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

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02214147
• Collaborator: (none)
• Enrollment: 36
• Locations: 7
• Arms: 3
• Actual Duration (Months): 22.9
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics of alisertib in adult participants with cancer.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumors; Relapsed/Refractory Lymphoma	Drug: Alisertib	Phase 1

Detailed Description

The drug being tested in this study is called alisertib. Alisertib was tested to assess how it was processed by the body in participants with advanced solid tumors or relapsed/refractory lymphoma with varying degrees of liver function. This study also assessed laboratory results and safety.

The study enrolled 36 participants. Participants were assigned to 1 of the 3 treatment groups based on the status of their liver function: Normal hepatic function (Total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN), moderate hepatic impairment (Total bilirubin > 1.5-3 x ULN and ALT level = Any), or severe hepatic impairment (Total bilirubin > 3 x ULN and ALT level = Any). All participants were administered one 50 mg dose of alisertib on Day 1, Cycle 1. Alisertib was administered again on Days 8 through 14 of Cycle 1, followed by a 14-day rest period. Doses administered on Days 8-14 were 50, 30, or 20 mg of alisertib, depending on hepatic function. Alisertib was then continued at the same dose as in Cycle 1, Days 8-14 in 21-day cycles (7 days of alisertib followed by a 14-day rest period) for up to 1 year (approximately 16 cycles).

This multicenter trial was conducted in USA only. The overall time to participate in this study was up to 312 Days. Participants made multiple visits to the clinic including an end-of-study visit 30 days after the last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics of Oral Alisertib (MLN8237) in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Function
• Actual Study Start Date: Aug 21, 2014
• Actual Primary Completion Date: Apr 5, 2016
• Actual Study Completion Date: Jul 18, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alisertib: Normal Hepatic Function 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.	Drug: Alisertib; Alisertib will be supplied as enteric coated tablets.; Other Names: MLN8237
Experimental: Alisertib: Moderate Hepatic Impairment 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.	Drug: Alisertib; Alisertib will be supplied as enteric coated tablets.; Other Names: MLN8237
Experimental: Alisertib: Severe Hepatic Impairment 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.	Drug: Alisertib; Alisertib will be supplied as enteric coated tablets.; Other Names: MLN8237

Outcome Measures

Primary Outcome Measures

1. Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib [Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose]

2. Unbound AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib [Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose]

3. Unbound AUC0-∞: Area Under the Concentration-Time Curve From Time 0 to Infinity for Alisertib [Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose]

Secondary Outcome Measures

1. Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event [Baseline to 30 days after last dose (Up to 312 Days)]

   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.

2. Percentage of Participants Who Experienced at Least 1 Serious Adverse Event [Baseline to 30 days after last dose (Up to 312 Days)]

   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.

3. Percentage of Participants With Clinically Significant Laboratory Values [Baseline to the end of the study (Up to 312 Days)]

   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.

4. Percentage of Participants With Clinically Significant Vital Signs [Baseline to the end of the study (Up to 312 days)]

   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.

5. Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 [Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose]

6. Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 [Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose]

7. AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 [Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose]

   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.

8. Dose-normalized Trough Concentration of Alisertib on Cycle 1 Day 14 [Pre-dose on Day 14 of Cycle 1]

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female participants 18 years of age or older.

2. 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.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

4. Female participants who:

• Are post-menopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).

1. Male participants, even if surgically sterilized (ie, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception).

1. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

2. Suitable venous access for the study-required blood sampling, including pharmacokinetics.

3. Ability to swallow tablets.

4. Participants with biliary obstruction for which a stent had been placed are eligible provided that the stent has been in place for more than 14 days before the first dose of alisertib and liver function has stabilized.

5. Recovered from the reversible effects of prior antineoplastic therapy (ie, ≤ Grade 1 toxicity or baseline).

6. Clinical laboratory values as specified below:

• Absolute neutrophil count (ANC) ≥ 1500/μL and platelet count ≥ 75,000/μL.

• Participants with normal hepatic function: Total bilirubin and alanine aminotransferase (ALT) must be ≤ upper limit of the normal range (ULN).

• Participants with moderate hepatic impairment: total bilirubin must be > 1.5 to 3 x ULN with any ALT level.

