Safety, Tolerability and Pharmacokinetic (PK) of Concomitant Esomeprazole and Rifampin, and QT Study on Single and Multiple-doses of Alisertib

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01844583
• Collaborator: (none)
• Enrollment: 55
• Locations: 7
• Arms: 2
• Actual Duration (Months): 38.4
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the drug-drug interaction (DDI) of either esomeprazole or rifampin on the single-dose PK of alisertib, and to complete an intensive QT study of single and multiple-dose alisertib.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors; Lymphoma	Drug: Alisertib; Drug: Esomeprazole; Drug: Rifampin	Phase 1

Detailed Description

The drug tested in this study is called alisertib. Alisertib is being tested to assess the effect of a proton pump inhibitor and strong metabolic inducer on the PK of a single 50 mg dose of alisertib administered as enteric-coated tablets (ECTs).

The study enrolled 55 patients. Participants received either:

• Esomeprazole 40 mg and Alisertib 50 mg

• Rifampin 600 mg and Alisertib 50 mg

All participants were asked to take one tablet of alisertib either once or twice daily in all cycles. In Cycle 2, participants were asked to take alisertib plus either esomeprazole or rifampin.

This trial was conducted the United States. The overall time to participate in this study was 10 months. Participants made multiple visits to the clinic plus a final visit, 30 days after receiving their last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study of the Effect of Esomeprazole or Rifampin on the Pharmacokinetics of Alisertib and Evaluation of the Effect of Alisertib on the QTc Interval in Patients With Advanced Solid Tumors or Lymphomas
• Actual Study Start Date: Jun 25, 2013
• Actual Primary Completion Date: Aug 4, 2014
• Actual Study Completion Date: Sep 6, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Esomeprazole 40 mg + Alisertib 50 mg Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Esomeprazole, 40 mg, delayed-release capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).	Drug: Alisertib; Alisertib tablets; Other Names: MLN8237 ; Drug: Esomeprazole; Esomeprazole capsules
Experimental: Rifampin 600 mg + Alisertib 50 mg Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 in Cycle 2 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).	Drug: Alisertib; Alisertib tablets; Other Names: MLN8237 ; Drug: Rifampin; Rifampin capsules

Outcome Measures

Primary Outcome Measures

1. Cmax: Maximum Observed Concentration for Alisertib in Presence and Absence of Esomeprazole [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm]

2. AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Presence and Absence of Esomeprazole [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm]

3. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alisertib in Presence and Absence of Esomeprazole [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm]

4. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib in Presence and Absence of Esomeprazole [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm]

5. Terminal Phase Elimination Half-life (T1/2) for Alisertib in Presence and Absence of Esomeprazole [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm]

6. Cmax: Maximum Observed Concentration for Alisertib in Presence and Absence of Rifampin [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm]

7. AUC(Last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Presence and Absence of Rifampin [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm]

8. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alisertib in Presence or Absence of Rifampin [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm]

9. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib in Presence and Absence of Rifampin [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm]

10. Phase Elimination Half-life (T1/2) for Alisertib in Presence and Absence of Rifampin [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm]

11. Change From the Time-matched Baseline in the Individually Corrected QTc Interval (QTcI) [Baseline, Days 1 and 10 multiple timepoints postdose (up to 24 hours) in Cycle 1]

Secondary Outcome Measures

1. Change From the Time-matched Baseline in the Fridericia Correction of QTc (QTcF) [Baseline, Days 1 and 10 multiple timepoints postdose (up to 24 hours) in Cycle 1]

2. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the first dose through 30 days after administration of the last dose of study drug (up to 328 days)]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female participants 18 years or older

• Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Expected survival longer than 3 months from enrollment in the study

• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse

• Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse

Exclusion Criteria:

• Treatment with any anticancer therapy or any investigational agents within 4 weeks before the first dose of alisertib

• Known hypersensitivity or intolerance to rifampin (for participants considered for the rifampin drug-drug interaction [DDI] group) or to esomeprazole (for participants considered for the esomeprazole DDI group)

• Recurrent nausea and/or vomiting within 14 days before the first dose of alisertib, and known gastrointestinal (GI) abnormality or GI procedure that could interfere with or modify the oral absorption or tolerance of alisertib

• Participants requiring treatment with clinically significant enzyme inducers within 14 days before the first dose of alisertib and/or requiring the use of these medications during the study

• A medical condition requiring use of pancreatic enzymes; or daily, chronic, or regular use of proton pump inhibitors (PPI); or histamine (H2) receptor antagonists

• Participants requiring systemic anticoagulation (excluding low-dose aspirin, or low-dose anticoagulation to maintain patency of venous access devices).

