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Clinical Trial Results:
A Phase 1 Study of Pevonedistat (MLN4924), a NEDD8 Activating Enzyme (NAE) Inhibitor, in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors

Summary
EudraCT number	2019-002934-35
Trial protocol	Outside EU/EEA
Global end of trial date	30 Sep 2020

Results information
Results version number	v1(current)
This version publication date	29 Dec 2021
First version publication date	29 Dec 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ADVL1615

ISRCTN number

US NCT number

NCT03323034

WHO universal trial number (UTN)

Sponsor organisation name

Children’s Oncology Group

Sponsor organisation address

800 Royal Oaks Dr Suite 210, Monrovia, United States, 91016

Public contact

Thalia Beeles, Children’s Oncology Group, tbeeles@childrensoncologygroup.org

Scientific contact

Thalia Beeles, Children’s Oncology Group, tbeeles@childrensoncologygroup.org

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002117-PIP01-17

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Sep 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Sep 2020

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of pevonedistat, to define and describe toxicities and to characterize the pharmacokinetics (PK) of pevonedistat.

Protection of trial subjects

All the participants or parents or patient’s guardian were required to read and sign the inform consent form.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Nov 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 30

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at approximately 20 investigative sites in the United States from 13 November 2017 up to 30 September 2020.

Screening details

Pediatric participants diagnosed with recurrent or refractory solid tumors, including CNS tumors and lymphoma were enrolled in the dose escalation study of pevonedistat in a rolling design to receive doses 15, 20, 25, 35 mg/m^2.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Arm description

Pevonedistat 15 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 15 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, capsules orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Pevonedistat

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Pevonedistat IV injection

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan IV injection

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Temozolomide oral capsules

Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Arm description

Pevonedistat 20 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 20 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, capsules orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Pevonedistat

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Pevonedistat IV injection

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Temozolomide oral capsules

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan IV injection

Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Arm description

Pevonedistat 25 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 25 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, capsules orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Pevonedistat

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Pevonedistat IV injection

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Temozolomide oral capsules

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan IV injection

Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Arm description

Pevonedistat 35 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 35 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, capsules orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Pevonedistat

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Pevonedistat IV injection

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan IV injection

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Temozolomide oral capsules

Number of subjects in period 1	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Started	6	6	6	12
Pharmacokinetic (PK) Analysis Set	5	6	6	12
Completed	0	2	0	0
Not completed	6	4	6	12
30 days after last dose of investigational agent	4	3	6	11
Enrollment onto another COG therapeutic study	2	1	-	1

Baseline characteristics

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Reporting group title

Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group title

Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group title

Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group title

Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Total
Number of subjects	6	6	6	12
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	13.00 ± 4.56	9.8 ± 6.08	11.3 ± 7.76	11.3 ± 5.29	-
Gender categorical
Units: Subjects
Male	5	4	2	8	19
Female	1	2	4	4	11
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	1	0	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	1	2	3	6
White	5	3	4	7	19
Unknown or Not Reported	1	1	0	1	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	1	4	5
Not Hispanic or Latino	5	6	5	8	24
Unknown or Not Reported	1	0	0	0	1

End points

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Reporting group title

Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group title

Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group title

Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Reporting group title

Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Subject analysis set title

Pevonedistat 15,20,25,35+Temozolomide100+Irinotecan50 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pevonedistat 15, 20, 25, 35 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12, along with temozolomide, orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 15, 20, 25, 35 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Primary: Maximum Tolerated Dose (MTD) of Pevonedistat in Combination With Irinotecan and Temozolomide

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End point title

Maximum Tolerated Dose (MTD) of Pevonedistat in Combination With Irinotecan and Temozolomide ^[1]

End point description

The MTD is the maximum dose at which fewer than one-third of participants experience dose limiting toxicities (DLTs). DLT Analysis Set included all participants who receive all prescribed doses of pevonedistat and at least 85% of the prescribed dose of irinotecan and temozolomide per protocol guidelines and must have the appropriate toxicity monitoring studies performed.