• Participants with severe hepatic impairment: total bilirubin must be > 3 x ULN with any ALT level.

• Measured creatinine clearance or calculated creatinine clearance > 30 mL/minute. Note: If a calculated creatinine clearance is used, it should be calculated according to the Cockcroft-Gault formula.

• Hemoglobin must be ≥ 8 g/dL.

Exclusion Criteria:

1. Participants of North/East Asian ethnicity (ie, Japanese, Chinese, Korean) will be excluded.

2. Recurrent nausea and/or vomiting within 14 days before the first dose of alisertib or known gastrointestinal (GI) abnormality or GI procedure that could interfere with or modify the oral absorption or tolerance of alisertib. Examples include, but are not limited to, disease-related bowel obstruction, pancreatic insufficiency, use of pancreatic enzymes, a gastric condition (such as severe reflux or active peptic ulcer disease) that requires chronic and uninterrupted use of proton pump inhibitors, partial gastrectomy, history of small intestine surgery, and celiac disease.

3. Participants requiring treatment with clinically significant enzyme inducers, such as the enzyme-inducing anti-epileptic drugs phenytoin, carbamazepine, phenobarbital, oxcarbazepine, primidone, rifampin, rifabutin, rifapentine, or St. John's wort within 14 days before the first dose of alisertib or requiring the use of these medications during the study.

4. A medical condition requiring use of pancreatic enzymes; daily, chronic, or regular use of proton pump inhibitors (PPIs); or histamine 2 (H2) receptor antagonists. Participants who intermittently use these medications, must meet the following criteria:

• No use of PPIs within 5 days before the first dose of alisertib.

• No use of H2 antagonist or pancreatic enzymes within 24 hours before the first dose of alisertib.

1. Inadequate bone marrow or other organ function (excluding hepatic impairment per eligibility criteria).

2. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of alisertib.

3. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

4. Treatment with any anticancer therapy or any investigational products within 3 weeks before the first dose of study drug.

5. Exposure to nitrosoureas or mitomycin C within 42 days before the first dose of study drug.

6. Radiotherapy within 14 days before the first dose of study drug.

7. Prior treatment with radiation therapy involving ≥ 25% of the hematopoietically active bone marrow within 42 days before the first dose of study drug.

8. Major surgery within 14 days before the first dose of study drug.

9. Serious infection within 14 days before the first dose of study drug. Participant must have recovered from infection before first dose.

10. Life-threatening illness unrelated to cancer.

11. Symptomatic brain metastasis. Participants with brain metastases:

• Must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks after completion of the definitive therapy AND

• Must be without neurologic dysfunction that would confound the evaluation of neurologic or other adverse events (AEs).

1. Clinically significant coagulopathy or bleeding disorder.

2. Severe central nervous system, pulmonary, or renal disease not related to the participant's cancer.

3. Known human immunodeficiency virus (HIV) positive.

4. Known history of hepatitis C infection or suspected currently active hepatitis C infection, or known or suspected history of hepatitis B infection. Participants with known or suspected history of hepatitis B infection were to be screened and excluded when any of the following conditions were met:

• Received hematopoietic stem cell transplantation (either allogeneic or autologous), or

• Received any rituximab-containing treatment regimen in the last 12 months before entering the study, or

• Tested positive for the presence of at least 1 of the following 3 markers in blood (evaluated at Screening): hepatitis B surface antigen (HBsAg), antibodies against hepatitis B core antigen (anti-HBc), or hepatitis B virus deoxyribonucleic acid (HBV DNA).

1. Any of the following cardiovascular conditions:

• Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

• Corrected QT interval (QTc) > 500 milliseconds in a 12-lead electrocardiogram (ECG) during screening.

1. History of uncontrolled sleep apnea syndrome or other condition that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.

2. Use of moderate or strong cytochrome P450 (CYP) 3A inhibitors or CYP3A inducers within 2 weeks before the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Miami	Florida	United States
2		Chicago	Illinois	United States
3		Ann Arbor	Michigan	United States
4		Saint Louis	Missouri	United States
5		Dallas	Texas	United States
6		Houston	Texas	United States
7		San Antonio	Texas	United States

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02214147
• Other Study ID Numbers: C14019; U1111-1155-6072
• First Posted: Aug 12, 2014
• Last Update Posted: Nov 15, 2018
• Last Verified: Apr 1, 2018

• 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 6 investigative sites in the United States from 21 August 2014 to 18 July 2016.
Pre-assignment Detail	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	16	12	8
NOT COMPLETED	0	0	0

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 Participants	16	12	8	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.2 (10.07)	54.9 (9.89)	54.0 (7.05)	57.5 (9.77)
Sex: Female, Male (Count of Participants)
Female	5 31.3%	7 58.3%	2 25%	14 38.9%
Male	11 68.8%	5 41.7%	6 75%	22 61.1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 6.3%	1 8.3%	2 25%	4 11.1%
Not Hispanic or Latino	14 87.5%	11 91.7%	6 75%	31 86.1%
Not Reported	1 6.3%	0 0%	0 0%	1 2.8%
Race/Ethnicity, Customized (Count of Participants)
White	14 87.5%	11 91.7%	6 75%	31 86.1%
Black or African American	2 12.5%	1 8.3%	2 25%	5 13.9%
Region of Enrollment (Count of Participants)
United States	16 100%	12 100%	8 100%	36 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.9 (14.62)	162.9 (7.79)	178.2 (8.10)	170.1 (12.66)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	84.6 (20.997)	85.5 (33.881)	85.8 (11.847)	85.2 (24.044)
Body surface area (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	2.030 (0.3073)	1.897 (0.4028)	2.056 (0.1970)	1.986 (0.3292)

Outcome Measures

1. Primary Outcome

Title	Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib
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.
Measure Participants	16	12	8
Mean (Standard Deviation) [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
	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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Geometric Mean Ratio
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 90%; 1.12 to 1.80
	Parameter Dispersion	Type: Value:
	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
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.
Measure Participants	16	10	8
Mean (Standard Deviation) [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
	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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Geometric Mean Ratio
	Estimated Value	3.21
	Confidence Interval	(2-Sided) 90%; 2.33 to 4.43
	Parameter Dispersion	Type: Value:
	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
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.
Measure Participants	12	10	7
Mean (Standard Deviation) [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
	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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Geometric Mean Ratio
	Estimated Value	2.54
	Confidence Interval	(2-Sided) 90%; 1.84 to 3.53
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	16	12	8
Number [percentage of participants]	100 625%	100 833.3%	100 1250%

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.
Measure Participants	16	12	8
Number [percentage of participants]	44 275%	67 558.3%	88 1100%

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.
Measure Participants	16	12	8
Gamma-glutamyltransferase increased	13 81.3%	0 0%	0 0%
Alanine aminotransferase increased	0 0%	8 66.7%	0 0%
Aspartate aminotransferase increased	0 0%	8 66.7%	0 0%
Blood bilirubin increased	0 0%	8 66.7%	0 0%
Transaminases increased	0 0%	8 66.7%	0 0%
Blood sodium decreased	6 37.5%	8 66.7%	0 0%
Blood calcium increased	6 37.5%	0 0%	0 0%
Blood phosphorus decreased	6 37.5%	0 0%	0 0%
Platelet count decreased	6 37.5%	8 66.7%	0 0%
Blood alkaline phosphatase increased	6 37.5%	8 66.7%	0 0%
Blood creatinine increased	0 0%	8 66.7%	0 0%
Neutrophil count decreased	0 0%	8 66.7%	0 0%
White blood cell count decreased	0 0%	8 66.7%	0 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.
Measure Participants	16	12	8
Pyrexia	25 156.3%	8 66.7%	38 475%
Sinus tachycardia	6 37.5%	0 0%	0 0%

8. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2
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.
Measure Participants	16	12	8
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
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.
Measure Participants	16	12	8
Metabolite M1	3.500	24.000	24.150
Metabolite M2	9.000	24.050	24.150

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.
Measure Participants	16	10	8
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.
Measure Participants	0	0	0

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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/16 (12.5%)		3/12 (25%)		4/8 (50%)
Serious Adverse Events
	Alisertib: Normal Hepatic Function		Alisertib: Moderate Hepatic Impairment		Alisertib: Severe Hepatic Impairment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)		8/12 (66.7%)		7/8 (87.5%)
Blood and lymphatic system disorders
Anaemia	0/16 (0%)		1/12 (8.3%)		1/8 (12.5%)
Cardiac disorders
Atrial fibrillation	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Gastrointestinal disorders
Abdominal pain	0/16 (0%)		2/12 (16.7%)		3/8 (37.5%)
Gastrointestinal haemorrhage	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Stomatitis	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
General disorders
Pyrexia	2/16 (12.5%)		0/12 (0%)		1/8 (12.5%)
Malaise	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Hepatic failure	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Bile duct obstruction	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Infections and infestations
Bacterial sepsis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Biliary tract infection	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Pneumonia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Sepsis	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Metabolism and nutrition disorders
Hyperkalaemia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Hyponatraemia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer metastatic	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Colorectal adenocarcinoma	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Rectal cancer	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Breast cancer	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Pancreatic neuroendocrine tumour metastatic	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Ovarian cancer metastatic	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Pancreatic carcinoma	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Nervous system disorders
Cerebral haemorrhage	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Psychiatric disorders
Confusional state	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Delirium	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Renal and urinary disorders
Acute kidney injury	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Hydronephrosis	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Dermatitis bullous	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Alisertib: Normal Hepatic Function		Alisertib: Moderate Hepatic Impairment		Alisertib: Severe Hepatic Impairment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)		12/12 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	1/16 (6.3%)		5/12 (41.7%)		0/8 (0%)
Anaemia	1/16 (6.3%)		3/12 (25%)		1/8 (12.5%)
Neutropenia	4/16 (25%)		1/12 (8.3%)		0/8 (0%)
Leukopenia	2/16 (12.5%)		1/12 (8.3%)		1/8 (12.5%)
Anaemia of malignant disease	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Haemolytic anaemia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Lymphadenopathy	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Pancytopenia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Cardiac disorders
Sinus tachycardia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Ear and labyrinth disorders
Cerumen impaction	0/16 (0%)		2/12 (16.7%)		0/8 (0%)
Deafness	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Eye disorders
Dry eye	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Eye irritation	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Vision blurred	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Gastrointestinal disorders
Nausea	9/16 (56.3%)		3/12 (25%)		0/8 (0%)
Diarrhoea	6/16 (37.5%)		4/12 (33.3%)		0/8 (0%)
Vomiting	4/16 (25%)		4/12 (33.3%)		0/8 (0%)
Ascites	0/16 (0%)		6/12 (50%)		1/8 (12.5%)
Constipation	5/16 (31.3%)		2/12 (16.7%)		0/8 (0%)
Stomatitis	5/16 (31.3%)		2/12 (16.7%)		0/8 (0%)
Abdominal pain	1/16 (6.3%)		3/12 (25%)		2/8 (25%)
Dyspepsia	3/16 (18.8%)		0/12 (0%)		0/8 (0%)
Retching	1/16 (6.3%)		2/12 (16.7%)		0/8 (0%)
Gingival pain	2/16 (12.5%)		0/12 (0%)		0/8 (0%)
Abdominal distension	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Abdominal pain upper	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Dysphagia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Epigastric discomfort	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Eructation	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Haematochezia	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Haemorrhoids	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Oral pain	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Tongue discolouration	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
General disorders
Fatigue	6/16 (37.5%)		3/12 (25%)		3/8 (37.5%)
Pyrexia	4/16 (25%)		1/12 (8.3%)		2/8 (25%)
Oedema peripheral	2/16 (12.5%)		3/12 (25%)		1/8 (12.5%)
Chills	4/16 (25%)		0/12 (0%)		1/8 (12.5%)
Chest pain	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Influenza like illness	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Mass	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Non-cardiac chest pain	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Pain	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Peripheral swelling	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/16 (0%)		5/12 (41.7%)		0/8 (0%)
Hepatic failure	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Hepatorenal syndrome	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Portal hypertension	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Portal vein thrombosis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Bile duct obstruction	0/16 (0%)		1/12 (8.3%)		1/8 (12.5%)
Infections and infestations
Pneumonia	2/16 (12.5%)		0/12 (0%)		0/8 (0%)
Oral candidiasis	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Sepsis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Urinary tract infection	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Injury, poisoning and procedural complications
Fall	1/16 (6.3%)		0/12 (0%)		1/8 (12.5%)
Pelvic fracture	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Investigations
Blood alkaline phosphatase increased	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Blood sodium decreased	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Gamma-glutamyltransferase increased	2/16 (12.5%)		0/12 (0%)		0/8 (0%)
Platelet count decreased	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Alanine aminotransferase increased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Aspartate aminotransferase increased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Blood bilirubin increased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Blood calcium increased	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Blood creatinine increased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Blood phosphorus decreased	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Neutrophil count decreased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Transaminases increased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
White blood cell count decreased	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Metabolism and nutrition disorders
Decreased appetite	4/16 (25%)		3/12 (25%)		1/8 (12.5%)
Hyponatraemia	3/16 (18.8%)		2/12 (16.7%)		1/8 (12.5%)
Dehydration	1/16 (6.3%)		4/12 (33.3%)		0/8 (0%)
Hyperkalaemia	2/16 (12.5%)		1/12 (8.3%)		0/8 (0%)
Hypoalbuminaemia	0/16 (0%)		1/12 (8.3%)		1/8 (12.5%)
Hypokalaemia	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Hypercalcaemia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Hypocalcaemia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Hypoglycaemia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Hypomagnesaemia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Lactic acidosis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Flank pain	0/16 (0%)		2/12 (16.7%)		1/8 (12.5%)
Back pain	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Arthralgia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Muscular weakness	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Musculoskeletal chest pain	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Myalgia	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Neck mass	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Neck pain	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Pain in extremity	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Polymyalgia rheumatica	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Nervous system disorders
Headache	4/16 (25%)		1/12 (8.3%)		1/8 (12.5%)
Dizziness	2/16 (12.5%)		3/12 (25%)		0/8 (0%)
Presyncope	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Amnesia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Balance disorder	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Cervical radiculopathy	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Dysgeusia	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Somnolence	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Tongue biting	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Psychiatric disorders
Confusional state	0/16 (0%)		3/12 (25%)		2/8 (25%)
Anxiety	1/16 (6.3%)		2/12 (16.7%)		0/8 (0%)
Insomnia	3/16 (18.8%)		0/12 (0%)		0/8 (0%)
Delirium	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Stress	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Renal and urinary disorders
Acute kidney injury	0/16 (0%)		1/12 (8.3%)		1/8 (12.5%)
Dysuria	0/16 (0%)		2/12 (16.7%)		0/8 (0%)
Nephrolithiasis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Pollakiuria	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Reproductive system and breast disorders
Pelvic pain	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/16 (18.8%)		1/12 (8.3%)		1/8 (12.5%)
Dyspnoea	2/16 (12.5%)		1/12 (8.3%)		1/8 (12.5%)
Pleural effusion	2/16 (12.5%)		1/12 (8.3%)		0/8 (0%)
Dyspnoea exertional	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Nasal congestion	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Choking sensation	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Haemoptysis	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Hypoxia	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Oropharyngeal pain	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Pulmonary embolism	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Rhinorrhoea	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Alopecia	6/16 (37.5%)		3/12 (25%)		1/8 (12.5%)
Dry skin	1/16 (6.3%)		1/12 (8.3%)		0/8 (0%)
Hyperhidrosis	2/16 (12.5%)		0/12 (0%)		0/8 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/16 (0%)		1/12 (8.3%)		1/8 (12.5%)
Dermatitis acneiform	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Eczema	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Pain of skin	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Pruritus	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Rash	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Rash maculo-papular	0/16 (0%)		0/12 (0%)		1/8 (12.5%)
Skin exfoliation	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Vascular disorders
Hypotension	0/16 (0%)		2/12 (16.7%)		1/8 (12.5%)
Deep vein thrombosis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)
Hot flush	1/16 (6.3%)		0/12 (0%)		0/8 (0%)
Jugular vein thrombosis	0/16 (0%)		1/12 (8.3%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.