A Study to Evaluate the Effects of Rifampin on Pharmacokinetics (PK) of Pevonedistat in Participants With Advanced Solid Tumors

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03486314
• Collaborator: (none)
• Enrollment: 20
• Locations: 4
• Arms: 2
• Actual Duration (Months): 30.6
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the effect of multiple-dose administration of rifampin on the single dose PK of pevonedistat in adult participants with advanced solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Neoplasm	Drug: Pevonedistat; Drug: Rifampin; Drug: Docetaxel; Drug: Carboplatin; Drug: Paclitaxel	Phase 1

Detailed Description

The study will enroll approximately 20 participants. The study will be conducted in two Parts: Part A and optional Part B. Part A will have a drug-drug interaction (DDI) assessment.

In Part A, participants will be assigned to:

• Pevonedistat 50 mg/m^2 + Rifampin

Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC chemotherapy, docetaxel or carboplatin plus paclitaxel. The investigator will decide which SoC combination partner a participant will receive.

• Pevonedistat 25 mg/m^2 + Docetaxel

• Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 18 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug or before the start of subsequent therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1 Study to Evaluate the Effects of Rifampin on Pharmacokinetics of Pevonedistat in Patients With Advanced Solid Tumors
• Actual Study Start Date: Aug 13, 2018
• Actual Primary Completion Date: May 10, 2019
• Actual Study Completion Date: Feb 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg Pevonedistat 50 milligram per square meter (mg/m^2), intravenous infusion, once on Day 1 and 10 along with rifampin 600 milligram (mg), capsule, orally, once daily from Day 3 up to Day 11 in Part A. After completion of Part A, participants had opportunity to continue into optional Part B.	Drug: Pevonedistat; Pevonedistat intravenous infusion.; Other Names: MLN4924, TAK-924 ; Drug: Rifampin; Rifampin capsules.
Experimental: Part B: Pevonedistat Pevonedistat 25 mg/m^2 intravenously in combination with docetaxel 75 mg/m^2 or at 20 mg/m^2 in combination with carboplatin +paclitaxel 175 mg/m^2; pevonedistat was given in combination on Day 1 and as a single agent on Days 3 and 5 of each 21-day cycle. Participants were treated for up to 12 cycles or symptomatic deterioration or PD, treatment was discontinued for another reason, or until the study is stopped in Part B. The choice of combination partner (docetaxel or carboplatin + paclitaxel) was based on investigator discretion. If the sponsor and investigator determine that a participant would derive clinical benefit from continued treatment, the participant may remain on the current combination therapy or receive pevonedistat as a single agent beyond 12 cycles.	Drug: Pevonedistat; Pevonedistat intravenous infusion.; Other Names: MLN4924, TAK-924 ; Drug: Docetaxel; Docetaxel intravenous infusion.; Drug: Carboplatin; Carboplatin intravenous infusion.; Drug: Paclitaxel; Paclitaxel intravenous infusion.

Outcome Measures

Primary Outcome Measures

1. Part A: Ratio of Maximum Observed Plasma Concentration (Cmax) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) [Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose]

   The Least square (LS) means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.

2. Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) [Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose]

   The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.

3. Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC∞) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) [Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose]

   The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.

Secondary Outcome Measures

1. Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) [Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose]

2. Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) [Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose]

3. Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) [Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose]

4. Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment [Up to Cycle 17 (end of treatment) (Cycle length =21 days)]

   Best overall response was defined as participants with best response among complete response (CR) or partial response (PR) or stable disease (SD), or progressive disease (PD). It was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target and non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter. PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Adult participants who have a histologically or cytologically confirmed metastatic or locally advanced solid tumor that is appropriate for treatment with either docetaxel or carboplatin + paclitaxel in Part B of this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

3. Expected survival of at least 3 months from the date of enrollment in the study.

4. Recovered (that is, less than or equal to (<=) Grade 1 toxicity) from the effects of prior antineoplastic therapy.

5. Adequate organ functions (kidney, liver, cardiac, bone marrow).

6. Suitable venous access for the study-required blood sampling (including PK sampling).

Exclusion Criteria:

1. Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow.

