Trial Outcomes & Findings for A Study of Pevonedistat in Adult East Asian Participants (NCT NCT02782468)

NCT ID: NCT02782468

Last Updated: 2023-11-03

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

23 participants

Primary outcome timeframe

From first dose through 30 days after the last dose of study drug: single agent arms (up to Cycle 19 [up to Day 429]) (Cycle=21 days); combination arms (up to Cycle 65 [up to Day 1850]) (Cycle=28 days)

Results posted on

2023-11-03

Participant Flow

Participants took part in the study at 8 investigative sites in Japan, Taiwan and South Korea from 16 May 2016 to 25 January 2022.

Participants with a historical diagnosis of relapsed/refractory (R/R) acute myeloid leukemia (AML) or R/R higher risk (HR) myelodysplastic syndromes (MDS) (including nonproliferative chronic myelomonocytic leukemia \[CMML\]) were enrolled to receive single agent pevonedistat or combination of pevonedistat and azacitidine.

Participant milestones

Participant milestones
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 Pevonedistat 25 milligram per square meter (mg/m\^2), infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Overall Study STARTED	3	7	3	10
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	3	7	3	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 Pevonedistat 25 milligram per square meter (mg/m\^2), infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Overall Study Progressive Disease	2	5	0	4
Overall Study Adverse Event	0	2	2	3
Overall Study Other	0	0	1	1
Overall Study Initiation of Hematopoietic Stem Cell Transplant	0	0	0	1
Overall Study Symptomatic Deterioration	0	0	0	1
Overall Study Withdrawal by Subject	1	0	0	0

Baseline Characteristics

A Study of Pevonedistat in Adult East Asian Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=10 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Total n=23 Participants Total of all reporting groups
Age, Continuous	78.0 years STANDARD_DEVIATION 5.20 • n=5 Participants	69.0 years STANDARD_DEVIATION 11.27 • n=7 Participants	65.0 years STANDARD_DEVIATION 9.54 • n=5 Participants	64.9 years STANDARD_DEVIATION 8.52 • n=4 Participants	67.9 years STANDARD_DEVIATION 9.72 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	4 Participants n=21 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	7 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants	19 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	7 Participants n=7 Participants	3 Participants n=5 Participants	10 Participants n=4 Participants	23 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	7 Participants n=7 Participants	3 Participants n=5 Participants	10 Participants n=4 Participants	23 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Region of Enrollment Japan	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	7 Participants n=4 Participants	12 Participants n=21 Participants
Region of Enrollment Korea, South	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants
Region of Enrollment Taiwan	0 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	7 Participants n=21 Participants
Body Surface Area (BSA)	1.5 square meter (m^2) STANDARD_DEVIATION 0.26 • n=5 Participants	1.7 square meter (m^2) STANDARD_DEVIATION 0.21 • n=7 Participants	1.7 square meter (m^2) STANDARD_DEVIATION 0.04 • n=5 Participants	1.7 square meter (m^2) STANDARD_DEVIATION 0.18 • n=4 Participants	1.7 square meter (m^2) STANDARD_DEVIATION 0.20 • n=21 Participants

PRIMARY outcome

Timeframe: From first dose through 30 days after the last dose of study drug: single agent arms (up to Cycle 19 [up to Day 429]) (Cycle=21 days); combination arms (up to Cycle 65 [up to Day 1850]) (Cycle=28 days)

Population: Safety population was defined as all enrolled participants who received at least 1 dose of any study drug, pevonedistat or azacitidine.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=10 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	3 Participants	7 Participants	3 Participants	10 Participants
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	2 Participants	7 Participants	3 Participants	6 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Population: The DLT evaluable population was defined as all participants who either experienced DLT during Cycle 1 or received all scheduled doses of study drug during Cycle 1 without DLT.