End point type

Primary

End point timeframe

Cycle 1 (28-day Cycle)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat 15,20,25,35+Temozolomide100+Irinotecan50 mg/m^2
Number of subjects analysed
Units: mg/m^2
number (not applicable)	35

No statistical analyses for this end point

Primary: Recommended Phase 2 Dose (RP2D) of Pevonedistat in Combination with Irinotecan and Temozolomide

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End point title

Recommended Phase 2 Dose (RP2D) of Pevonedistat in Combination with Irinotecan and Temozolomide ^[2]

End point description

The RP2D is the maximum dose at which fewer than one-third of participants experience dose limiting toxicities (DLTs). DLT Analysis Set included all participants who receive all prescribed doses of pevonedistat and at least 85% of the prescribed dose of irinotecan and temozolomide per protocol guidelines and must have the appropriate toxicity monitoring studies performed.

End point type

Primary

End point timeframe

Cycle 1 (28-day Cycle)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat 15,20,25,35+Temozolomide100+Irinotecan50 mg/m^2
Number of subjects analysed
Units: mg/m^2
number (not applicable)	35

No statistical analyses for this end point

Primary: Percentage of Participants Who Experienced At Least one Grade 3 or Higher Toxicity by Dose Level

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End point title

Percentage of Participants Who Experienced At Least one Grade 3 or Higher Toxicity by Dose Level ^[3]

End point description

An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered drug; it does not necessarily have to have a causal relationship with the treatment. The common terminology criteria for adverse events (CTCAE) version (v) 4.0 includes Grades 1 through 5 where each AE based on this general guideline: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to adverse event. Safety Analysis Set included all participants who received at least one dose of the study drug.

End point type

Primary

End point timeframe

Up to approximately 4 years

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	6	6	6	12
Units: percentage of participants
number (not applicable)	83.3	50.0	83.3	50.0

No statistical analyses for this end point

Primary: Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 1

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End point title

Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 1 ^[4]

End point description

Pharmacokinetic (PK) Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 1 of Cycle 1 (Cycle length = 28 days)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: ng/mL
geometric mean (geometric coefficient of variation)	137.2 ± 45.92	205.6 ± 30.68	293.0 ± 39.77	441.9 ± 92.03

No statistical analyses for this end point

Primary: Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 8

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End point title

Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 8 ^[5]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 8 of Cycle 1 (Cycle length = 28 days)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: ng/mL
geometric mean (geometric coefficient of variation)	134.5 ± 33.05	239.0 ± 26.35	242.1 ± 27.93	380.6 ± 38.56

No statistical analyses for this end point

Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 1

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End point title

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 1 ^[6]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 1 of Cycle 1 (Cycle length = 28 days)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: hours (h)
median (full range (min-max))	1.1 (1 to 2)	1.0 (1 to 1)	1.0 (1 to 1)	1.0 (1 to 2)

No statistical analyses for this end point

Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 8

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End point title

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 8 ^[7]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 8 of Cycle 1 (Cycle length = 28 days)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: hours (h)
median (full range (min-max))	1.0 (1.0 to 1.0)	1.0 (1.0 to 1.0)	1.0 (1.0 to 1.0)	1.0 (1.0 to 1.0)

No statistical analyses for this end point

Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 1

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End point title

AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 1 ^[8]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 1 of Cycle 1 (Cycle length = 28 days)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	663.2 ± 17.51	917.3 ± 34.63	1177.3 ± 18.70	1869.6 ± 50.98

No statistical analyses for this end point

Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 8

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End point title

AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 8 ^[9]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 8 of Cycle 1 (Cycle length = 28 days)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	664.3 ± 19.48	1007.6 ± 35.92	1042.8 ± 21.08	1670.2 ± 23.93

No statistical analyses for this end point

Primary: CL/F: Clearance of Pevonedistat Cycle 1 Day 1

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End point title

CL/F: Clearance of Pevonedistat Cycle 1 Day 1 ^[10]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 1 of Cycle 1 (Cycle length = 28 days)

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: L/h
geometric mean (geometric coefficient of variation)	29.8 ± 51.87	22.8 ± 53.68	23.1 ± 55.05	21.5 ± 86.23