2. Life-threatening illness or serious (acute or chronic) medical or psychiatric illness unrelated to cancer.

3. Active, uncontrolled infection or severe infectious disease.

4. Known human immunodeficiency virus (HIV) seropositive or known hepatitis B or hepatitis C infection.

5. With significant heart or pulmonary disease.

6. Requiring chronic treatment with breast cancer resistance protein (BCRP) inhibitors.

Criteria for Continuation into Optional Part B:

To be eligible for Part B, participants must have completed Part A and be reassessed to determine if they meet the continuation criteria for Part B.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30308
2	Robert H. Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois	United States	60611
3	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-2013
4	Greenville Health System - Institute for Translational Oncology Research	Greenville	South Carolina	United States	29605

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Sep 4, 2018
• Statistical Analysis Plan - Jun 11, 2019

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03486314
• Other Study ID Numbers: Pevonedistat-1015; U1111-1202-2144
• First Posted: Apr 3, 2018
• Last Update Posted: Apr 18, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug therapy
• Additional relevant MeSH terms: Rifampin; Paclitaxel; Docetaxel; Carboplatin; Pevonedistat

Study Results

Participant Flow

Recruitment Details

Participants took part in the study at 4 investigative sites in the United States from 13 August 2018 to 28 February 2021.

Pre-assignment Detail

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 along with rifampin capsule 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.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg	Part B: Pevonedistat 25 mg/m^2 + Docetaxel 75 mg/m^2	Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5+ Paclitaxel 175 mg/m^2
Arm/Group Description	Pevonedistat 50 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1 and 10, and then rifampin 600 milligram (mg), capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.	Pevonedistat 25 mg/m^2, infusion, intravenously in combination with docetaxel 75 mg/m^2, infusion, intravenously on Day 1 of 21-day cycle, followed by pevonedistat 25 mg/m^2, infusion, intravenously alone once on Days 3 and 5 in each 21-day cycle for up to 17 cycles or symptomatic deterioration or disease progression, treatment discontinuation for another reason, or until the study was stopped in Part B. Participants who completed Part A and provided consent for Part B continued treatment in Part B.	Pevonedistat 20 mg/m^2, infusion, intravenously in combination with carboplatin area under the plasma concentration (AUC) at the dose of 5 milligram* minute per milliliter (mg*min/mL), infusion, intravenously and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 of 21-day cycle, followed by pevonedistat 20 mg/m^2, infusion, intravenously alone once on Days 3 and 5 in each 21-day cycle for up to 17 cycles or symptomatic deterioration or disease progression, treatment was discontinued for another reason, or until the study was stopped in Part B. 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.
Period Title: Part A
STARTED	20	0	0
COMPLETED	17	0	0
NOT COMPLETED	3	0	0
Period Title: Part A
STARTED	0	9	8
COMPLETED	0	9	8
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.9 (8.70)
Sex: Female, Male (Count of Participants)
Female	10 50%
Male	10 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	20 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 20%
White	15 75%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	20 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	171.91 (10.235)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	87.13 (22.667)
Body Surface Area (BSA) (square meter (m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [square meter (m^2)]	2.03 (0.307)

Outcome Measures

1. Primary Outcome

Title	Part A: Ratio of Maximum Observed Plasma Concentration (Cmax) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Description	The Least square (LS) means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
Time Frame	Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here "overall number of participants" analyzed are those who were evaluable for this outcome measure.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Measure Participants	17
Least Squares Mean (90% Confidence Interval) [ratio]	0.962

2. Primary Outcome

Title	Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Description	The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
Time Frame	Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here "overall number of participants" analyzed are those who were evaluable for this outcome measure.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Measure Participants	17
Least Squares Mean (90% Confidence Interval) [ratio]	0.785

3. Primary Outcome

Title	Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC∞) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Description	The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
Time Frame	Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here "overall number of participants" analyzed are those who were evaluable for this outcome measure.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Measure Participants	17
Least Squares Mean (90% Confidence Interval) [ratio]	0.790

4. Secondary Outcome

Title	Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Time Frame	Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here number analyzed "n" signifies participants who were evaluable for this outcome measure at given time points.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Measure Participants	20
Pevonedistat without rifampin (Day 1)	35.22 (10.980)
Pevonedistat with rifampin (Day 10)	43.77 (12.604)

5. Secondary Outcome

Title	Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Time Frame	Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here number analyzed "n" signifies participants who were evaluable for this outcome measure at given time points.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Measure Participants	20
Pevonedistat without rifampin (Day 1)	312.82 (144.495)
Pevonedistat with rifampin (Day 10)	296.10 (136.297)

6. Secondary Outcome

Title	Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Time Frame	Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here number analyzed "n" signifies participants who were evaluable for this outcome measure at given time points.

Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.
Measure Participants	20
Pevonedistat without rifampin (Day 1)	7.442 (1.3846)
Pevonedistat with rifampin (Day 10)	5.708 (1.3665)

7. Secondary Outcome

Title	Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment
Description	Best overall response was defined as participants with best response among complete response (CR) or partial response (PR) or stable disease (SD), or progressive disease (PD). It was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target and non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter. PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study.
Time Frame	Up to Cycle 17 (end of treatment) (Cycle length =21 days)

Outcome Measure Data

Analysis Population Description

The response-evaluable population was defined as all 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. As planned, this outcome measure was only assessed in Part B.

Arm/Group Title	Part B: Pevonedistat 25 mg/m^2 + Docetaxel 75 mg/m^2	Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5 + Paclitaxel 175 mg/m^2
Arm/Group Description	Pevonedistat 25 mg/m^2, infusion, intravenously in combination with docetaxel 75 mg/m^2, infusion, intravenously on Day 1 of 21-day cycle, followed by pevonedistat 25 mg/m^2, infusion, intravenously alone once on Days 3 and 5 in each 21-day cycle for up to 17 cycles or symptomatic deterioration or disease progression, treatment discontinuation for another reason, or until the study was stopped in Part B. Participants who completed Part A and provided consent for Part B continued treatment in Part B.	Pevonedistat 20 mg/m^2, infusion, intravenously in combination with carboplatin AUC at the dose of 5 mg*min/mL, infusion, intravenously and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 of 21-day cycle, followed by pevonedistat 20 mg/m^2, infusion, intravenously alone once on Days 3 and 5 in each 21-day cycle for up to 17 cycles or symptomatic deterioration or disease progression, treatment was discontinued for another reason, or until the study was stopped in Part B. 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.
Measure Participants	6	7
CR	0 0%	0 NaN
PR	2 10%	1 NaN
SD	2 10%	3 NaN
PD	2 10%	3 NaN

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (From first dose of study drug up to Day 41 [Part A]; From first dose of study drug up to Cycle 17 Day 35 (Cycle length =21 days) [Part B])
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg		Part B: Pevonedistat 25 mg/m^2 + Docetaxel 75 mg/m^2		Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5+ Paclitaxel 175 mg/m^2
Arm/Group Description	Pevonedistat 50 mg/m^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9.		Pevonedistat 25 mg/m^2, infusion, intravenously in combination with docetaxel 75 mg/m^2, infusion, intravenously on Day 1 of 21-day cycle, followed by pevonedistat 25 mg/m^2, infusion, intravenously alone once on Days 3 and 5 in each 21-day cycle for up to 17 cycles or symptomatic deterioration or disease progression, treatment discontinuation for another reason, or until the study was stopped in Part B. Participants who completed Part A and provided consent for Part B continued treatment in Part B.		Pevonedistat 20 mg/m^2, infusion, intravenously in combination with carboplatin AUC at the dose of 5 mg*min/mL, infusion, intravenously and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 of 21-day cycle, followed by pevonedistat 20 mg/m^2, infusion, intravenously alone once on Days 3 and 5 in each 21-day cycle for up to 17 cycles or symptomatic deterioration or disease progression, treatment was discontinued for another reason, or until the study was stopped in Part B. 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.
All Cause Mortality
	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg		Part B: Pevonedistat 25 mg/m^2 + Docetaxel 75 mg/m^2		Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5+ Paclitaxel 175 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/9 (0%)		1/8 (12.5%)
Serious Adverse Events
	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg		Part B: Pevonedistat 25 mg/m^2 + Docetaxel 75 mg/m^2		Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5+ Paclitaxel 175 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		3/9 (33.3%)		4/8 (50%)
Blood and lymphatic system disorders
Febrile neutropenia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Gastrointestinal disorders
Rectal haemorrhage	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Nausea	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Immune system disorders
Hypersensitivity	1/20 (5%)		0/9 (0%)		0/8 (0%)
Infections and infestations
Pneumonia	1/20 (5%)		2/9 (22.2%)		0/8 (0%)
Septic shock	1/20 (5%)		0/9 (0%)		0/8 (0%)
Enterocolitis infectious	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Sepsis	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Renal and urinary disorders
Acute kidney injury	1/20 (5%)		0/9 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Hypoxia	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg		Part B: Pevonedistat 25 mg/m^2 + Docetaxel 75 mg/m^2		Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5+ Paclitaxel 175 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/20 (55%)		9/9 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Anaemia	0/20 (0%)		0/9 (0%)		3/8 (37.5%)
Thrombocytopenia	0/20 (0%)		1/9 (11.1%)		1/8 (12.5%)
Febrile neutropenia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Neutropenia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Eye disorders
Dry eye	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Lacrimation increased	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Photopsia	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Visual impairment	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Gastrointestinal disorders
Diarrhoea	6/20 (30%)		3/9 (33.3%)		2/8 (25%)
Abdominal pain upper	2/20 (10%)		0/9 (0%)		0/8 (0%)
Nausea	2/20 (10%)		2/9 (22.2%)		2/8 (25%)
Abdominal pain	0/20 (0%)		1/9 (11.1%)		3/8 (37.5%)
Constipation	0/20 (0%)		0/9 (0%)		3/8 (37.5%)
Abdominal tenderness	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Colitis	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Dry mouth	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Dysphagia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Proctalgia	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Stomatitis	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
General disorders
Fatigue	3/20 (15%)		5/9 (55.6%)		2/8 (25%)
Oedema peripheral	2/20 (10%)		2/9 (22.2%)		1/8 (12.5%)
Pyrexia	2/20 (10%)		3/9 (33.3%)		0/8 (0%)
Asthenia	0/20 (0%)		2/9 (22.2%)		0/8 (0%)
Chest pain	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Localised oedema	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Medical device site oedema	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Peripheral swelling	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Infections and infestations
Urinary tract infection	0/20 (0%)		4/9 (44.4%)		1/8 (12.5%)
Conjunctivitis	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Herpes zoster	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Pneumonia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Injury, poisoning and procedural complications
Fall	2/20 (10%)		1/9 (11.1%)		1/8 (12.5%)
Skin abrasion	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Vulvovaginal injury	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Investigations
Aspartate aminotransferase increased	2/20 (10%)		2/9 (22.2%)		0/8 (0%)
Blood bilirubin increased	0/20 (0%)		0/9 (0%)		2/8 (25%)
Platelet count decreased	0/20 (0%)		0/9 (0%)		2/8 (25%)
Alanine aminotransferase increased	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Haematocrit decreased	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Liver function test increased	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Neutrophil count decreased	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Red blood cell count decreased	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Metabolism and nutrition disorders
Decreased appetite	4/20 (20%)		2/9 (22.2%)		1/8 (12.5%)
Hypoalbuminaemia	0/20 (0%)		1/9 (11.1%)		1/8 (12.5%)
Hypophosphataemia	0/20 (0%)		2/9 (22.2%)		0/8 (0%)
Fluid overload	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Hyperglycaemia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Hypokalaemia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Hypomagnesaemia	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Hyponatraemia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Hypovolaemia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/20 (10%)		0/9 (0%)		1/8 (12.5%)
Flank pain	2/20 (10%)		0/9 (0%)		0/8 (0%)
Pain in extremity	0/20 (0%)		0/9 (0%)		3/8 (37.5%)
Arthralgia	0/20 (0%)		1/9 (11.1%)		1/8 (12.5%)
Bone pain	0/20 (0%)		2/9 (22.2%)		0/8 (0%)
Joint swelling	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Myalgia	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Nervous system disorders
Dizziness	2/20 (10%)		1/9 (11.1%)		1/8 (12.5%)
Headache	2/20 (10%)		0/9 (0%)		1/8 (12.5%)
Peripheral sensory neuropathy	0/20 (0%)		2/9 (22.2%)		4/8 (50%)
Peripheral motor neuropathy	0/20 (0%)		2/9 (22.2%)		0/8 (0%)
Dysgeusia	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Paraesthesia	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Syncope	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Psychiatric disorders
Anxiety	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Renal and urinary disorders
Haematuria	0/20 (0%)		0/9 (0%)		2/8 (25%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	2/20 (10%)		0/9 (0%)		1/8 (12.5%)
Sinus congestion	0/20 (0%)		1/9 (11.1%)		1/8 (12.5%)
Cough	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Dyspnoea	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Epistaxis	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Hiccups	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Pleural effusion	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Pneumothorax	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Productive cough	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Respiratory disorder	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Wheezing	0/20 (0%)		0/9 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Alopecia	0/20 (0%)		2/9 (22.2%)		1/8 (12.5%)
Palmar-plantar erythrodysaesthesia syndrome	0/20 (0%)		2/9 (22.2%)		0/8 (0%)
Erythema	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Nail disorder	0/20 (0%)		1/9 (11.1%)		0/8 (0%)
Vascular disorders
Hypotension	0/20 (0%)		2/9 (22.2%)		0/8 (0%)
Hypertension	0/20 (0%)		1/9 (11.1%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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.