Trial Outcomes & Findings for Study of MLN8237 in Participants With Advanced Solid Tumors (NCT NCT00962091)

NCT ID: NCT00962091

Last Updated: 2019-03-12

Results Overview

Dose normalized Cmax was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

53 participants

Primary outcome timeframe

Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual adverse event (AE) that was judged by the investigator to be treatment related.

Results posted on

2019-03-12

Participant Flow

Participants took part in the study at 3 investigative sites in the United States from 25 September 2009 to 01 July 2014.

Participants with a diagnosis of advanced solid tumors were enrolled to receive alisertib in 1 of 4 parts: Dose Escalation, Part A (relative bioavailability), Part B (food effect and multiple-dose pharmacokinetics of alisertib oral solution \[OS\]), and Part C (food effect and safety of alisertib enteric-coated tablets \[ECT\]).

Participant milestones

Participant milestones
Measure	Dose Escalation Cohort A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part A: Relative Bioavailability OS/PIC (Sequence A) A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part A: Relative Bioavailability PIC/OS (Sequence B) A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fed/Fasted (Sequence A) Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Overall Study STARTED	4	9	10	3	3	12	12
Overall Study COMPLETED	3	7	9	2	3	11	11
Overall Study NOT COMPLETED	1	2	1	1	0	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Dose Escalation Cohort A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part A: Relative Bioavailability OS/PIC (Sequence A) A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part A: Relative Bioavailability PIC/OS (Sequence B) A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fed/Fasted (Sequence A) Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Overall Study Withdrawal by Subject	1	2	1	1	0	1	0
Overall Study Adverse Event	0	0	0	0	0	0	1

Baseline Characteristics

Number analyzed is the number of participants with available Baseline Height data.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose Escalation Cohort n=4 Participants A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part A: Relative Bioavailability OS/PIC (Sequence A) n=9 Participants A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part A: Relative Bioavailability PIC/OS (Sequence B) n=10 Participants A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fed/Fasted (Sequence A) n=3 Participants Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) n=3 Participants A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) n=12 Participants Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) n=12 Participants Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Total n=53 Participants Total of all reporting groups
Age, Continuous	58.3 years n=4 Participants	54.6 years n=9 Participants	54.0 years n=10 Participants	51.7 years n=3 Participants	57.7 years n=3 Participants	57.4 years n=12 Participants	55.2 years n=12 Participants	55.5 years n=53 Participants
Sex: Female, Male Female	3 Participants n=4 Participants	2 Participants n=9 Participants	5 Participants n=10 Participants	1 Participants n=3 Participants	1 Participants n=3 Participants	7 Participants n=12 Participants	9 Participants n=12 Participants	28 Participants n=53 Participants
Sex: Female, Male Male	1 Participants n=4 Participants	7 Participants n=9 Participants	5 Participants n=10 Participants	2 Participants n=3 Participants	2 Participants n=3 Participants	5 Participants n=12 Participants	3 Participants n=12 Participants	25 Participants n=53 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 participants n=4 Participants	0 participants n=9 Participants	2 participants n=10 Participants	0 participants n=3 Participants	1 participants n=3 Participants	2 participants n=12 Participants	1 participants n=12 Participants	6 participants n=53 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	4 participants n=4 Participants	9 participants n=9 Participants	8 participants n=10 Participants	3 participants n=3 Participants	2 participants n=3 Participants	10 participants n=12 Participants	11 participants n=12 Participants	47 participants n=53 Participants
Race/Ethnicity, Customized White	4 participants n=4 Participants	8 participants n=9 Participants	9 participants n=10 Participants	3 participants n=3 Participants	2 participants n=3 Participants	12 participants n=12 Participants	11 participants n=12 Participants	49 participants n=53 Participants
Race/Ethnicity, Customized Black or African American	0 participants n=4 Participants	0 participants n=9 Participants	1 participants n=10 Participants	0 participants n=3 Participants	1 participants n=3 Participants	0 participants n=12 Participants	1 participants n=12 Participants	3 participants n=53 Participants
Race/Ethnicity, Customized Asian	0 participants n=4 Participants	1 participants n=9 Participants	0 participants n=10 Participants	0 participants n=3 Participants	0 participants n=3 Participants	0 participants n=12 Participants	0 participants n=12 Participants	1 participants n=53 Participants
Region of Enrollment United States	4 participants n=4 Participants	9 participants n=9 Participants	10 participants n=10 Participants	3 participants n=3 Participants	3 participants n=3 Participants	12 participants n=12 Participants	12 participants n=12 Participants	53 participants n=53 Participants
Height	167.7 cm n=4 Participants • Number analyzed is the number of participants with available Baseline Height data.	172.6 cm n=9 Participants • Number analyzed is the number of participants with available Baseline Height data.	172.8 cm n=10 Participants • Number analyzed is the number of participants with available Baseline Height data.	160.3 cm n=3 Participants • Number analyzed is the number of participants with available Baseline Height data.	169.1 cm n=3 Participants • Number analyzed is the number of participants with available Baseline Height data.	169.2 cm n=11 Participants • Number analyzed is the number of participants with available Baseline Height data.	160.5 cm n=10 Participants • Number analyzed is the number of participants with available Baseline Height data.	167.4 cm n=50 Participants • Number analyzed is the number of participants with available Baseline Height data.
Weight	72.7 kg n=4 Participants	85.5 kg n=9 Participants	81.4 kg n=10 Participants	66.3 kg n=3 Participants	77.7 kg n=3 Participants	73.0 kg n=12 Participants	66.1 kg n=12 Participants	74.7 kg n=53 Participants
Body Surface Area (BSA)	1.84 m^2 n=4 Participants • Number analyzed is the number of participants with available Baseline BSA data.	2.02 m^2 n=9 Participants • Number analyzed is the number of participants with available Baseline BSA data.	1.97 m^2 n=10 Participants • Number analyzed is the number of participants with available Baseline BSA data.	1.69 m^2 n=3 Participants • Number analyzed is the number of participants with available Baseline BSA data.	1.90 m^2 n=3 Participants • Number analyzed is the number of participants with available Baseline BSA data.	1.82 m^2 n=11 Participants • Number analyzed is the number of participants with available Baseline BSA data.	1.68 m^2 n=10 Participants • Number analyzed is the number of participants with available Baseline BSA data.	1.85 m^2 n=50 Participants • Number analyzed is the number of participants with available Baseline BSA data.