• Any cardiovascular condition

• Female participants who are lactating or have a positive serum pregnancy test

• Major surgery within the 14 days preceding the first dose of alisertib

• Life-threatening or uncontrolled medical illness unrelated to cancer

• Newly diagnosed or uncontrolled cancer-related central nervous system (CNS) disease

• Autologous stem cell transplant within 3 months

• Prior allogeneic bone marrow or other organ transplantation

• Other severe acute or chronic medical or psychiatric condition

• Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

Please note there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Sarasota	Florida	United States
2		Saint Louis	Missouri	United States
3		Oklahoma City	Oklahoma	United States
4		Nashville	Tennessee	United States
5		Dallas	Texas	United States
6		San Antonio	Texas	United States
7		Madison	Wisconsin	United States

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01844583
• Other Study ID Numbers: C14015
• First Posted: May 1, 2013
• Last Update Posted: Mar 25, 2019
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Lymphoma; Rifampin; Esomeprazole

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 6 investigative sites in the United States from 25 June 2013 to 06 September 2016. Data cut-off for primary analysis was 04 August 2014.
Pre-assignment Detail	Participants with a diagnosis of advanced solid tumors or lymphomas were enrolled to receive alisertib 50 mg tablets, orally along with esomeprazole 40 mg, delayed release capsule once daily and alisertib 50 mg along with rifampin 600 mg capsule.

Arm/Group Title	Esomeprazole 40 mg + Alisertib 50 mg	Rifampin 600 mg + Alisertib 50 mg
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Esomeprazole, 40 mg, delayed-release capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 in Cycle 2 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).
Period Title: Overall Study
STARTED	26	29
COMPLETED	18	19
NOT COMPLETED	8	10

Baseline Characteristics

Arm/Group Title	Esomeprazole 40 mg + Alisertib 50 mg	Rifampin 600 mg + Alisertib 50 mg	Total
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Esomeprazole, 40 mg, delayed-release capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 in Cycle 2 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).	Total of all reporting groups
Overall Participants	26	29	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.2 (6.90)	60.4 (10.58)	61.3 (8.99)
Sex: Female, Male (Count of Participants)
Female	14 53.8%	21 72.4%	35 63.6%
Male	12 46.2%	8 27.6%	20 36.4%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	3 11.5%	4 13.8%	7 12.7%
Not Hispanic or Latino	22 84.6%	24 82.8%	46 83.6%
Not Reported	1 3.8%	1 3.4%	2 3.6%
Race/Ethnicity, Customized (Count of Participants)
White	22 84.6%	26 89.7%	48 87.3%
Black or African American	2 7.7%	1 3.4%	3 5.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
American Indian or Alaska Native	1 3.8%	1 3.4%	2 3.6%
Other	0 0%	1 3.4%	1 1.8%
Not Reported	1 3.8%	0 0%	1 1.8%
Region of Enrollment (Count of Participants)
United States	26 100%	29 100%	55 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	166.6 (8.90)	164.8 (9.09)	165.7 (8.97)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	82.07 (20.765)	77.37 (33.801)	79.59 (28.242)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.557 (7.2787)	28.026 (9.4175)	28.750 (8.4327)

Outcome Measures

1. Primary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib in Presence and Absence of Esomeprazole
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included participants who completed the protocol-specified dosing and PK sampling requirements in cycle 1 and cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Esomeprazole	Alisertib With Esomeprazole
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Esomeprazole 40 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17 in Cycle 2.
Measure Participants	18	18
Mean (Standard Deviation) [nmol/L]	1542.6 (357.19)	1804.8 (571.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib Without Esomeprazole, Alisertib With Esomeprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 90%; 0.97 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for each PK parameter were obtained using a mixed effects model of log (PK parameter) with fixed terms for the esomeprazole effect and random terms for participants within sequence.