No statistical analyses for this end point

Primary: CL/F: Clearance of Pevonedistat Cycle 1 Day 8

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End point title

CL/F: Clearance of Pevonedistat Cycle 1 Day 8 ^[11]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 8 of Cycle 1 (Cycle length = 28 days)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: L/h
geometric mean (geometric coefficient of variation)	29.8 ± 52.42	20.7 ± 46.89	25.8 ± 43.88	23.9 ± 37.24

No statistical analyses for this end point

Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 1

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End point title

T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 1 ^[12]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 1 of Cycle 1 (Cycle length = 28 days)

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: hours (h)
median (full range (min-max))	5.0 (3 to 9)	5.4 (4 to 6)	5.3 (5 to 6)	5.2 (4 to 8)

No statistical analyses for this end point

Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 8

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End point title

T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 8 ^[13]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 8 of Cycle 1 (Cycle length = 28 days)

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: hours (h)
median (full range (min-max))	5.9 (5 to 8)	5.1 (4 to 7)	5.6 (4 to 8)	4.8 (2 to 9)

No statistical analyses for this end point

Primary: AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 1

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End point title

AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 1 ^[14]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 1 of Cycle 1 (Cycle length = 28 days)

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	706.1 ± 13.27	952.7 ± 35.46	1222.3 ± 18.35	1959.5 ± 49.13

No statistical analyses for this end point

Primary: AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 8

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End point title

AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 8 ^[15]

End point description

PK Analysis Set included all participants in the safety analysis set and for whom at least 1 PK parameter is evaluable.

End point type

Primary

End point timeframe

Pre and Post pevonedistat infusion on Day 8 of Cycle 1 (Cycle length = 28 days)

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	5	6	6	12
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	707.3 ± 18.67	1050.1 ± 38.86	1091.9 ± 23.63	1756.9 ± 26.27

No statistical analyses for this end point

Secondary: Best Overall Response Rate as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)

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End point title

Best Overall Response Rate as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)

End point description

Percentage of participants with the best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started. Progression is the appearance of one or more new lesions. Response-Evaluable Analysis Set included all participants who received at least 1 dose of study drug, have a Baseline disease assessment, and have at least 1 post-baseline disease assessment.

End point type

Secondary

End point timeframe

Up to 4 years

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	6	6	6	12
Units: percentage of participants
number (not applicable)	16.7	16.7	0.0	0.0

No statistical analyses for this end point

Secondary: Biologic Activity of Pevonedistat in Combination with Irinotecan and Temozolomide

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End point title

Biologic Activity of Pevonedistat in Combination with Irinotecan and Temozolomide

End point description

AAAA

End point type

Secondary

End point timeframe

week 10

End point values	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Number of subjects analysed	0 ^[16]	0 ^[17]	0 ^[18]	0 ^[19]
Units: subjects

Notes
[16] - The data for this outcome measure is not available as per the planned analysis.
[17] - The data for this outcome measure is not available as per the planned analysis.
[18] - The data for this outcome measure is not available as per the planned analysis.
[19] - The data for this outcome measure is not available as per the planned analysis.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to approximately 4 years

Adverse event reporting additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Pevonedistat 15 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, capsules, orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 15 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Reporting group title

Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Pevonedistat 20 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, capsules orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 20 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Reporting group title

Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Pevonedistat 25 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, capsules orally,100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 25 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Reporting group title

Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2

Reporting group description

Pevonedistat 35 mg/m^2, Intravenously (IV) over 60 minutes on Days 1, 8, 10, and 12 of Cycle 1 and Days 1, 3, 5 on Cycles 2+, along with temozolomide, capsules orally, 100 mg/m^2 on Days 8-12, and irinotecan 50 mg/m^2, IV over 90 minutes, administered 1 hour after temozolomide on Days 8-12 in 28 day-Cycle 1. Following Cycle 1, participants received pevonedistat 35 mg/m^2, IV over 60 minutes on Days 1, 3, and 5 along with temozolomide, orally, 100 mg/m^2 on Days 1-5, and irinotecan 50 mg/m^2, IV over 90 minutes, on Days 1-5 in 21 day-Cycle 2 for up to 15 Cycles until disease progression or unacceptable toxicity.