PRIMARY outcome

Timeframe: Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual adverse event (AE) that was judged by the investigator to be treatment related.

Population: Pharmacokinetic (PK)-evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. Data for Cycle 1 and Cycle 2 were combined for analyses.

Dose normalized Cmax was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=17 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=18 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Part A: Dose-normalized Cmax (Maximum Observed Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC)	58.78 nM/mg Standard Deviation 22.583	31.40 nM/mg Standard Deviation 11.404	—	—	—	—	—

PRIMARY outcome

Timeframe: Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

Population: PK evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. Data for Cycle 1 and Cycle 2 were combined for analyses.

Dose normalized AUClast was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=17 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=17 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Part A: Dose-normalized AUClast (Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC)	530.18 nM*hr/mg Standard Deviation 177.750	372.53 nM*hr/mg Standard Deviation 145.190	—	—	—	—	—

PRIMARY outcome

Population: Data from Part B were not analyzed as planned because this part of the study was terminated after only 6 of the planned 14 PK-evaluable participants were enrolled, as the OS was not stable and gelled prior to dosing. With PK evaluability being compromised by gelling of the OS, the data were not analyzed as planned.

Not performed.

Outcome measures

Outcome data not reported

PRIMARY outcome

Not performed.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

Not performed.

Outcome measures

Outcome data not reported

PRIMARY outcome

Not performed.

Outcome measures

Outcome data not reported

PRIMARY outcome

Not performed.

Outcome measures

Outcome data not reported

PRIMARY outcome

Population: PK-evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.

Participants were randomized to receive 50-mg alisertib as an ECT (single, 50-mg strength tablets) under fasted or fed (following a standardized high-fat meal) conditions.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=14 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=14 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Part C: Cmax: Maximum Observed Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food	1757.9 nM Standard Deviation 924.5	1401.2 nM Standard Deviation 501.0	—	—	—	—	—

PRIMARY outcome

Timeframe: Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related.

Population: The PK evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=14 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=14 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Part C: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food	23928.6 nM*h Standard Deviation 14343.56	24135.0 nM*h Standard Deviation 11757.15	—	—	—	—	—

PRIMARY outcome

Population: The PK evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=11 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=14 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Part C: AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food	30627.3 nM*h Standard Error 21000.29	28507.1 nM*h Standard Error 15637.50	—	—	—	—	—

PRIMARY outcome

Timeframe: Up to 30 days after the last dose of study drug (up to 27.4 months)

Population: Safety population was defined as all participants who receive any amount of alisertib.

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.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=4 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=19 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect n=6 Participants Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect n=24 Participants Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AE	4 participants	19 participants	6 participants	24 participants	—	—	—
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAE	2 participants	4 participants	2 participants	11 participants	—	—	—

PRIMARY outcome

Timeframe: Up to 30 days after the last dose of study drug (up to 27.4 months)

Population: Safety Population is defined as all participants who receive any amount of alisertib.

Laboratory AEs reported at an incidence of at least 5% overall in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, metabolism and nutrition disorders, investigations, and hepatobiliary disorders. Abnormal laboratory value were assessed as an AE if the value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline. A treatment--emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=4 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=19 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect n=6 Participants Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect n=24 Participants Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Gamma-glutamyltransferase increased	0 participants	1 participants	0 participants	2 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Lymphocyte count decreased	0 participants	0 participants	0 participants	3 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Neutropenia	3 participants	8 participants	2 participants	21 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Anaemia	3 participants	4 participants	2 participants	15 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Thrombocytopenia	4 participants	3 participants	3 participants	10 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Leukopenia	3 participants	7 participants	2 participants	17 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Lymphopenia	0 participants	3 participants	0 participants	3 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Hypomagnesaemia	0 participants	0 participants	1 participants	7 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Hyperglycaemia	0 participants	1 participants	1 participants	3 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Hypokalaemia	0 participants	0 participants	1 participants	3 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% White blood cell count decreased	0 participants	0 participants	1 participants	5 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Aspartate aminotransferase increased	1 participants	0 participants	0 participants	6 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Neutrophil count decreased	0 participants	1 participants	0 participants	2 participants	—	—	—
Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% Hyperbilirubinaemia	1 participants	0 participants	0 participants	3 participants	—	—	—

PRIMARY outcome

Timeframe: Up to 30 days after the last dose of study drug (up to 24 months approximately)

Population: Safety Population is defined as all participants who receive any amount of alisertib.

Vital signs (blood pressure, heart rate, and oral temperature) measurements were obtained throughout the study.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=4 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=19 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect n=6 Participants Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect n=24 Participants Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Number of Participants With Abnormal Vital Signs Reported as Adverse Events Sinus bradycardia	0 participants	0 participants	0 participants	1 participants	—	—	—
Number of Participants With Abnormal Vital Signs Reported as Adverse Events Hypertension	1 participants	0 participants	1 participants	1 participants	—	—	—
Number of Participants With Abnormal Vital Signs Reported as Adverse Events Hypotension	0 participants	1 participants	1 participants	0 participants	—	—	—
Number of Participants With Abnormal Vital Signs Reported as Adverse Events Tachycardia	1 participants	1 participants	1 participants	0 participants	—	—	—

SECONDARY outcome

Timeframe: At the completion of Cycle 2 and every 2 cycles (every 6 weeks) until Cycle 6 (18 weeks). After Cycle 6 (18 weeks), CT/MRI scans (with contrast) were to be performed every 3 cycles (9 weeks) until PD was documented.

Population: Efficacy analysis included all participants who had a baseline response assessment and at least one on-study response assessment.

Best overall response is defined as the number of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT or MRI. CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter (LD) of target lesions. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease, taking as reference the smallest sum LD since the treatment started.

Outcome measures

Outcome measures
Measure	Part A: Alisertib OS n=2 Participants Alisertib 25 mg, OS, once on Day 1 in Cycle 1 or Cycle 2.	Part A: Alisertib PIC n=8 Participants Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2.	Part B: OS Food Effect n=9 Participants Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect n=3 Participants Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part B: OS Food Effect Fasted/Fed (Sequence B) n=3 Participants A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fed/Fasted (Sequence A) n=12 Participants Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.	Part C: ECT Food Effect Fasted/Fed (Sequence B) n=12 Participants Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy.
Best Overall Response (CR+PR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Best Overall Response of CR or PR	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants
Best Overall Response (CR+PR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Best Overall Response of Stable Disease	0 participants	1 participants	5 participants	2 participants	1 participants	6 participants	6 participants

Adverse Events

Dose Escalation Cohort

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Part A: Relative Bioavailability

Serious events: 4 serious events

Other events: 19 other events

Deaths: 0 deaths

Part B: OS Food Effect

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Part C: ECT Food Effect

Serious events: 11 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER