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Clinical Trial Results:
A Phase 2b, Open-Label, Single-Arm Study of Selinexor (KPT-330) Plus Low-Dose Dexamethasone (Sd) in Patients with Multiple Myeloma Previously Treated with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib, and Daratumumab, and Refractory to Prior Treatment with Glucocorticoids, an Immunomodulatory Agent, a Proteasome Inhibitor, and the anti-CD38 mAb Daratumumab

Summary
EudraCT number	2016-003094-18
Trial protocol	DE AT BE GR
Global end of trial date	26 Jul 2019

Results information
Results version number	v1(current)
This version publication date	19 Sep 2021
First version publication date	19 Sep 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

KCP-330-012

ISRCTN number

US NCT number

NCT02336815

WHO universal trial number (UTN)

Sponsor organisation name

Karyopharm Therapeutics Inc.

Sponsor organisation address

85 Wells Avenue, Newton, MA, United States, 02459

Public contact

Clinical Trials Information, Karyopharm Therapeutic Inc., +1 617658 0600, clinicaltrials@karyopharm.com

Scientific contact

Clinical Trials Information, Karyopharm Therapeutic Inc., +1 617658 0600, clinicaltrials@karyopharm.com

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

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

26 Jul 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

The primary purpose of the study is to evaluate the efficacy of selinexor 80 mg PO plus low-dose dexamethasone 20 mg PO (Sd) on Days 1 and 3 twice weekly in subjects with penta-exposed, triple-class-refractory MM enrolled in Part 2 of the study.

Protection of trial subjects

The study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki in place at the time of study conduct. The study was conducted in compliance with the International Council on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) (Committee for Proprietary Medicinal Products [CPMP] guideline CPMP/ICH/135/95), United States Code of Federal Code of Regulations, and all applicable local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 May 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Greece: 7

Country: Number of subjects enrolled

United States: 163

Worldwide total number of subjects

202

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)

104

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Part 1 of the study was conducted at 32 sites in the United States and Part 2 of the study was conducted at 59 sites in France, Germany, Belgium, Greece, Austria and United States. Enrollment in both parts was between from 26 May 2015 (first subject first visit)) and 26 July 2019 (last subject last visit).

Screening details

A total of 202 subjects were enrolled in the study, out of which 79 subjects were treated in Part 1 and 123 subjects were treated in Part 2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1

Arm description

Subjects with quad-exposed, double-class-refractory (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, but not an anti-CD38 mAb) and penta-exposed, triple-class-refractory MM (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, and refractory to prior treatment with glucocorticoids, an IMiD, a PI, and the anti-CD38 mAb daratumumab) received, two dosing schedules (1) selinexor 80 mg plus low-dose dexamethasone 20 mg (Sd) twice-weekly on Days 1 and 3 for 3 weeks of each 4-week cycle; (2) selinexor 80 mg plus low-dose dexamethasone 20 mg (Sd) twice-weekly continuously in 4-week cycles; until disease progression, death, or unacceptable toxicity (maximum duration of approximately 13 months).

Arm type

Experimental

Investigational medicinal product name

Selinexor

Investigational medicinal product code

KPT-330

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received two dosing schedules (1) selinexor 80mg twice-weekly on Days 1 and 3 for 3 weeks of each 4-week cycle; (2) selinexor 80mg twice-weekly continuously in 4-week cycles.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received two dosing schedules (1) low-dose dexamethasone 20 mg (Sd) twice-weekly on Days 1 and 3 for 3 weeks of each 4-week cycle; (2) low-dose dexamethasone 20 mg (Sd) twice-weekly continuously in 4-week cycles.

Part 2

Arm description

Subjects who previously had received more than 3 anti-MM regimens and had penta-exposed, triple class-refractory MM (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, and refractory to prior treatment with glucocorticoids, an IMiD, a PI, and the anti-CD38 mAb daratumumab) received, selinexor 80 mg post oral (PO) plus low-dose dexamethasone 20 mg Sd twice-weekly on Days 1 and 3 until disease progression, death, or unacceptable toxicity (maximum duration of approximately 17 months).