Serious adverse events	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	4 / 6 (66.67%)	4 / 12 (33.33%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Lymphocyte count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Medical procedure
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 12 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pevonedistat15mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat20mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat25mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2	Pevonedistat35mg/m^2+Temozolomide100mg/m^2+Irinotecan50mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	12 / 12 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	2
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0
Hypotension
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	1	0	2	0
Hot flush
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Surgical and medical procedures
Medical procedure
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	7 / 12 (58.33%)
occurrences all number	2	3	2	9
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	6 / 6 (100.00%)	1 / 12 (8.33%)
occurrences all number	2	3	6	1
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	0	1	2	1
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Reproductive system and breast disorders
Reproductive tract disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 12 (16.67%)
occurrences all number	3	2	4	2
Nasal congestion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	1	0	1	1
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 12 (0.00%)
occurrences all number	0	1	2	0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Hiccups
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Rhinitis allergic
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Tachypnoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	0	0
Psychiatric disorders
Irritability
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	1	0	1
Hallucination
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Insomnia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Personality change
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Investigations
White blood cell count decreased
subjects affected / exposed	5 / 6 (83.33%)	6 / 6 (100.00%)	5 / 6 (83.33%)	12 / 12 (100.00%)
occurrences all number	9	17	19	21
Alanine aminotransferase increased
subjects affected / exposed	4 / 6 (66.67%)	5 / 6 (83.33%)	5 / 6 (83.33%)	8 / 12 (66.67%)
occurrences all number	6	13	14	14
Lymphocyte count decreased
subjects affected / exposed	6 / 6 (100.00%)	3 / 6 (50.00%)	3 / 6 (50.00%)	7 / 12 (58.33%)
occurrences all number	12	4	6	9
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	6 / 6 (100.00%)	5 / 6 (83.33%)	6 / 12 (50.00%)
occurrences all number	4	14	22	9
Neutrophil count decreased
subjects affected / exposed	5 / 6 (83.33%)	4 / 6 (66.67%)	3 / 6 (50.00%)	6 / 12 (50.00%)
occurrences all number	11	12	8	13
Platelet count decreased
subjects affected / exposed	3 / 6 (50.00%)	4 / 6 (66.67%)	4 / 6 (66.67%)	7 / 12 (58.33%)
occurrences all number	6	7	10	12
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 12 (16.67%)
occurrences all number	3	0	0	3
Blood bicarbonate decreased
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	2	0	1
Blood creatinine increased
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	2	0	1	0
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	2
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	2
Investigation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	0	0	2	1
Blood cholesterol increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Blood urea increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Haemoglobin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Red blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Weight increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Vascular access complication
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 6 (50.00%)	2 / 12 (16.67%)
occurrences all number	1	2	8	3
Sinus bradycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)	3 / 12 (25.00%)
occurrences all number	1	4	3	5
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)
occurrences all number	0	0	1	2
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1
Cognitive disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Dyskinesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Hemiparesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Nervous system disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Paraesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Tremor
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 6 (100.00%)	5 / 6 (83.33%)	6 / 6 (100.00%)	9 / 12 (75.00%)
occurrences all number	11	14	16	17
Eosinophilia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	0	0	2	1
Eye disorders
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Eyelid function disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	2
Photophobia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	4 / 6 (66.67%)	4 / 6 (66.67%)	6 / 6 (100.00%)	5 / 12 (41.67%)
occurrences all number	6	8	9	9
Nausea
subjects affected / exposed	5 / 6 (83.33%)	5 / 6 (83.33%)	3 / 6 (50.00%)	6 / 12 (50.00%)
occurrences all number	10	8	6	6
Vomiting
subjects affected / exposed	5 / 6 (83.33%)	4 / 6 (66.67%)	4 / 6 (66.67%)	6 / 12 (50.00%)
occurrences all number	12	8	9	10
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 12 (8.33%)
occurrences all number	2	4	4	1
Constipation
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	2 / 6 (33.33%)	1 / 12 (8.33%)
occurrences all number	3	3	3	1
Abdominal pain upper
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 12 (0.00%)
occurrences all number	1	0	2	0
Oral pain
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0
Anal incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Flatulence
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Oral pruritus
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Salivary hypersecretion
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0
Small intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Toothache
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0
Rash maculo-papular
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	2
Pruritus
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0
Dysuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 6 (0.00%)	3 / 12 (25.00%)
occurrences all number	1	4	0	4
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)
occurrences all number	1	0	2	2
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	2	0	1
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	0	0
Joint range of motion decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0
Bacteraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Conjunctivitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Enterocolitis infectious
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1
Rash pustular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0
Rhinitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	4 / 6 (66.67%)	7 / 12 (58.33%)
occurrences all number	1	4	4	11
Hyperglycaemia
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	5 / 6 (83.33%)	5 / 12 (41.67%)
occurrences all number	2	3	8	7
Hypoalbuminaemia
subjects affected / exposed	3 / 6 (50.00%)	0 / 6 (0.00%)	4 / 6 (66.67%)	7 / 12 (58.33%)
occurrences all number	5	0	6	9
Hypocalcaemia
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	8 / 12 (66.67%)
occurrences all number	3	2	3	11
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	3 / 6 (50.00%)	5 / 12 (41.67%)
occurrences all number	4	4	3	5
Hypokalaemia
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	4 / 6 (66.67%)	4 / 12 (33.33%)
occurrences all number	3	2	4	4
Hypophosphataemia
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	3 / 6 (50.00%)	3 / 12 (25.00%)
occurrences all number	4	3	8	3
Hypermagnesaemia
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	4 / 12 (33.33%)
occurrences all number	3	2	4	7
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	3 / 6 (50.00%)	3 / 12 (25.00%)
occurrences all number	0	2	4	4
Hyperphosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	3 / 12 (25.00%)
occurrences all number	0	0	2	3
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 12 (16.67%)
occurrences all number	0	0	3	3
Dehydration
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	1	0	1
Hypercalcaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 12 (0.00%)
occurrences all number	0	1	6	0
Hyperkalaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)
occurrences all number	1	0	4	1
Hypernatraemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0
Metabolic disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

30 Jul 2018

The following changes were made in amendment 1: - The study committee contact information regulatory address was updated. - Clarifications were made in accordance with update to Common Terminology Criteria for Adverse Events (CTCAE v.5). This included aligning hepatic function and decreased tendon reflexes in eligibility, definitions of dose limiting toxicity, and addition of appendix for protocol specific reference values. - Renal function eligibility criterion was updated. - Language regarding the event of emesis after temozolomide was added as “For infusion related reactions consider premedication with diphenhydramine for subsequent doses and increasing infusion duration to 2 hours. Other supportive care measures may be used at the investigator’s discretion.” - Pulse oximetry and bone marrow evaluations were added to the table of required observations and to the therapy delivery maps. - The pharmacokinetic (PK) and pharmacodynamic (PD) details were updated. - Drug name, solution preparation/administration instructions and drug interactions were updated; risks were updated in accordance with the RA. - The toxicities for cefixime were administratively updated. - The date of the irinotecan monograph was updated. - The following criterion was added for Off Study: “Patient did not receive protocol treatment after study enrollment.” - A typo in age range was corrected. - The definition of evaluable for adverse events was updated for clarity. - Reference to the obsolete Pregnancy form was deleted. - The former Pregnancy Form was removed and replaced with a table of toxicity-specific grading. - List of cytochrome P3A4 (CYP3A4) substrates, inducers, and inhibitors has been administratively updated. - Shipping guidelines were added. - The table was updated to reflect the 99th percentile for consistency with the eligibility criteria.

27 Jan 2019

The following changes were made in amendment 2: - The adverse events of risk were added to the protocol.

