Trial Outcomes & Findings for MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine (NCT NCT01397825)

Last Updated: 2018-03-27

Results Overview

Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

45 participants

Primary outcome timeframe

First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

Results posted on

2018-03-27

Participant Flow

Participants took part in the Phase 1 portion of the study at 10 investigative sites in the United States from 09 August 2011 to 05 October 2016. The Phase 2 portion of the study was cancelled by the sponsor.

Participants with a diagnosis of relapsed or refractory Diffuse Large B-cell lymphoma (DLBCL)/transformed Follicular lymphoma (TFL), Mantle Cell lymphoma, or Burkitt's Lymphoma were enrolled to receive alisertib open label at doses 30 mg, 40 mg or 50 mg.

Participant milestones

Participant milestones
Measure	Safety Lead-in Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Overall Study STARTED	13	4	25	3
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	13	4	25	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Safety Lead-in Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Overall Study Progressive Disease	10	3	11	1
Overall Study Symptomatic Deterioration	2	0	4	0
Overall Study Adverse Event	0	1	5	1
Overall Study Withdrawal by Subject	1	0	5	1

Baseline Characteristics

MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Total n=45 Participants Total of all reporting groups
Age, Continuous	60.3 years STANDARD_DEVIATION 14.06 • n=5 Participants	51.3 years STANDARD_DEVIATION 21.65 • n=7 Participants	62.8 years STANDARD_DEVIATION 10.51 • n=5 Participants	66.7 years STANDARD_DEVIATION 12.86 • n=4 Participants	61.3 years STANDARD_DEVIATION 12.89 • n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	1 Participants n=7 Participants	10 Participants n=5 Participants	2 Participants n=4 Participants	16 Participants n=21 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	3 Participants n=7 Participants	15 Participants n=5 Participants	1 Participants n=4 Participants	29 Participants n=21 Participants
Race/Ethnicity, Customized Hispanic or Latino	7 participants n=5 Participants	1 participants n=7 Participants	6 participants n=5 Participants	1 participants n=4 Participants	15 participants n=21 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	6 participants n=5 Participants	3 participants n=7 Participants	19 participants n=5 Participants	2 participants n=4 Participants	30 participants n=21 Participants
Race/Ethnicity, Customized White	12 participants n=5 Participants	4 participants n=7 Participants	21 participants n=5 Participants	3 participants n=4 Participants	40 participants n=21 Participants
Race/Ethnicity, Customized Black or African American	0 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	0 participants n=4 Participants	2 participants n=21 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Race/Ethnicity, Customized Not Reported	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Region of Enrollment United States	13 participants n=5 Participants	4 participants n=7 Participants	25 participants n=5 Participants	3 participants n=4 Participants	45 participants n=21 Participants
Height	167.9 cm STANDARD_DEVIATION 10.90 • n=5 Participants	178.2 cm STANDARD_DEVIATION 7.15 • n=7 Participants	168.4 cm STANDARD_DEVIATION 10.76 • n=5 Participants	166.5 cm STANDARD_DEVIATION 5.32 • n=4 Participants	169.0 cm STANDARD_DEVIATION 10.44 • n=21 Participants
Weight	70.98 kg STANDARD_DEVIATION 16.18 • n=5 Participants	89.51 kg STANDARD_DEVIATION 23.89 • n=7 Participants	82.21 kg STANDARD_DEVIATION 16.4 • n=5 Participants	71.94 kg STANDARD_DEVIATION 14.55 • n=4 Participants	78.93 kg STANDARD_DEVIATION 17.46 • n=21 Participants
Body Surface Area	1.815 m^2 STANDARD_DEVIATION 0.25 • n=5 Participants	2.093 m^2 STANDARD_DEVIATION 0.31 • n=7 Participants	1.940 m^2 STANDARD_DEVIATION 0.23 • n=5 Participants	1.823 m^2 STANDARD_DEVIATION 0.21 • n=4 Participants	1.910 m^2 STANDARD_DEVIATION 0.25 • n=21 Participants

PRIMARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

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

Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] Hypotension	0 participants	0 participants	3 participants	1 participants
Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] Orthostatic hypotension	2 participants	2 participants	0 participants	0 participants
Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] Hypertension	1 participants	0 participants	0 participants	0 participants
Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] Pyrexia	3 participants	0 participants	2 participants	1 participants

PRIMARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

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

Abnormal ECGs findings determined by the investigator to be clinically significant were reported as adverse events.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1]	0 participants	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

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

Abnormal changes in MUGA and ECHO findings determined by the investigator to be clinically significant were reported as adverse events.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1]	0 participants	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

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

Abnormal Physical Examination findings determined by the investigator to be clinically significant were reported as Adverse Events.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1]	0 participants	0 participants	2 participants	2 participants

PRIMARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

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

Abnormal treatment-emergent Chemistry and Hematology Laboratory values determined by the investigator to be clinically significant were reported as adverse events.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Blood bilirubin increased	1 participants	0 participants	0 participants	0 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Anaemia	6 participants	3 participants	14 participants	2 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Neutropenia	7 participants	2 participants	11 participants	2 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Febrile neutropenia	0 participants	0 participants	4 participants	3 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Leukopenia	8 participants	2 participants	9 participants	3 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Lymphopenia	2 participants	2 participants	1 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Thrombocytopenia	7 participants	1 participants	7 participants	3 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypokalaemia	5 participants	0 participants	6 participants	2 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hyperkalaemia	0 participants	0 participants	1 participants	0 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypomagnesaemia	2 participants	0 participants	5 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypermagnesaemia	0 participants	0 participants	0 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypocalcaemia	2 participants	0 participants	1 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypercalcaemia	1 participants	0 participants	2 participants	0 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hyperglycaemia	1 participants	1 participants	2 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypoalbuminaemia	3 participants	0 participants	0 participants	2 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hyponatraemia	2 participants	0 participants	0 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypernatraemia	0 participants	0 participants	1 participants	0 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Hypophosphataemia	1 participants	0 participants	1 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Neutrophil count decreased	1 participants	0 participants	3 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Lymphocyte count decreased	1 participants	0 participants	0 participants	0 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] White blood cell count decreased	0 participants	0 participants	0 participants	1 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Aspartate aminotransferase increased	0 participants	0 participants	1 participants	2 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Alanine aminotransferase increased	0 participants	0 participants	0 participants	2 participants
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] Platelet count decreased	1 participants	0 participants	1 participants	1 participants

PRIMARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

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 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	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Number of Participants With Treatment-Emergent Adverse Events [Phase 1]	13 participants	4 participants	25 participants	3 participants

PRIMARY outcome

Timeframe: At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years

Population: The Phase 2 portion of the study was cancelled by the sponsor.

Overall Response Rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) as assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)

Population: Response-Evaluable Population was defined as all participants with measurable disease who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=12 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=3 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=20 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=2 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Overall Response Rate as Assessed by the Investigator [Phase 1]	25 percentage of participants Interval 5.0 to 57.0	33 percentage of participants Interval 0.84 to 91.0	45 percentage of participants Interval 23.0 to 68.0	50 percentage of participants Interval 1.0 to 99.0

SECONDARY outcome

Timeframe: Duration of study until disease progression, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

Complete response rate was defined as the percentage of participants with Complete Response (CR). CR was assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Duration of study until disease progression, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

DOR was defined as the time from the date of first documentation of a response to the date of first documentation of Progressive Disease (PD).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Duration of study until disease progression, approximately 2 years

Population: The Phase 2 portion of the study was cancelled by the sponsor.

PFS was defined as the time from the date of first study drug administration to the date of first documentation of PD or death.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From screening period to 30 days after last dose of study drug, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From screening period to 30 days after last dose of study drug, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From screening period to 30 days after last dose of study drug, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From screening period to 30 days after last dose of study drug, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From screening period to 30 days after last dose of study drug, approximately 2 years

Population: Phase 2 portion of the study was cancelled by the sponsor.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose

Population: Alisertib Pharmacokinetic (PK)-Evaluable Population was defined as all participants with sufficient dosing and alisertib concentration-time data to permit non-compartmental PK analysis. Number analyzed is the number of participants with data available at the given time-point.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Cmax: Maximum Plasma Concentration for Alisertib Day 1	1624.1 nanoMolar (nM) Standard Deviation 929.68	893.3 nanoMolar (nM) Standard Deviation 350.03	1159.7 nanoMolar (nM) Standard Deviation 391.78	1746.7 nanoMolar (nM) Standard Deviation 594.75
Cmax: Maximum Plasma Concentration for Alisertib Day 7	2915.8 nanoMolar (nM) Standard Deviation 1537.03	1672.5 nanoMolar (nM) Standard Deviation 183.92	2223.3 nanoMolar (nM) Standard Deviation 1217.22	3670.0 nanoMolar (nM) Standard Deviation 1541.49

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose

Population: Alisertib PK-Evaluable Population was defined as all participants with sufficient dosing and alisertib concentration-time data to permit non-compartmental PK analysis. Number analyzed is the number of participants with data available at the given time-point.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Tmax: Time to First Occurrence of Cmax fo Alisertib Day 1	3.0 hours (hr) Interval 2.0 to 8.0	3.5 hours (hr) Interval 3.0 to 6.0	3.0 hours (hr) Interval 1.0 to 12.0	6.1 hours (hr) Interval 3.0 to 12.0
Tmax: Time to First Occurrence of Cmax fo Alisertib Day 7	2.0 hours (hr) Interval 0.0 to 8.0	3.1 hours (hr) Interval 2.0 to 6.0	3.1 hours (hr) Interval 2.0 to 8.0	2.5 hours (hr) Interval 2.0 to 3.0

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose

Outcome measures

Outcome measures
Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib Day 1	10116.7 nanomoles/literhour (nmol/Lhr) Standard Deviation 6683.97	5817.5 nanomoles/literhour (nmol/Lhr) Standard Deviation 2966.26	8005.9 nanomoles/literhour (nmol/Lhr) Standard Deviation 3251.32	13096.7 nanomoles/literhour (nmol/Lhr) Standard Deviation 7453.39
AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib Day 7	21812.5 nanomoles/literhour (nmol/Lhr) Standard Deviation 13090.21	12227.5 nanomoles/literhour (nmol/Lhr) Standard Deviation 3480.09	17996.0 nanomoles/literhour (nmol/Lhr) Standard Deviation 11555.15	33800.0 nanomoles/literhour (nmol/Lhr) Standard Deviation 16263.46

SECONDARY outcome

Timeframe: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose

Population: Vincristine PK-evaluable population was defined as all participants with sufficient dosing and vincristine concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine. Number analyzed is the number of participants with data available at the given time-point.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=4 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=25 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=3 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Cmax: Maximum Plasma Concentration for Vincristine Cycle 1, Day 1	132.2 ng/mL Standard Deviation 54.57	105.4 ng/mL Standard Deviation 78.93	158.4 ng/mL Standard Deviation 67.94	—
Cmax: Maximum Plasma Concentration for Vincristine Cycle 2, Day 1	113.9 ng/mL Standard Deviation 53.86	124.4 ng/mL Standard Deviation 157.70	122.3 ng/mL Standard Deviation 36.42	—

SECONDARY outcome

Timeframe: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose

Population: Vincristine PK-evaluable population was defined as all participants with sufficient dosing and vincristine concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine Number analyzed is the number of participants with data available at the given time-point.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=4 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=24 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=3 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine Cycle 1, Day 1	69.8 ng/mL*hr Standard Deviation 9.92	69.1 ng/mL*hr Standard Deviation 33.24	104.1 ng/mL*hr Standard Deviation 43.34	—
AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine Cycle 2, Day 1	60.8 ng/mL*hr Standard Deviation 2.26	72.8 ng/mL*hr Standard Deviation 30.40	72.2 ng/mL*hr Standard Deviation 32.60	—

SECONDARY outcome

Timeframe: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose

Population: Vincristine PK-evaluable population was defined as participants with sufficient dosing and concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine. Number analyzed is the number of participants with data available at the time-point. No data was collected for the alisertib 50 mg arm in Cycle 2.

Outcome measures

Outcome measures
Measure	Safety Lead-in n=4 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=22 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=3 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine Cycle 1, Day 1	77.9 ng/mL*hr Standard Deviation 11.25	84.8 ng/mL*hr Standard Deviation 36.21	116.8 ng/mL*hr Standard Deviation 44.95	—
AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine Cycle 2, Day 1	69.0 ng/mL*hr Standard Deviation 4.45	82.7 ng/mL*hr Standard Deviation 35.39	—	—

SECONDARY outcome

Timeframe: Cycles 1 and 2 on Day prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose

Outcome measures

Outcome measures
Measure	Safety Lead-in n=4 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=25 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=3 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
T1/2: Terminal Disposition Phase Half-life for Vincristine Cycle 1, Day 1	20.2 nanogram/milliliter (ng/mL) Standard Deviation 5.04	20.0 nanogram/milliliter (ng/mL) Standard Deviation 5.89	25.6 nanogram/milliliter (ng/mL) Standard Deviation 4.55	—
T1/2: Terminal Disposition Phase Half-life for Vincristine Cycle 2, Day 1	19.9 nanogram/milliliter (ng/mL) Standard Deviation 0.92	20.2 nanogram/milliliter (ng/mL) Standard Deviation 4.66	—	—

Adverse Events

Safety Lead-in

Serious events: 6 serious events

Other events: 13 other events

Deaths: 0 deaths

Dose Escalation, Alisertib 30 mg

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Dose Escalation, Alisertib 40 mg

Serious events: 12 serious events

Other events: 25 other events

Deaths: 0 deaths

Dose Escalation, Alisertib 50 mg

Serious events: 3 serious events

Other events: 3 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

Measure	Safety Lead-in n=13 Participants Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 30 mg n=4 Participants Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 40 mg n=25 Participants Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.	Dose Escalation, Alisertib 50 mg n=3 Participants Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib Day 1	10116.7 nanomoles/literhour (nmol/Lhr) Standard Deviation 6683.97	5817.5 nanomoles/literhour (nmol/Lhr) Standard Deviation 2966.26	8005.9 nanomoles/literhour (nmol/Lhr) Standard Deviation 3251.32	13096.7 nanomoles/literhour (nmol/Lhr) Standard Deviation 7453.39
AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib Day 7	21812.5 nanomoles/literhour (nmol/Lhr) Standard Deviation 13090.21	12227.5 nanomoles/literhour (nmol/Lhr) Standard Deviation 3480.09	17996.0 nanomoles/literhour (nmol/Lhr) Standard Deviation 11555.15	33800.0 nanomoles/literhour (nmol/Lhr) Standard Deviation 16263.46