DLT: Any of following events considered possibly related to study drug(s) by investigator: Grade (G) 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis; G3 diarrhea occurred despite maximal supportive therapy; G3 arthralgia/myalgia despite use of optimal analgesia; G3 nonhematologic toxicity with exceptions: 1) Brief fatigue, 2) hypophosphatemia; Persistent elevations of transaminases/bilirubin above G2 beyond 2 days between doses; Other study drug-related nonhematologic toxicities G2 or greater, required a dose reduction/discontinuation of pevonedistat. G3 or greater hematologic toxicities, including G3 or 4 febrile neutropenia, considered DLTs if: A delay in initiation of Cycle 2 due to lack of adequate recovery from treatment-related toxicity: 1) Of more than (\>) 4 weeks due to hematologic toxicity believed not related to leukemic infiltration. Bone marrow (BM) evaluation may have been required. 2) Of \>2 weeks due to nonhematologic toxicities.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=6 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=8 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Number of Participants With Dose Limiting Toxicities (DLTs) Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 During Cycle 1	0 Participants	0 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to Cycle 19 (up to Day 399) in single agent arms (Cycle=21days) and Cycle 65 (up to Day 1820) in combination arms (Cycle=28 days)

Population: Safety population was defined as all enrolled participants who received at least 1 dose of any study drug, pevonedistat or azacitidine.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=10 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Number of Participants With Clinically Significant Abnormal Laboratory Values	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Population: Pharmacokinetic (PK) evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and pevonedistat concentration-time data to reliably estimate PK parameters by noncompartmental analysis methods and who had not received any excluded concomitant medications per the protocol.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=10 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1	253 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 37.6	410 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 45.5	67.0 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 5.9	160 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 25.7

PRIMARY outcome

Timeframe: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Population: PK evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and pevonedistat concentration-time data to reliably estimate PK parameters by noncompartmental analysis methods and who had not received any excluded concomitant medications per the protocol. Here, "overall number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=8 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Cmax: Maximum Observed Plasma Concentration for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5	252 ng/mL Geometric Coefficient of Variation 9.9	453 ng/mL Geometric Coefficient of Variation 38.7	76.1 ng/mL Geometric Coefficient of Variation 17.6	170 ng/mL Geometric Coefficient of Variation 33.7

PRIMARY outcome

Timeframe: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=8 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5	1515 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 9.1	2163 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 25.7	647 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 41.3	1224 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 14.9

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=10 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 1	24.1 liter per hour Geometric Coefficient of Variation 20.1	32.6 liter per hour Geometric Coefficient of Variation 41.7	22.8 liter per hour Geometric Coefficient of Variation 48.8	28.4 liter per hour Geometric Coefficient of Variation 23.9

PRIMARY outcome

Timeframe: Cycle 1 Day 5: pre-infusion and at multiple time points (up to 48 hours) post-infusion (Cycle length = 21 days [single agent arms]; 28 days [combination arms])

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=7 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=8 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
CL: Total Clearance for Pevonedistat When Administered Alone and in Combination With Azacitidine on Cycle 1 Day 5	24.0 liter per hour Geometric Coefficient of Variation 23.0	34.8 liter per hour Geometric Coefficient of Variation 34.6	28.1 liter per hour Geometric Coefficient of Variation 38.3	28.9 liter per hour Geometric Coefficient of Variation 23.7

SECONDARY outcome

Timeframe: From first dose up to 30 days after last dose of study drug or before start of subsequent antineoplastic therapy, whichever comes earlier up to Cycle 19 (up to Day 429, single agent)(Cycle=21 days) and Cycle 65 (up to Day 1850, combination)(Cycle=28 days)

Population: Response evaluable population was defined as all participants who received at least 1 dose of study drug, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Here, "overall number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

ORR for AML was defined as the percentage of participants with a complete remission (CR), CR with incomplete blood count recovery (CRi), or partial remission (PR) based on Modified International Working Group (IWG) Response Criteria for AML. CR was defined as participant achieved the morphologic leukemia-free state and had an absolute neutrophil count (ANC) of more than 1,000 per microliter (/mcL) and platelets of greater than or equal to (\>=) 100,000/mcL. A morphologic leukemia-free state requires less than (\<) 5 percent (%) blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. CRi was, after chemotherapy, some participants who fulfilled all of the criteria for CR except for residual neutropenia (\<1,000/mcL) or thrombocytopenia (\<100,000/mcL). PR designation required all the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to between 5% and 25% in the bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=3 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=2 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=5 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Overall Response Rate (ORR) for Participants With AML	0 percentage of participants	0 percentage of participants	50 percentage of participants	80 percentage of participants