13 Mar 2019

The following changes were made in amendment 3: - Children’s oncology group Phase 1/Pilot Consortium (COGC) was replaced with Children’s oncology group Pediatric Early Phase Clinical Trials Network (PEP-CTN). - Pediatric Early Phase Clinical Trials Network (PEP-CTN) logo was added throughout the protocol - Pediatric Early Phase Clinical Trials Network (PEP-CTN) replaced COGC as the lead organization. - Protocol Coordinator contact was updated to Pediatric Early Phase Clinical Trials Network (PEP-CTN) Operations and Data/Statistics - This trial was covered by a Certificate of Confidentiality from the federal government. - PEPCTNAERS@childrensoncologygroup.org - Developmental therapeutics was replaced with Children’s oncology group Pediatric Early Phase Clinical Trials Network (COG PEP-CTN) to show that the study was monitored in accordance with PEP-CTN polices for data and safety monitoring. - The upper limit of normal (ULN) for alanine aminotransferase (ALT) is 45 units per litre (U/L) - The ULN for AST is 50 U/L

24 Sep 2019

The following changes were made in amendment 4: - Toxicity Risk Table has been replaced with National Cancer Institute (NCI) provided Comprehensive Adverse Events and Potential Risks (CAEPR) version 2.2.

10 Dec 2019

The following changes were made in amendment 5: - Research Coordinator was removed. - Rationale for amendment #5 was added. - Dose Level 4 at 35 mg/m ^2 was added. - Pevonedistat drug formulation was updated - Dilute pevonedistat injection in … - Once pevonedistat injection is diluted… - Infusion line should be flushed with 5% Dextrose immediately after IV administration is complete. - Patient Care Considerations was added. - Statistical sample size and study duration was updated to include information regarding this amendment. - The Domestic Planned Enrollment Report table was updated to reflect current enrollment on this study. - Dose Level 4 was added to the therapy delivery maps (TDMs).

20 Jul 2020

The following changes were made in amendment 6: - The preparation, storage, and administration sections were updated per the request for amendment (RA).

27 Aug 2020

The following changes were made in amendment 7. - Administrative changes made in the committee - Inserted revised CAEPR for MLN4924 (Pevonedistat hydrochloride [HCl]) - Added New Risk: Also Reported on MLN4924 Trials But With Insufficient Evidence for Attribution: Ascites; Hypertension; Non-cardiac chest pain; Treatment related secondary malignancy; Urinary retention; White blood cell decreased. - Increase in Risk Attribution: Changed to Less Likely from Also Reported on MLN4924 Trials But With Insufficient Evidence for Attribution: Urinary tract infection. - Decrease in Risk Attribution: Changed to Less Likely from Likely: Constipation; Dizziness Changed to Also Reported on MLN4924 Trials But With Insufficient Evidence for Attribution from Less Likely: Rash maculo-papular

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1 Study of Pevonedistat (MLN4924), a NEDD8 Activating Enzyme (NAE) Inhibitor, in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum Tolerated Dose (MTD) of Pevonedistat in Combination With Irinotecan and Temozolomide

Primary: Maximum Tolerated Dose (MTD) of Pevonedistat in Combination With Irinotecan and Temozolomide

Primary: Recommended Phase 2 Dose (RP2D) of Pevonedistat in Combination with Irinotecan and Temozolomide

Primary: Recommended Phase 2 Dose (RP2D) of Pevonedistat in Combination with Irinotecan and Temozolomide

Primary: Percentage of Participants Who Experienced At Least one Grade 3 or Higher Toxicity by Dose Level

Primary: Percentage of Participants Who Experienced At Least one Grade 3 or Higher Toxicity by Dose Level

Primary: Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 1

Primary: Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 1

Primary: Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 8

Primary: Cmax : Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 8

Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 1

Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 1

Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 8

Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 8

Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 1

Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 1

Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 8

Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 8

Primary: CL/F: Clearance of Pevonedistat Cycle 1 Day 1

Primary: CL/F: Clearance of Pevonedistat Cycle 1 Day 1

Primary: CL/F: Clearance of Pevonedistat Cycle 1 Day 8

Primary: CL/F: Clearance of Pevonedistat Cycle 1 Day 8

Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 1

Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 1

Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 8

Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 8

Primary: AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 1

Primary: AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 1

Primary: AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 8

Primary: AUC(0-infinity) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 8

Secondary: Best Overall Response Rate as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)

Secondary: Best Overall Response Rate as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)

Secondary: Biologic Activity of Pevonedistat in Combination with Irinotecan and Temozolomide

Secondary: Biologic Activity of Pevonedistat in Combination with Irinotecan and Temozolomide

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1 Study of Pevonedistat (MLN4924), a NEDD8 Activating Enzyme (NAE) Inhibitor, in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors