Trial Outcomes & Findings for A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors (NCT NCT03330106)

Last Updated: 2023-03-28

Results Overview

Change from time-matched baseline in QTcF was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. Data is reported at pre-dose and at multiple timepoints (1, 2, 3, 4, 6, 9, 11 and 24 hours) postdose up to Day 8 in Part A. Analysis of variance (ANOVA) was used for the analysis.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

68 participants

Primary outcome timeframe

Baseline up to Day 8

Results posted on

2023-03-28

Participant Flow

A total of 44 participants took part in this study at 8 investigative sites in the United States from 15 November 2017 to 21 June 2021.

Participants with histologically or cytologically confirmed metastatic or locally advanced solid tumor were enrolled in this 2-part study to receive intravenous infusion of pevonedistat in Part A and pevonedistat in combination with chemotherapy agents in Part B (optional part). After completion of Part A, participants had an opportunity to continue into optional Part B.

Participant milestones

Participant milestones
Measure	Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2 Pevonedistat 25 mg/m\^2, infusion, intravenously (IV), once on Day 1, followed by pevonedistat 50 mg/m\^2, infusion, IV, once on Day 8 in Part A.	Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2 Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1, followed by pevonedistat 25 mg/m\^2, infusion, IV, once on Day 8 in Part A.	Part B: Pevonedistat 25 mg/m^2 + Docetaxel Pevonedistat 25 mg/m\^2 in combination with docetaxel 75 mg/m\^2, infusion, IV, once on Day 1 followed by pevonedistat 25 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to Cycle 45 or symptomatic deterioration or progressive disease (PD), or until treatment is discontinued for another reason. Pevonedistat was administered after the docetaxel chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.	Part B: Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel Pevonedistat 20 mg/m\^2 in combination with carboplatin area under the plasma concentration (AUC) at the dose of 5 milligram per minute per milliliter (mg/min/mL), infusion, IV and paclitaxel 175 mg/m\^2, infusion, IV, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 20 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to 20 cycles or symptomatic deterioration or PD, or until treatment is discontinued for another reason. Pevonedistat was administered after the paclitaxel and carboplatin chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.
Part A STARTED	22	22	0	0
Part A COMPLETED	18	17	0	0
Part A NOT COMPLETED	4	5	0	0
Part B STARTED	0	0	23	12
Part B COMPLETED	0	0	5	4
Part B NOT COMPLETED	0	0	18	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2 Pevonedistat 25 mg/m\^2, infusion, intravenously (IV), once on Day 1, followed by pevonedistat 50 mg/m\^2, infusion, IV, once on Day 8 in Part A.	Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2 Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1, followed by pevonedistat 25 mg/m\^2, infusion, IV, once on Day 8 in Part A.	Part B: Pevonedistat 25 mg/m^2 + Docetaxel Pevonedistat 25 mg/m\^2 in combination with docetaxel 75 mg/m\^2, infusion, IV, once on Day 1 followed by pevonedistat 25 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to Cycle 45 or symptomatic deterioration or progressive disease (PD), or until treatment is discontinued for another reason. Pevonedistat was administered after the docetaxel chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.	Part B: Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel Pevonedistat 20 mg/m\^2 in combination with carboplatin area under the plasma concentration (AUC) at the dose of 5 milligram per minute per milliliter (mg/min/mL), infusion, IV and paclitaxel 175 mg/m\^2, infusion, IV, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 20 mg/m\^2 IV, once on Days 3 and 5 in each 21-day treatment cycle for up to 20 cycles or symptomatic deterioration or PD, or until treatment is discontinued for another reason. Pevonedistat was administered after the paclitaxel and carboplatin chemotherapy. Participants who completed Part A and provided consent for Part B continued treatment in Part B.
Part A Withdrawal by Subject	1	1	0	0
Part A Death	2	1	0	0
Part A Adverse Event	0	1	0	0
Part A Subjects Outside Eligibility Window for Part B due to Serious Adverse Event (SAE)	0	1	0	0
Part A Worsening Creatinine Clearance and Thrombocytopenia	1	0	0	0
Part A Progressive Disease	0	1	0	0
Part B Lost to Follow-up	0	0	0	1
Part B Withdrawal by Subject	0	0	4	0
Part B Death	0	0	2	0
Part B Clinical Progression	0	0	1	1
Part B Symptomatic Deterioration	0	0	0	1
Part B Symptomatic Deterioration, Participant Placed on Hospice	0	0	0	1
Part B Progressive Disease	0	0	11	4

Baseline Characteristics

A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2 n=22 Participants Pevonedistat 25 mg/m\^2, infusion, intravenously (IV), once on Day 1, followed by pevonedistat 50 mg/m\^2, infusion, IV, once on Day 8 in Part A.	Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2 n=22 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1, followed by pevonedistat 25 mg/m\^2, infusion, IV, once on Day 8 in Part A.	Total n=44 Participants Total of all reporting groups
Age, Continuous	61.1 years STANDARD_DEVIATION 9.15 • n=5 Participants	59.5 years STANDARD_DEVIATION 11.36 • n=7 Participants	60.3 years STANDARD_DEVIATION 10.23 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	18 Participants n=7 Participants	31 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	17 Participants n=5 Participants	18 Participants n=7 Participants	35 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 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
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	16 Participants n=5 Participants	17 Participants n=7 Participants	33 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	22 Participants n=5 Participants	22 Participants n=7 Participants	44 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to Day 8

Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient electrocardiogram (ECG) assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=42 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=40 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration Predose	1.310 milliseconds Interval -2.238 to 4.857	-2.231 milliseconds Interval -5.79 to 1.328
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 1 Hour Postdose	3.180 milliseconds Interval -0.367 to 6.727	-0.639 milliseconds Interval -4.213 to 2.935
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 2 Hours Postdose	0.840 milliseconds Interval -2.694 to 4.375	-2.127 milliseconds Interval -5.688 to 1.434
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 3 Hours Postdose	1.754 milliseconds Interval -1.783 to 5.291	-1.184 milliseconds Interval -4.747 to 2.379
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 4 Hours Postdose	2.567 milliseconds Interval -0.98 to 6.114	-1.127 milliseconds Interval -4.688 to 2.434
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 6 Hours Postdose	0.598 milliseconds Interval -2.963 to 4.159	-3.465 milliseconds Interval -7.04 to 0.111
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 9 Hours Postdose	-2.998 milliseconds Interval -6.548 to 0.552	-6.898 milliseconds Interval -10.475 to -3.322
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 11 Hours Postdose	-2.478 milliseconds Interval -6.113 to 1.158	-8.638 milliseconds Interval -12.33 to -4.946
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration 24 Hours Postdose	-2.930 milliseconds Interval -6.566 to 0.706	-7.653 milliseconds Interval -11.307 to -4.0

SECONDARY outcome

Timeframe: Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A

Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient ECG assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.

Change from time-matched baseline in QTcI was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=42 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=40 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration Predose	2.099 milliseconds Interval -2.86 to 7.058	-1.884 milliseconds Interval -6.852 to 3.084
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 1 Hour Postdose	3.580 milliseconds Interval -1.378 to 8.538	-0.206 milliseconds Interval -5.185 to 4.774
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 2 Hours Postdose	1.477 milliseconds Interval -3.471 to 6.425	-0.099 milliseconds Interval -5.068 to 4.87
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 3 Hours Postdose	3.074 milliseconds Interval -1.877 to 8.024	1.877 milliseconds Interval -3.093 to 6.848
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 4 Hours Postdose	3.816 milliseconds Interval -1.144 to 8.776	1.305 milliseconds Interval -3.665 to 6.275
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 6 Hours Postdose	2.143 milliseconds Interval -2.826 to 7.112	0.198 milliseconds Interval -4.783 to 5.179
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 9 Hours Postdose	-1.419 milliseconds Interval -6.378 to 3.54	-2.482 milliseconds Interval -7.462 to 2.499
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 11 Hours Postdose	0.020 milliseconds Interval -5.009 to 5.049	-5.250 milliseconds Interval -10.323 to -0.177
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration 24 Hours Postdose	-1.897 milliseconds Interval -6.926 to 3.132	-3.105 milliseconds Interval -8.147 to 1.937

SECONDARY outcome

Timeframe: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A

Change from time-matched baseline in QRS was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=42 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=40 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration Predose	-0.459 milliseconds Interval -2.687 to 1.768	-0.482 milliseconds Interval -2.713 to 1.748
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 1 Hour Postdose	1.447 milliseconds Interval -0.78 to 3.675	0.850 milliseconds Interval -1.384 to 3.084
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 2 Hours Postdose	-0.212 milliseconds Interval -2.437 to 2.013	-0.043 milliseconds Interval -2.274 to 2.188
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 3 Hours Postdose	0.138 milliseconds Interval -2.088 to 2.363	0.184 milliseconds Interval -2.048 to 2.415
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 4 Hours Postdose	-1.068 milliseconds Interval -3.296 to 1.159	-0.241 milliseconds Interval -2.471 to 1.99
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 6 Hours Postdose	-0.192 milliseconds Interval -2.423 to 2.038	-0.319 milliseconds Interval -2.552 to 1.915
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 9 Hours Postdose	-0.791 milliseconds Interval -3.019 to 1.437	-0.221 milliseconds Interval -2.455 to 2.013
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 11 Hours Postdose	-0.551 milliseconds Interval -2.799 to 1.696	-0.769 milliseconds Interval -3.029 to 1.491
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration 24 Hours Postdose	-0.946 milliseconds Interval -3.193 to 1.301	-0.470 milliseconds Interval -2.721 to 1.781

SECONDARY outcome

Timeframe: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A

Change from time-matched baseline in PR was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=42 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=40 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration Predose	-2.894 milliseconds Interval -8.227 to 2.44	-1.220 milliseconds Interval -6.563 to 4.122
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 1 Hour Postdose	1.152 milliseconds Interval -4.181 to 6.486	3.360 milliseconds Interval -1.989 to 8.709
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 2 Hours Postdose	-0.090 milliseconds Interval -5.419 to 5.24	1.514 milliseconds Interval -3.83 to 6.857
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 3 Hours Postdose	-1.557 milliseconds Interval -6.886 to 3.773	-0.167 milliseconds Interval -5.51 to 5.177
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 4 Hours Postdose	-3.406 milliseconds Interval -8.74 to 1.927	-1.802 milliseconds Interval -7.146 to 3.542
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 6 Hours Postdose	-4.665 milliseconds Interval -10.004 to 0.674	-4.463 milliseconds Interval -9.812 to 0.887
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 9 Hours Postdose	-4.499 milliseconds Interval -9.833 to 0.836	-3.608 milliseconds Interval -8.957 to 1.742
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 11 Hours Postdose	-3.018 milliseconds Interval -8.385 to 2.349	-2.333 milliseconds Interval -7.729 to 3.062
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration 24 Hours Postdose	-5.245 milliseconds Interval -10.617 to 0.128	-6.499 milliseconds Interval -11.878 to -1.12

SECONDARY outcome

Timeframe: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A

Change from time-matched baseline in HR was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=42 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=40 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration Predose	0.602 beats per minute (bpm) Interval -2.627 to 3.831	0.981 beats per minute (bpm) Interval -2.258 to 4.22
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 1 Hour Postdose	-2.068 beats per minute (bpm) Interval -5.297 to 1.162	-1.595 beats per minute (bpm) Interval -4.848 to 1.659
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 2 Hours Postdose	-1.812 beats per minute (bpm) Interval -5.03 to 1.406	-0.556 beats per minute (bpm) Interval -3.797 to 2.686
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 3 Hours Postdose	-0.993 beats per minute (bpm) Interval -4.212 to 2.225	1.929 beats per minute (bpm) Interval -1.313 to 5.171
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 4 Hours Postdose	-0.279 beats per minute (bpm) Interval -3.507 to 2.95	2.736 beats per minute (bpm) Interval -0.504 to 5.977
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 6 Hours Postdose	2.712 beats per minute (bpm) Interval -0.536 to 5.96	6.411 beats per minute (bpm) Interval 3.15 to 9.671
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 9 Hours Postdose	2.545 beats per minute (bpm) Interval -0.686 to 5.775	7.134 beats per minute (bpm) Interval 3.879 to 10.389
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 11 Hours Postdose	2.794 beats per minute (bpm) Interval -0.517 to 6.105	7.511 beats per minute (bpm) Interval 4.149 to 10.872
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration 24 Hours Postdose	4.432 beats per minute (bpm) Interval 1.124 to 7.74	7.609 beats per minute (bpm) Interval 4.288 to 10.93

SECONDARY outcome

Timeframe: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A

Population: Pharmacokinetic (PK) Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses by dose.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=44 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=43 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat	197 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 38.7	509 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 35.6

SECONDARY outcome

Timeframe: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A

Population: PK Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses by dose.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=43 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=43 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat	1190 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 22.0	2510 hournanogram per milliliter (hng/mL) Geometric Coefficient of Variation 25.2

SECONDARY outcome

Timeframe: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=43 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=42 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat	7.21 hours (h) Standard Deviation 1.35	6.73 hours (h) Standard Deviation 1.15

SECONDARY outcome

Timeframe: Up to Cycle 45 (end of treatment) (Cycle length=21 days)

Population: Disease-response population included participants who received at least 1 dose of study drug in Part B, had measurable disease as entry criteria for Part B, and had at least 1 postbaseline disease assessment.

Percentage of participants who achieve an overall response per investigator's assessment at end of treatment,according to Response Evaluation Criteria in Solid Tumor(RECIST),version 1.1 guideline. Complete response(CR):Disappearance of all target lesions.Any pathological lymph nodes(whether target and non target)must have reduction in short axis to \<10 millimeter(mm).Partial Response(PR):atleast 30% decrease in sum of diameter of target lesions,taking as reference baseline sum of diameter.Stable Disease(SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression(PD),taking as reference smallest sum of diameter; PD:atleast 20% increase in sum of diameter of target lesions,taking as reference,smallest sum on study(this includes baseline sum if that is smallest on study).In addition to relative increase of 20%,sum must also demonstrate an absolute increase of atleast 5 mm.Appearance of 1 or more new lesions is also considered progression.

Outcome measures

Outcome measures
Measure	Pevonedistat 25 mg/m^2 n=22 Participants Pevonedistat 25 mg/m\^2, infusion, IV, once on Day 1 or Day 8.	Pevonedistat 50 mg/m^2 n=12 Participants Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1 or Day 8.
Part B: Overall Response Rate (ORR)	9.1 percentage of participants Interval 1.0 to 10.0	8.3 percentage of participants Interval 6.2 to 9.1

Adverse Events

Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2

Serious events: 3 serious events

Other events: 13 other events

Deaths: 2 deaths

Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2

Serious events: 5 serious events

Other events: 17 other events

Deaths: 4 deaths

Part B: Pevonedistat 25 mg/m^2 + Docetaxel

Serious events: 13 serious events

Other events: 23 other events

Deaths: 2 deaths

Part B: Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel

Serious events: 5 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

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Restriction type: OTHER