SECONDARY outcome

ORR for MDS: Percentage of participants with CR,PR or hematologic improvement(HI) based on IWG Response Criteria. CR: BM:\<=5% myeloblasts with normal maturation of all cell lines; persistent dysplasia noted peripheral blood: hemoglobin (Hgb)\>=11 gram per deciliter (g/dL),platelets\>=100\*10\^9/L,neutrophils \>=1.0\*10\^9/L, blasts 0%. PR:CR criteria if abnormal before treatment except: BM blasts decreased by \>=50% from pretreatment but still\>5%; cellularity, morphology not relevant. HI criteria: Erythroid response:Hgb up by \>=1.5 g/dL; transfused RBC reduced by at least 4 red blood cell (RBC) transfusions/8 weeks comparatively last 8 weeks; Platelet response: Increase of \>=30\*10\^9/L for participants starting with \>20\*10\^9/L platelets; increase from \<20\*10\^9/L to \>20\*10\^9/L and by 100%; Neutrophil response: At least 100% and absolute increase \>0.5\*10\^9/L; Progression/relapse after HI: Granulocytes/platelets decreased by 50% from maximum; Hgb reduced by \>=1.5 g/dL; transfusion dependence.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=2 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=1 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
ORR for Participants With MDS	—	0 percentage of participants	100 percentage of participants	0 percentage of participants

SECONDARY outcome

CR was defined as participant achieved the morphologic leukemia-free state and had an ANC of more than 1,000/mcL and platelets of \>=100,000/mcL. A morphologic leukemia-free state requires \<5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. CR assessment was based on IWG Response Criteria.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 n=3 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=3 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=2 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=5 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Percentage of Participants With CR for Participants With AML	0 percentage of participants	0 percentage of participants	50 percentage of participants	0 percentage of participants

SECONDARY outcome

CR was defined as participant with bone marrow: less than or equal to (\<=) 5% myeloblasts with normal maturation of all cell lines; persistent dysplasia was noted peripheral blood: Hgb \>=11 g/dL, platelets \>=100\*10\^9/L, neutrophils \>=1.0\*10\^9 per liter (/L), blasts 0%. CR assessment was based on IWG Response Criteria.

Outcome measures

Outcome measures
Measure	Single Agent Arm: Pevonedistat 25 mg/m^2 Pevonedistat 25 mg/m\^2, infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Single Agent Arm: Pevonedistat 44 mg/m^2 n=2 Participants Pevonedistat 44 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in each 21-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2 n=1 Participants Pevonedistat 10 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.	Combination Arm: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2 n=3 Participants Pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 along with azacitidine 75 mg/m\^2, injection, intravenously in Cycle 1 and intravenously or subcutaneously from Cycle 2 onwards, on Days 1 to 5, and Days 8 and 9, followed by a rest period of 19 days, in each 28-day treatment cycle until disease progression or symptomatic deterioration.
Percentage of Participants With CR for Participants With MDS	—	0 percentage of participants	0 percentage of participants	0 percentage of participants

Adverse Events

Single Agent Arm: Pevonedistat 25 mg/m^2

Serious events: 2 serious events

Other events: 3 other events

Deaths: 1 deaths

Single Agent Arm: Pevonedistat 44 mg/m^2

Serious events: 7 serious events

Other events: 7 other events

Deaths: 2 deaths

Combination Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2

Serious events: 3 serious events

Other events: 3 other events

Deaths: 1 deaths

Combination Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2

Serious events: 6 serious events

Other events: 10 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.
Publication restrictions are in place

Restriction type: OTHER