2. Primary Outcome

Title	AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Presence and Absence of Esomeprazole
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Esomeprazole	Alisertib With Esomeprazole
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Esomeprazole 40 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17 in Cycle 2.
Measure Participants	18	18
Mean (Standard Deviation) [hr*nmol/L]	20427.8 (6813.46)	25094.4 (5574.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib Without Esomeprazole, Alisertib With Esomeprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 90%; 1.08 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for each PK parameter were obtained using a mixed effects model of log (PK parameter) with fixed terms for the esomeprazole effect and random terms for participants within sequence.

3. Primary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alisertib in Presence and Absence of Esomeprazole
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed protocol-specified dosing and PK sampling requirements in Cycle 1 and 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters. Here number of participants analyzed are participants who were evaluable for this outcome measure at specified time points.

Arm/Group Title	Alisertib Without Esomeprazole	Alisertib With Esomeprazole
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Esomeprazole 40 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17 in Cycle 2.
Measure Participants	14	16
Mean (Standard Deviation) [hr*nmol/L]	21371.4 (8138.55)	26612.5 (6626.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib Without Esomeprazole, Alisertib With Esomeprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 90%; 1.07 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for each PK parameter were obtained using a mixed effects model of log (PK parameter) with fixed terms for the esomeprazole effect and random terms for participants within sequence.

4. Primary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib in Presence and Absence of Esomeprazole
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Esomeprazole	Alisertib With Esomeprazole
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Esomeprazole 40 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17 in Cycle 2.
Measure Participants	18	18
Median (Full Range) [hours]	4.0	3.0

5. Primary Outcome

Title	Terminal Phase Elimination Half-life (T1/2) for Alisertib in Presence and Absence of Esomeprazole
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without esomeprazole arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with esomeprazole arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Esomeprazole	Alisertib With Esomeprazole
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Esomeprazole 40 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17 in Cycle 2.
Measure Participants	14	16
Mean (Standard Deviation) [hours]	16.06 (5.398)	15.96 (5.234)

6. Primary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib in Presence and Absence of Rifampin
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Rifampin	Alisertib With Rifampin
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on up Days 11 to 17 in Cycle 2.
Measure Participants	20	20
Mean (Standard Deviation) [nmol/L]	1561.4 (661.81)	1581.5 (519.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib Without Esomeprazole, Alisertib With Esomeprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 90%; 0.84 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for each PK parameter were obtained using a mixed effects model of log (PK parameter) with fixed terms for the esomeprazole effect and random terms for participants within sequence.

7. Primary Outcome

Title	AUC(Last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Presence and Absence of Rifampin
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Rifampin	Alisertib With Rifampin
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on up Days 11 to 17 in Cycle 2.
Measure Participants	20	20
Mean (Standard Deviation) [hr*nmol/L]	19732.0 (8489.24)	9470.5 (2653.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib Without Esomeprazole, Alisertib With Esomeprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 90%; 0.41 to 0.62
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for each PK parameter were obtained using a mixed effects model of log (PK parameter) with fixed terms for the esomeprazole effect and random terms for participants within sequence.

8. Primary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alisertib in Presence or Absence of Rifampin
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed protocol-specified dosing and PK sampling requirements in Cycle 1 and 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters. Here number of participants analyzed are participants who were evaluable for this outcome measure at specified time points.

Arm/Group Title	Alisertib Without Rifampin	Alisertib With Rifampin
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on up Days 11 to 17 in Cycle 2.
Measure Participants	12	8
Mean (Standard Deviation) [hr*nmol/L]	17258.3 (6163.60)	8955.0 (2389.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib Without Esomeprazole, Alisertib With Esomeprazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Ratio
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 90%; 0.41 to 0.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for each PK parameter were obtained using a mixed effects model of log (PK parameter) with fixed terms for the esomeprazole effect and random terms for participants within sequence.

9. Primary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib in Presence and Absence of Rifampin
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Rifampin	Alisertib With Rifampin
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on up Days 11 to 17 in Cycle 2.
Measure Participants	20	20
Median (Full Range) [hours]	4.0	2.1

10. Primary Outcome

Title	Phase Elimination Half-life (T1/2) for Alisertib in Presence and Absence of Rifampin
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 1 for alisertib without rifampin arm; Day 8 pre-dose and at multiple time points (up to 72 hours) post-dose in Cycle 2 for alisertib with rifampin arm

Outcome Measure Data

Analysis Population Description

The PK Population included participants who completed the protocol-specified dosing and PK sampling requirements in Cycle 1 and Cycle 2 to have sufficient dosing and plasma concentration-time data to permit calculation of PK parameters.

Arm/Group Title	Alisertib Without Rifampin	Alisertib With Rifampin
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1 in Cycle 1.	Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on up Days 11 to 17 in Cycle 2.
Measure Participants	12	8
Mean (Standard Deviation) [hours]	16.30 (6.608)	8.17 (5.476)

11. Primary Outcome

Title	Change From the Time-matched Baseline in the Individually Corrected QTc Interval (QTcI)
Time Frame	Baseline, Days 1 and 10 multiple timepoints postdose (up to 24 hours) in Cycle 1

Outcome Measure Data

Analysis Population Description

The electrocardiogram (ECG) QTc population included participants who received at least 1 dose of alisertib and have at least 1 post-baseline ECG.

Arm/Group Title	Alisertib
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1.
Measure Participants	55
Day 10, 0 hour postdose	-2.2
Day 1, 0.5 hour postdose	-3.7
Day 10, 0.5 hour postdose	-5.4
Day 1, 1 hour postdose	-4.5
Day 10, 1 hour postdose	-3.5
Day 1, 2 hours postdose	-4.0
Day 10, 2 hours postdose	-1.6
Day 1, 3 hours postdose	-2.5
Day 10, 3 hours postdose	-2.3
Day 1, 4 hours postdose	-1.2
Day 10, 4 hours postdose	-1.2
Day 1, 6 hours postdose	-0.9
Day 10, 6 hours postdose	-3.5
Day 1, 8 hours postdose	-0.5
Day 10, 8 hours postdose	-0.4
Day 1, 10 hours postdose	-1.5
Day 10, 10 hours postdose	-2.4
Day 1, 24 hours postdose	-3.3

12. Secondary Outcome

Title	Change From the Time-matched Baseline in the Fridericia Correction of QTc (QTcF)
Time Frame	Baseline, Days 1 and 10 multiple timepoints postdose (up to 24 hours) in Cycle 1

Outcome Measure Data

Analysis Population Description

The electrocardiogram (ECG) QTc population included participants who received at least 1 dose of alisertib and have at least 1 post-baseline ECG.

Arm/Group Title	Alisertib
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1.
Measure Participants	55
Day 10, 0 hour postdose	-2.4
Day 1, 0.5 hour postdose	-3.9
Day 10, 0.5 hour postdose	-5.3
Day 1, 1 hour postdose	-4.6
Day 10, 1 hour postdose	-3.9
Day 1, 2 hours postdose	-3.5
Day 10, 2 hours postdose	-2.5
Day 1, 3 hours postdose	-2.1
Day 10, 3 hours postdose	-2.6
Day 1, 4 hours postdose	0
Day 10, 4 hours postdose	-1.3
Day 1, 6 hours postdose	-0.5
Day 10, 6 hours postdose	-4.1
Day 1, 8 hours postdose	0
Day 10, 8 hours postdose	-1.6
Day 1, 10 hours postdose	-1.2
Day 10, 10 hours postdose	-3.5
Day 1, 24 hours postdose	-3.8

13. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time Frame	From the first dose through 30 days after administration of the last dose of study drug (up to 328 days)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of alisertib. According to the protocol analysis planned, primary purpose of the study was to observe the drug-drug interaction of either esomeprazole or rifampin on the single-dose of alisertib.