Arm type

Experimental

Investigational medicinal product name

Selinexor

Investigational medicinal product code

KPT-330

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received selinexor 80mg PO Sd twice-weekly on Days 1 and 3.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received low-dose dexamethasone 20 mg Sd twice-weekly on Days 1 and 3.

Number of subjects in period 1	Part 1	Part 2
Started	79	123
Completed	0	0
Not completed	79	123
Physician decision	11	4
Consent withdrawn by subject	3	2
Adverse event, non-fatal	18	39
Unspecified	1	5
Lost to follow-up	1	3
Disease Progression	45	70

Baseline characteristics

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Reporting group title

Part 1

Reporting group description

Reporting group title

Part 2

Reporting group description

Reporting group values	Part 1	Part 2	Total
Number of subjects	79	123	202
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	62.9 ± 8.79	64.5 ± 9.41	-
Gender categorical
Units: Subjects
Female	42	52	94
Male	37	71	108
Ethnicity
Units: Subjects
Hispanic or Latino	2	9	11
Not Hispanic or Latino	75	97	172
Unknown or Not Reported	2	17	19
Race
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	0	2	2
Native Hawaiian or Other Pacific Islander	0	1	1
Black or African American	14	21	35
White	62	86	148
More than one race	2	8	10
Unknown or Not Reported	1	5	6
Region of Enrollment
Units: Subjects
Austria	0	1	1
Belgium	0	7	7
France	0	14	14
Germany	0	10	10
Greece	0	7	7
United States	79	84	163

End points

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Reporting group title

Part 1

Reporting group description

Reporting group title

Part 2

Reporting group description

Primary: Part 2: Percentage of Subjects With Overall Response Rate (ORR) Per International Myeloma Working Group (IMWG) as Assessed by an Independent Review Committee (IRC)

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End point title

Part 2: Percentage of Subjects With Overall Response Rate (ORR) Per International Myeloma Working Group (IMWG) as Assessed by an Independent Review Committee (IRC) ^[1] ^[2]

End point description

IRC assessed ORR per 2016 IMWG criteria: Percentage of subjects who experienced Partial response (PR): >=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by >=90% or to lesser than (<) 200mg per 24 hours; Very good partial response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100mg per 24 hours; Complete response (CR): Negative immunofixation on the serum, urine and disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; or stringent complete response (sCR): CR as defined by Normal free light chain (FLC) ratio + Absence of clonal cells in bone marrow biopsy by immunohistochemistry). Modified intent-to-treat (mITT) population: Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment.

End point type

Primary

End point timeframe

Baseline until disease progression/discontinuation from the study, or death, whichever occurred first (maximum duration of 17 months)

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: Per protocol, only descriptive analyses was planned for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was not planned to be collected and analyzed for Part 1.

End point values	Part 2
Number of subjects analysed	122
Units: Percentage of Subjects
number (confidence interval 95%)	26.2 (18.7 to 35.0)

No statistical analyses for this end point

Secondary: Part 1: Duration of Response (DoR) Per IMWG as Assessed by IRC

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End point title

Part 1: Duration of Response (DoR) Per IMWG as Assessed by IRC ^[3]

End point description

IRC assessed DoR per 2016 IMWG criteria: time (in months) from the first documentation of objective response (confirmed CR or PR) to the date of first documentation of progressive disease (PD) or death due to any cause. PR: >50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1 g/dL if the lowest M-component was >=5g/dL; Urine M-protein (absolute increase must be >=200mg per 24 hours). Safety population: all subjects, who had received at least 1 dose of study treatment and had any post-baseline safety information. Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

First response subsequently confirmed to disease progression/discontinuation from the study, or death, whichever occurred first (maximum duration of 13 months)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	16
Units: Months
median (confidence interval 95%)	6.2 (3.6 to 9.8)

No statistical analyses for this end point

Secondary: Part 2: Duration of Response (DoR) Per IMWG as Assessed by an IRC

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End point title

Part 2: Duration of Response (DoR) Per IMWG as Assessed by an IRC ^[4]

