractory lymphoma were assigned to 1 of 3 hepatic function groups (normal hepatic function, moderate hepatic impairment, or severe hepatic impairment) on the basis of their total bilirubin and alanine aminotransferase (ALT) values. All participants received alisertib.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Period Title: Overall Study
Started	16	12	8
Completed [1]	16	12	8
Not Completed	0	0	0
[1] Completed=Completed protocol-specified dosing and PK assessment.

Baseline Characteristics

Arm/Group Title		Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment	Total
Arm/Group Description		Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.	Total of all reporting groups
Overall Number of Baseline Participants		16	12	8	36
Baseline Analysis Population Description		Safety population was defined as all participants who received at least 1 dose of alisertib.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		61.2 (10.07)	54.9 (9.89)	54.0 (7.05)	57.5 (9.77)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	16 participants	12 participants	8 participants	36 participants
	Female	5 31.3%	7 58.3%	2 25.0%	14 38.9%
	Male	11 68.8%	5 41.7%	6 75.0%	22 61.1%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Hispanic or Latino	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		1 6.3%	1 8.3%	2 25.0%	4 11.1%
Not Hispanic or Latino	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		14 87.5%	11 91.7%	6 75.0%	31 86.1%
Not Reported	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		1 6.3%	0 0.0%	0 0.0%	1 2.8%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
White	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		14 87.5%	11 91.7%	6 75.0%	31 86.1%
Black or African American	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		2 12.5%	1 8.3%	2 25.0%	5 13.9%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		16 100.0%	12 100.0%	8 100.0%	36 100.0%
Height [1]; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	14 participants	11 participants	5 participants	30 participants
		172.9 (14.62)	162.9 (7.79)	178.2 (8.10)	170.1 (12.66)
		[1] Measure Analysis Population Description: Height data is only available for n=14,11,5 participants.
Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	16 participants	12 participants	8 participants	36 participants
		84.6 (20.997)	85.5 (33.881)	85.8 (11.847)	85.2 (24.044)
Body surface area [1] [2]; Mean (Standard Deviation); Unit of measure: M^2
	Number Analyzed	14 participants	11 participants	5 participants	30 participants
		2.030 (0.3073)	1.897 (0.4028)	2.056 (0.1970)	1.986 (0.3292)
		[1] Measure Description: Body surface area=square root[height(cm)*weight(kg)/3600]; [2] Measure Analysis Population Description: Body surface area data is only available for n=14,11,5 participants.

Outcome Measures

1. Primary Outcome

Title	Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib
Description	[Not Specified]
Time Frame	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-evaluable population was defined as all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Mean (Standard Deviation); Unit of Measure: nmol/L
	17.3 (9.09)	28.1 (7.82)	18.5 (5.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib: Normal Hepatic Function, Alisertib: Moderate Hepatic Impairment, Alisertib: Severe Hepatic Impairment
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	The effect of hepatic impairment on alisertib PK. Combined analysis of moderate and severe hepatic impairment in reference to normal hepatic function.
Method of Estimation	Estimation Parameter	Least Squares Geometric Mean Ratio
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 90%; 1.12 to 1.80
	Estimation Comments	Least Squares Geometric Means Ratio= Moderate + Severe Hepatic Impairment/Normal Hepatic Function

2. Primary Outcome

Title	Unbound AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib
Description	[Not Specified]
Time Frame	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants from the PK-evaluable population, all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	10	8
Mean (Standard Deviation); Unit of Measure: h*nmol/L
	248.5 (131.41)	859.1 (387.85)	735.4 (444.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib: Normal Hepatic Function, Alisertib: Moderate Hepatic Impairment, Alisertib: Severe Hepatic Impairment
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	The effect of hepatic impairment on alisertib PK. Combined analysis of moderate and severe hepatic impairment in reference to normal hepatic function.
Method of Estimation	Estimation Parameter	Least Squares Geometric Mean Ratio
	Estimated Value	3.21
	Confidence Interval	(2-Sided) 90%; 2.33 to 4.43
	Estimation Comments	Least Squares Geometric Mean Ratio=Moderate + Severe Hepatic Impairment/Normal Hepatic Function

3. Primary Outcome

Title	Unbound AUC0-∞: Area Under the Concentration-Time Curve From Time 0 to Infinity for Alisertib
Description	[Not Specified]
Time Frame	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants from the PK-evaluable population, all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	12	10	7
Mean (Standard Deviation); Unit of Measure: h*nmol/L
	304.3 (119.09)	937.6 (428.98)	778.0 (610.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib: Normal Hepatic Function, Alisertib: Moderate Hepatic Impairment, Alisertib: Severe Hepatic Impairment
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	The effect of hepatic impairment on alisertib PK. Combined analysis of moderate and severe hepatic impairment in reference to normal hepatic function.
Method of Estimation	Estimation Parameter	Least Squares Geometric Mean Ratio
	Estimated Value	2.54
	Confidence Interval	(2-Sided) 90%; 1.84 to 3.53
	Estimation Comments	Least Squares Geometric Mean Ratio=Moderate + Severe Hepatic Impairment/Normal Hepatic Function

4. Secondary Outcome

Title	Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event
Description	An adverse event is any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	Baseline to 30 days after last dose (Up to 312 Days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of alisertib.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Measure Type: Number; Unit of Measure: percentage of participants
	100	100	100

5. Secondary Outcome

Title	Percentage of Participants Who Experienced at Least 1 Serious Adverse Event
Description	A serious adverse event is any untoward medical occurrence or effect that at any dose of a drug results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically important due to other reasons than the above mentioned criteria.
Time Frame	Baseline to 30 days after last dose (Up to 312 Days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of alisertib.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Measure Type: Number; Unit of Measure: percentage of participants
	44	67	88

6. Secondary Outcome

Title	Percentage of Participants With Clinically Significant Laboratory Values
Description	Laboratory assessments include serum chemistry and hematology. An abnormal laboratory value was assessed as an AE if that value led 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	Baseline to the end of the study (Up to 312 Days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of alisertib.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Measure Type: Number; Unit of Measure: percentage of participants
Gamma-glutamyltransferase increased	13	0	0
Alanine aminotransferase increased	0	8	0
Aspartate aminotransferase increased	0	8	0
Blood bilirubin increased	0	8	0
Transaminases increased	0	8	0
Blood sodium decreased	6	8	0
Blood calcium increased	6	0	0
Blood phosphorus decreased	6	0	0
Platelet count decreased	6	8	0
Blood alkaline phosphatase increased	6	8	0
Blood creatinine increased	0	8	0
Neutrophil count decreased	0	8	0
White blood cell count decreased	0	8	0

7. Secondary Outcome

Title	Percentage of Participants With Clinically Significant Vital Signs
Description	Vital signs include measurements of sitting diastolic and systolic blood pressure, heart rate, and temperature. Any vital signs determined by the investigator to be clinically significant were recorded as AEs.
Time Frame	Baseline to the end of the study (Up to 312 days)

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of alisertib.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Measure Type: Number; Unit of Measure: percentage of participants
Pyrexia	25	8	38
Sinus tachycardia	6	0	0

8. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2
Description	[Not Specified]
Time Frame	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population was defined as all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Mean (Standard Deviation); Unit of Measure: nmol/L
Metabolite M1	370.3 (282.02)	1774.0 (904.10)	2001.9 (1094.75)
Metabolite M2	154.6 (82.54)	173.8 (54.39)	207.3 (151.60)

9. Secondary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2
Description	[Not Specified]
Time Frame	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK-evaluable population was defined as all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	12	8
Median (Full Range); Unit of Measure: hours
Metabolite M1	3.500; (1.88 to 7.92)	24.000; (1.00 to 48.30)	24.150; (9.08 to 96.70)
Metabolite M2	9.000; (5.88 to 49.30)	24.050; (9.00 to 72.10)	24.150; (9.08 to 96.70)

10. Secondary Outcome

Title	AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2
Description	The area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-last) of the alisertib metabolites M1 and M2 was determined from the concentration-time curve of each participant using non-compartmental methods.
Time Frame	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants from the PK-evaluable population, all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	16	10	8
Mean (Standard Deviation); Unit of Measure: h*nmol/L
Metabolite M1	8366.3 (10790.88)	159665.0 (116960.23)	196750.0 (117472.08)
Metabolite M2	8923.1 (6539.00)	17326.0 (8562.96)	16987.5 (9384.25)

11. Secondary Outcome

Title	Dose-normalized Trough Concentration of Alisertib on Cycle 1 Day 14
Description	A single blood sample will be collected pre-dose on Cycle 1 Day 14. The concentration of alisertib was determined in the plasma sample and dose-normalized.
Time Frame	Pre-dose on Day 14 of Cycle 1

Outcome Measure Data

Analysis Population Description

Data was not collected, as many participants dropped out of the study prior to Day 14 trough concentration collection.

Arm/Group Title	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description:	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	First dose of study drug to 30 days past last dose (Up to 312 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: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
Arm/Group Description	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.	Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
All-Cause Mortality
	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/16 (12.50%)	3/12 (25.00%)	4/8 (50.00%)
Serious Adverse Events
	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	7/16 (43.75%)	8/12 (66.67%)	7/8 (87.50%)
Blood and lymphatic system disorders
Anaemia † 1	0/16 (0.00%)	1/12 (8.33%)	1/8 (12.50%)
Cardiac disorders
Atrial fibrillation † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	0/16 (0.00%)	2/12 (16.67%)	3/8 (37.50%)
Gastrointestinal haemorrhage † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Stomatitis † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
General disorders
Pyrexia † 1	2/16 (12.50%)	0/12 (0.00%)	1/8 (12.50%)
Malaise † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Hepatobiliary disorders
Hyperbilirubinaemia † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Hepatic failure † 1 [1]	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Bile duct obstruction † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Infections and infestations
Bacterial sepsis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Biliary tract infection † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Pneumonia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Sepsis † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Metabolism and nutrition disorders
Hyperkalaemia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Hyponatraemia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer metastatic † 1 [1]	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Colorectal adenocarcinoma † 1 [1]	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Rectal cancer † 1 [1]	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Breast cancer † 1 [1]	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Pancreatic neuroendocrine tumour metastatic † 1 [1]	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Ovarian cancer metastatic † 1 [1]	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Pancreatic carcinoma † 1 [1]	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Nervous system disorders
Cerebral haemorrhage † 1 [1]	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Psychiatric disorders
Confusional state † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Delirium † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Hydronephrosis † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis bullous † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
1 Term from vocabulary, MedDRA version: 19.0; † Indicates events were collected by systematic assessment; [1] One treatment-emergent death occurred during treatment with alisertib and is not related.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Alisertib: Normal Hepatic Function	Alisertib: Moderate Hepatic Impairment	Alisertib: Severe Hepatic Impairment
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/16 (93.75%)	12/12 (100.00%)	8/8 (100.00%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	1/16 (6.25%)	5/12 (41.67%)	0/8 (0.00%)
Anaemia † 1	1/16 (6.25%)	3/12 (25.00%)	1/8 (12.50%)
Neutropenia † 1	4/16 (25.00%)	1/12 (8.33%)	0/8 (0.00%)
Leukopenia † 1	2/16 (12.50%)	1/12 (8.33%)	1/8 (12.50%)
Anaemia of malignant disease † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Haemolytic anaemia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Lymphadenopathy † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Pancytopenia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Cardiac disorders
Sinus tachycardia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Ear and labyrinth disorders
Cerumen impaction † 1	0/16 (0.00%)	2/12 (16.67%)	0/8 (0.00%)
Deafness † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Eye disorders
Dry eye † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Eye irritation † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Vision blurred † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Gastrointestinal disorders
Nausea † 1	9/16 (56.25%)	3/12 (25.00%)	0/8 (0.00%)
Diarrhoea † 1	6/16 (37.50%)	4/12 (33.33%)	0/8 (0.00%)
Vomiting † 1	4/16 (25.00%)	4/12 (33.33%)	0/8 (0.00%)
Ascites † 1	0/16 (0.00%)	6/12 (50.00%)	1/8 (12.50%)
Constipation † 1	5/16 (31.25%)	2/12 (16.67%)	0/8 (0.00%)
Stomatitis † 1	5/16 (31.25%)	2/12 (16.67%)	0/8 (0.00%)
Abdominal pain † 1	1/16 (6.25%)	3/12 (25.00%)	2/8 (25.00%)
Dyspepsia † 1	3/16 (18.75%)	0/12 (0.00%)	0/8 (0.00%)
Retching † 1	1/16 (6.25%)	2/12 (16.67%)	0/8 (0.00%)
Gingival pain † 1	2/16 (12.50%)	0/12 (0.00%)	0/8 (0.00%)
Abdominal distension † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Abdominal pain upper † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Dysphagia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Epigastric discomfort † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Eructation † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Haematochezia † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Haemorrhoids † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Oral pain † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Tongue discolouration † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
General disorders
Fatigue † 1	6/16 (37.50%)	3/12 (25.00%)	3/8 (37.50%)
Pyrexia † 1	4/16 (25.00%)	1/12 (8.33%)	2/8 (25.00%)
Oedema peripheral † 1	2/16 (12.50%)	3/12 (25.00%)	1/8 (12.50%)
Chills † 1	4/16 (25.00%)	0/12 (0.00%)	1/8 (12.50%)
Chest pain † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Influenza like illness † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Mass † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Non-cardiac chest pain † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Pain † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Peripheral swelling † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Hepatobiliary disorders
Hyperbilirubinaemia † 1	0/16 (0.00%)	5/12 (41.67%)	0/8 (0.00%)
Hepatic failure † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Hepatorenal syndrome † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Portal hypertension † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Portal vein thrombosis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Bile duct obstruction † 1	0/16 (0.00%)	1/12 (8.33%)	1/8 (12.50%)
Infections and infestations
Pneumonia † 1	2/16 (12.50%)	0/12 (0.00%)	0/8 (0.00%)
Oral candidiasis † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Sepsis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Urinary tract infection † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Injury, poisoning and procedural complications
Fall † 1	1/16 (6.25%)	0/12 (0.00%)	1/8 (12.50%)
Pelvic fracture † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Investigations
Blood alkaline phosphatase increased † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Blood sodium decreased † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Gamma-glutamyltransferase increased † 1	2/16 (12.50%)	0/12 (0.00%)	0/8 (0.00%)
Platelet count decreased † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Alanine aminotransferase increased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Aspartate aminotransferase increased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Blood bilirubin increased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Blood calcium increased † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Blood creatinine increased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Blood phosphorus decreased † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Neutrophil count decreased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Transaminases increased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
White blood cell count decreased † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	4/16 (25.00%)	3/12 (25.00%)	1/8 (12.50%)
Hyponatraemia † 1	3/16 (18.75%)	2/12 (16.67%)	1/8 (12.50%)
Dehydration † 1	1/16 (6.25%)	4/12 (33.33%)	0/8 (0.00%)
Hyperkalaemia † 1	2/16 (12.50%)	1/12 (8.33%)	0/8 (0.00%)
Hypoalbuminaemia † 1	0/16 (0.00%)	1/12 (8.33%)	1/8 (12.50%)
Hypokalaemia † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Hypercalcaemia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Hypocalcaemia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Hypoglycaemia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Hypomagnesaemia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Lactic acidosis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Musculoskeletal and connective tissue disorders
Flank pain † 1	0/16 (0.00%)	2/12 (16.67%)	1/8 (12.50%)
Back pain † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Arthralgia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Muscular weakness † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Musculoskeletal chest pain † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Myalgia † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Neck mass † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Neck pain † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Pain in extremity † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Polymyalgia rheumatica † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Nervous system disorders
Headache † 1	4/16 (25.00%)	1/12 (8.33%)	1/8 (12.50%)
Dizziness † 1	2/16 (12.50%)	3/12 (25.00%)	0/8 (0.00%)
Presyncope † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Amnesia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Balance disorder † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Cervical radiculopathy † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Dysgeusia † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Somnolence † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Tongue biting † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Psychiatric disorders
Confusional state † 1	0/16 (0.00%)	3/12 (25.00%)	2/8 (25.00%)
Anxiety † 1	1/16 (6.25%)	2/12 (16.67%)	0/8 (0.00%)
Insomnia † 1	3/16 (18.75%)	0/12 (0.00%)	0/8 (0.00%)
Delirium † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Stress † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/16 (0.00%)	1/12 (8.33%)	1/8 (12.50%)
Dysuria † 1	0/16 (0.00%)	2/12 (16.67%)	0/8 (0.00%)
Nephrolithiasis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Pollakiuria † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Reproductive system and breast disorders
Pelvic pain † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	3/16 (18.75%)	1/12 (8.33%)	1/8 (12.50%)
Dyspnoea † 1	2/16 (12.50%)	1/12 (8.33%)	1/8 (12.50%)
Pleural effusion † 1	2/16 (12.50%)	1/12 (8.33%)	0/8 (0.00%)
Dyspnoea exertional † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Nasal congestion † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Choking sensation † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Haemoptysis † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Hypoxia † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Oropharyngeal pain † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Pulmonary embolism † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Rhinorrhoea † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Skin and subcutaneous tissue disorders
Alopecia † 1	6/16 (37.50%)	3/12 (25.00%)	1/8 (12.50%)
Dry skin † 1	1/16 (6.25%)	1/12 (8.33%)	0/8 (0.00%)
Hyperhidrosis † 1	2/16 (12.50%)	0/12 (0.00%)	0/8 (0.00%)
Palmar-plantar erythrodysaesthesia syndrome † 1	0/16 (0.00%)	1/12 (8.33%)	1/8 (12.50%)
Dermatitis acneiform † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Eczema † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Pain of skin † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Pruritus † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Rash † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Rash maculo-papular † 1	0/16 (0.00%)	0/12 (0.00%)	1/8 (12.50%)
Skin exfoliation † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Vascular disorders
Hypotension † 1	0/16 (0.00%)	2/12 (16.67%)	1/8 (12.50%)
Deep vein thrombosis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
Hot flush † 1	1/16 (6.25%)	0/12 (0.00%)	0/8 (0.00%)
Jugular vein thrombosis † 1	0/16 (0.00%)	1/12 (8.33%)	0/8 (0.00%)
1 Term from vocabulary, MedDRA version: 19.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

Results Point of Contact

• Name/Title: Medical Director
• Organization: Takeda
• Phone: +1-877-825-3327
• EMail: trialdisclosures@takeda.com

• Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
• ClinicalTrials.gov Identifier: NCT02214147
• Other Study ID Numbers: C14019; U1111-1155-6072 ( Other Identifier: World Health Organization )
• First Submitted: July 30, 2014
• First Posted: August 12, 2014
• Results First Submitted: April 9, 2018
• Results First Posted: November 15, 2018
• Last Update Posted: November 15, 2018