Arm/Group Title	Esomeprazole 40 mg + Alisertib 50 mg	Rifampin 600 mg + Alisertib 50 mg
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Esomeprazole, 40 mg, delayed-release capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 in Cycle 2 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).
Measure Participants	26	29
AEs	25 96.2%	27 93.1%
SAEs	9 34.6%	11 37.9%

Adverse Events

Time Frame	From the first dose through 30 days after administration of the last dose of study drug (up to 328 days)
Adverse Event Reporting Description	Any AE spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. According to the protocol analysis planned, primary purpose of the study was to observe the drug-drug interaction of either esomeprazole or rifampin on the single-dose of alisertib.
Arm/Group Title	Esomeprazole 40 mg + Alisertib 50 mg		Rifampin 600 mg + Alisertib 50 mg
Arm/Group Description	Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Esomeprazole, 40 mg, delayed-release capsules, orally, once daily on Days 1 to 10 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).		Alisertib 50 mg, tablets, orally, once on Day 1, followed by twice daily on Days 4 to 10, followed by a 14-day rest period in Cycle 1. Rifampin 600 mg, capsules, orally, once daily on Days 1 to 10 in Cycle 2 plus alisertib, 50 mg, tablets, orally, once on Day 8, followed by twice daily on Days 11 to 17, followed by a 14-day rest period in Cycle 2. Alisertib 50 mg, tablets, orally, twice daily on Days 1 to 7 beginning with Cycle 3 (21-day cycles) to the end of study (Up to 15 Cycles).
All Cause Mortality
	Esomeprazole 40 mg + Alisertib 50 mg		Rifampin 600 mg + Alisertib 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		3/29 (10.3%)
Serious Adverse Events
	Esomeprazole 40 mg + Alisertib 50 mg		Rifampin 600 mg + Alisertib 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		11/29 (37.9%)
Blood and lymphatic system disorders
Febrile neutropenia	1/26 (3.8%)		0/29 (0%)
Neutropenia	1/26 (3.8%)		0/29 (0%)
Pancytopenia	1/26 (3.8%)		0/29 (0%)
Gastrointestinal disorders
Vomiting	1/26 (3.8%)		2/29 (6.9%)
Nausea	0/26 (0%)		2/29 (6.9%)
Abdominal pain	1/26 (3.8%)		1/29 (3.4%)
Colitis	1/26 (3.8%)		0/29 (0%)
Small intestinal obstruction	0/26 (0%)		1/29 (3.4%)
Gastric ulcer perforation	0/26 (0%)		1/29 (3.4%)
Ascites	1/26 (3.8%)		0/29 (0%)
Hepatobiliary disorders
Hepatic failure	0/26 (0%)		1/29 (3.4%)
Infections and infestations
Pyelonephritis	0/26 (0%)		1/29 (3.4%)
Urinary tract infection	1/26 (3.8%)		0/29 (0%)
Septic shock	1/26 (3.8%)		0/29 (0%)
Injury, poisoning and procedural complications
Hip fracture	1/26 (3.8%)		0/29 (0%)
Metabolism and nutrition disorders
Hyponatraemia	0/26 (0%)		1/29 (3.4%)
Dehydration	1/26 (3.8%)		0/29 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/26 (0%)		1/29 (3.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma	0/26 (0%)		1/29 (3.4%)
Non-small cell lung cancer	1/26 (3.8%)		0/29 (0%)
Pancreatic carcinoma metastatic	0/26 (0%)		1/29 (3.4%)
Nervous system disorders
Cerebrovascular accident	1/26 (3.8%)		0/29 (0%)
Hepatic encephalopathy	0/26 (0%)		1/29 (3.4%)
Neuropathy peripheral	1/26 (3.8%)		0/29 (0%)
Psychiatric disorders
Mental status changes	1/26 (3.8%)		0/29 (0%)
Renal and urinary disorders
Acute kidney injury	1/26 (3.8%)		0/29 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/26 (3.8%)		1/29 (3.4%)
Acute respiratory failure	1/26 (3.8%)		0/29 (0%)
Vascular disorders
Deep vein thrombosis	0/26 (0%)		2/29 (6.9%)
Orthostatic hypotension	1/26 (3.8%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	Esomeprazole 40 mg + Alisertib 50 mg		Rifampin 600 mg + Alisertib 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/26 (96.2%)		25/29 (86.2%)
Blood and lymphatic system disorders
Neutropenia	10/26 (38.5%)		7/29 (24.1%)
Anaemia	7/26 (26.9%)		8/29 (27.6%)
Leukopenia	4/26 (15.4%)		6/29 (20.7%)
Thrombocytopenia	5/26 (19.2%)		4/29 (13.8%)
Lymphopenia	0/26 (0%)		3/29 (10.3%)
Eye disorders
Vision blurred	2/26 (7.7%)		2/29 (6.9%)
Gastrointestinal disorders
Diarrhoea	15/26 (57.7%)		4/29 (13.8%)
Stomatitis	11/26 (42.3%)		6/29 (20.7%)
Vomiting	7/26 (26.9%)		5/29 (17.2%)
Nausea	7/26 (26.9%)		4/29 (13.8%)
Abdominal pain	4/26 (15.4%)		5/29 (17.2%)
Constipation	4/26 (15.4%)		1/29 (3.4%)
Dry mouth	3/26 (11.5%)		1/29 (3.4%)
Dyspepsia	3/26 (11.5%)		1/29 (3.4%)
General disorders
Fatigue	12/26 (46.2%)		10/29 (34.5%)
Oedema peripheral	2/26 (7.7%)		3/29 (10.3%)
Asthenia	3/26 (11.5%)		0/29 (0%)
Pyrexia	2/26 (7.7%)		1/29 (3.4%)
Non-cardiac chest pain	0/26 (0%)		2/29 (6.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/26 (7.7%)		1/29 (3.4%)
Infections and infestations
Upper respiratory tract infection	3/26 (11.5%)		0/29 (0%)
Urinary tract infection	1/26 (3.8%)		2/29 (6.9%)
Injury, poisoning and procedural complications
Fall	2/26 (7.7%)		0/29 (0%)
Investigations
Gamma-glutamyltransferase increased	3/26 (11.5%)		4/29 (13.8%)
Alanine aminotransferase increased	3/26 (11.5%)		1/29 (3.4%)
Aspartate aminotransferase increased	2/26 (7.7%)		2/29 (6.9%)
Weight decreased	3/26 (11.5%)		1/29 (3.4%)
Metabolism and nutrition disorders
Decreased appetite	7/26 (26.9%)		3/29 (10.3%)
Dehydration	4/26 (15.4%)		3/29 (10.3%)
Hypokalaemia	5/26 (19.2%)		2/29 (6.9%)
Hypomagnesaemia	2/26 (7.7%)		2/29 (6.9%)
Hypophosphataemia	3/26 (11.5%)		0/29 (0%)
Musculoskeletal and connective tissue disorders
Back pain	4/26 (15.4%)		3/29 (10.3%)
Arthralgia	5/26 (19.2%)		0/29 (0%)
Bone pain	3/26 (11.5%)		0/29 (0%)
Musculoskeletal chest pain	2/26 (7.7%)		1/29 (3.4%)
Pain in extremity	2/26 (7.7%)		1/29 (3.4%)
Nervous system disorders
Dizziness	3/26 (11.5%)		1/29 (3.4%)
Headache	2/26 (7.7%)		2/29 (6.9%)
Peripheral sensory neuropathy	1/26 (3.8%)		2/29 (6.9%)
Respiratory, thoracic and mediastinal disorders
Cough	2/26 (7.7%)		5/29 (17.2%)
Nasal congestion	4/26 (15.4%)		0/29 (0%)
Oropharyngeal pain	2/26 (7.7%)		1/29 (3.4%)
Skin and subcutaneous tissue disorders
Alopecia	14/26 (53.8%)		6/29 (20.7%)
Pruritus	4/26 (15.4%)		3/29 (10.3%)
Rash	1/26 (3.8%)		2/29 (6.9%)
Rash macular	3/26 (11.5%)		0/29 (0%)
Rash maculo-papular	2/26 (7.7%)		0/29 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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