End point description

IRC assessed DoR per 2016 IMWG criteria: time (in months) from the first documentation of objective response (confirmed CR or PR) to the date of first documentation of progressive disease (PD) or death due to any cause. PR: >50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1 g/dL if the lowest M-component was >=5g/dL; Urine M-protein (absolute increase must be >=200mg per 24 hours). mITT population. Here, "number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

First response subsequently confirmed to disease progression/discontinuation from the study, or death, whichever occurred first (maximum duration of 17 months)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	32
Units: Months
median (confidence interval 95%)	4.4 (3.7 to 10.8)

No statistical analyses for this end point

Secondary: Part 1: Percentage of Subjects With Clinical Benefit Rate (CBR) ) Per IMWG as Assessed by IRC

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End point title

Part 1: Percentage of Subjects With Clinical Benefit Rate (CBR) ) Per IMWG as Assessed by IRC ^[5]

End point description

IRC assessed CBR per 2016 IMWG criteria: Percentage of subjects with a confirmed minimal response (MR) or better (PR, VGPR, CR or sCR) before confirmed disease progression or initiating new MM treatment. MR: >=25% but <49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%. PR: >=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <= 5% plasma cells in bone marrow; or sCR: CR as defined by Normal FLC ratio + Absence of clonal cells by immunohistochemistry). Safety population consisted of all subjects, who had received at least 1 dose of study treatment and had any post-baseline safety information.

End point type

Secondary

End point timeframe

Baseline up to a maximum of 13 months

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	79
Units: Percentage of Subjects
number (confidence interval 95%)	31.6 (21.6 to 43.1)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With Clinical Benefit Rate (CBR) Per IMWG as Assessed by IRC

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End point title

Part 2: Percentage of Subjects With Clinical Benefit Rate (CBR) Per IMWG as Assessed by IRC ^[6]

End point description

IRC assessed CBR per 2016 IMWG criteria: Percentage of subjects with a confirmed MR or better (PR, VGPR, CR or sCR) before confirmed disease progression or initiating new MM treatment. MR: >=25% but <49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%. PR: >=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by >=90% or to <200mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; or sCR: CR as defined by Normal FLC ratio + Absence of clonal cells by immunohistochemistry). mITT population consisted of Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment.

End point type

Secondary

End point timeframe

Baseline up to a maximum of 17 months

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	122
Units: Percentage of Subjects
number (confidence interval 95%)	39.3 (30.6 to 48.6)

No statistical analyses for this end point

Secondary: Part 1: Duration of Clinical Benefit Per IMWG as Assessed by IRC

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End point title

Part 1: Duration of Clinical Benefit Per IMWG as Assessed by IRC ^[7]

End point description

IRC assessed duration of clinical benefit per 2016 IMWG criteria: Duration from first response (at least MR) to time of IRC-determined PD or death due to disease progression, whichever occurs first. MR: >=25% but <49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%. PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5 g/dL; Serum M-protein increase >=1 g/dL if the lowest M-component was >=5 g/dL; Urinary M-protein (absolute increase must be >= 200 mg per 24 hours). Safety population consisted of all subject, who had received at least 1 dose of study treatment and had any post-baseline safety information. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

First response subsequently confirmed to disease progression, or death, whichever occurred first (maximum duration of 13 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	25
Units: Months
median (confidence interval 95%)	5.6 (4.4 to 10.3)

No statistical analyses for this end point

Secondary: Part 2: Duration of Clinical Benefit Per IMWG as Assessed by IRC

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End point title

Part 2: Duration of Clinical Benefit Per IMWG as Assessed by IRC ^[8]

End point description

IRC assessed duration of clinical benefit per 2016 IMWG criteria: Duration from first response (at least MR) to time of IRC-determined PD or death due to disease progression, whichever occurs first. MR: >=25% but <49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%. PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1g/dL if the lowest M-component was >=5g/dL; Urinary M-protein (absolute increase must be >=200mg per 24 hours). Analysis was performed using Kaplan-Meier method. miTT population consisted of Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

First response subsequently confirmed to disease progression, or death, whichever occurred first (maximum duration of 17 months)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	48
Units: Months
median (confidence interval 95%)	3.8 (3.2 to 10.9)

No statistical analyses for this end point

Secondary: Part 2: Disease Control Rate (DCR)

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End point title

Part 2: Disease Control Rate (DCR) ^[9]

End point description

DCR was defined as the percentage of subjects who achieved stable disease (SD) or better (MR, PR, VGPR, CR, sCR) for a minimum of 12 weeks. SD: Not recommended for use as an indicator of response; stability of disease was best described by providing the time to progression (TTP) estimates. MR: >=25% but <49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%. PR: >=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; or sCR: CR as defined by Normal FLC ratio + Absence of clonal cells by immunohistochemistry). mITT population.

End point type

Secondary

End point timeframe

Every 12 weeks until progressive disease or death due to any cause, up to 17 months

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was not planned to be collected and analyzed for Part 1.

End point values	Part 2
Number of subjects analysed	122
Units: Percentage of subjects
number (confidence interval 95%)	44.3 (35.3 to 53.5)

No statistical analyses for this end point

Secondary: Part 1: Progression Free Survival (PFS) Per IMWG as Assessed by IRC

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End point title

Part 1: Progression Free Survival (PFS) Per IMWG as Assessed by IRC ^[10]

End point description

IRC assessed PFS per 2016 IMWG criteria: Duration from start of study treatment until IRC-determined progressive disease (PD) or death from any cause, whichever occurred first. PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1g/dL if the lowest M-component was >=5g/dL; Urinary M-protein (absolute increase must be >=200mg/24 hours). Analysis was performed using Kaplan-Meier method. Safety population consisted of all subjects, who had received at least 1 dose of study treatment and had any post-baseline safety information.

End point type

Secondary

End point timeframe

From start of study treatment to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 13 months)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	79
Units: Months
median (confidence interval 95%)	4.7 (3.3 to 7.6)

No statistical analyses for this end point

Secondary: Part 2: Progression Free Survival (PFS) Per IMWG as Assessed by IRC

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End point title

Part 2: Progression Free Survival (PFS) Per IMWG as Assessed by IRC ^[11]

End point description

IRC assessed PFS per 2016 IMWG criteria: Duration from start of study treatment until IRC-determined progressive disease (PD) or death from any cause, whichever occurred first. PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1g/dL if the lowest M-component was >=5g/dL; Urinary M-protein (absolute increase must be >=200 mg/24 hours). Analysis was performed using Kaplan-Meier method. mITT population consisted of Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment.

End point type

Secondary

End point timeframe

From start of study treatment to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 17 months)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	122
Units: Months
median (confidence interval 95%)	3.7 (2.8 to 4.7)

No statistical analyses for this end point

Secondary: Part 1: Time to Progression (TTP) Per IMWG as Assessed by IRC

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End point title

Part 1: Time to Progression (TTP) Per IMWG as Assessed by IRC ^[12]

End point description

IRC assessed TTP per 2016 IMWG criteria: Duration from start of study treatment until PD or death due to PD (per IRC), whichever occurred first. PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1g/dL if the lowest M-component was >=5g/dL; Urinary M-protein (absolute increase must be >=200mg/24 hours). Analysis was performed using Kaplan-Meier method. Safety population consisted of all subjects, who had received at least 1 dose of study treatment and had any post-baseline safety information.

End point type

Secondary

End point timeframe

From start of study treatment to progression of disease or death, whichever occurred first (maximum duration of 13 months)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	79
Units: Months
median (confidence interval 95%)	5.5 (3.3 to 10.7)

No statistical analyses for this end point

Secondary: Part 2: Time to Progression (TTP) Per IMWG as Assessed by IRC

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End point title

Part 2: Time to Progression (TTP) Per IMWG as Assessed by IRC ^[13]

End point description

IRC assessed TTP per 2016 IMWG criteria: Duration from start of study treatment until PD or death due to PD (per IRC), whichever occurred first. PD: Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of >=0.5g/dL; Serum M-protein increase >=1g/dL if the lowest M-component was >=5g/dL; Urinary M-protein (absolute increase must be >=200mg/24 hours). Analysis was performed using Kaplan-Meier method. mITT population consisted of Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment.

End point type

Secondary

End point timeframe

From start of study treatment to progression of disease or death, whichever occurred first (maximum duration of 17 months)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	122
Units: Months
median (confidence interval 95%)	4.1 (3.0 to 6.2)

No statistical analyses for this end point

Secondary: Part 1: Time to Next Treatment (TTNT)

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End point title

Part 1: Time to Next Treatment (TTNT) ^[14]

End point description

TTNT was defined as the duration from start of study treatment to start of next anti-MM treatment or death due to disease progression, whichever occurred first. Analysis was performed using Kaplan-Meier method. Safety population consisted of all subjects, who had received at least 1 dose of study treatment and had any post-baseline safety information.

End point type

Secondary

End point timeframe

From start of study treatment to start of next anti-MM treatment or death due to disease progression, whichever occurs first (maximum duration of 13 months)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	79
Units: Months
median (confidence interval 95%)	2.6 (1.8 to 4.2)

No statistical analyses for this end point

Secondary: Part 2: Time to Next Treatment (TTNT)

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End point title

Part 2: Time to Next Treatment (TTNT) ^[15]

End point description

TTNT was defined as the duration from start of study treatment to start of next anti-MM treatment or death due to disease progression, whichever occurred first. Analysis was performed using Kaplan-Meier method. mITT population consisted of Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment.

End point type

Secondary

End point timeframe

From start of study treatment to start of next anti-MM treatment or death due to disease progression, whichever occurs first (maximum duration of 17 months)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	122
Units: Months
median (confidence interval 95%)	3.2 (2.6 to 3.8)

No statistical analyses for this end point

Secondary: Part 1: Overall Survival (OS)

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End point title

Part 1: Overall Survival (OS) ^[16]

End point description

OS was defined as the duration (in months) from start of study treatment to death from any cause. Subjects last known to be alive were censored at the date of discontinuation from the study, or database cut date, whichever was earlier. Analysis was performed using Kaplan-Meier method. Safety population consisted of all subjects, who had received at least 1 dose of study treatment and had any post-baseline safety information.

End point type

Secondary

End point timeframe

From start of study treatment to death (maximum duration of 13 months)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 1
Number of subjects analysed	79
Units: Months
median (confidence interval 95%)	7.3 (5.8 to 10.9)

No statistical analyses for this end point

Secondary: Part 2: Overall Survival (OS)

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End point title

Part 2: Overall Survival (OS) ^[17]

End point description

OS was defined as the duration (in months) from start of study treatment to death from any cause. Subjects last known to be alive were censored at the date of discontinuation from the study, or database cut date, whichever was earlier. Analysis was performed using Kaplan-Meier method. mITT population consisted of Part 2 subjects with penta-refractory MM who met all eligibility criteria and received at least one dose of study treatment.

End point type

Secondary

End point timeframe

From start of study treatment to death (maximum duration of 17 months)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was separately analysed for both the Part 1 and 2.

End point values	Part 2
Number of subjects analysed	122
Units: Months
median (confidence interval 95%)	8.4 (6.2 to 11.2)

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in Health-related Quality of Life (HRQL) Score Based on Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) Questionnaire

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End point title

Part 2: Change From Baseline in Health-related Quality of Life (HRQL) Score Based on Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) Questionnaire ^[18]

End point description

FACT-MM combines the general version of the FACT (FACT-G) with a MM-specific sub-scale (14 items). Sub-scales for the FACT-G are Physical Well-Being (7 items), Social/Family Well-Being (7 items), Emotional Well-Being (6 items), and Functional Well-Being (7 items). Trial outcomes index (TOI); total of (41 items) was the primary measurement of interest, comprised of the Physical and Functional sub-scales plus the MM-specific sub-scale. Each item is rated on a 5-point Likert scale, ranging from 0 ("Not at all") to 4 ("Very much"), therefore the TOI has a score ranging from 0-120. Higher scores indicated improvement in well being. mITT population. Here “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n=number analysed” signifies those subjects who were evaluable at specified time points. Here, '99999' indicates standard deviation was not estimated due to single subject and '9999' indicates no subject was estimated at specified time point.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycle 2 to Cycle 20 (up to a maximum of 17 months)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was not planned to be collected and analyzed for Part 1.

End point values	Part 2
Number of subjects analysed	107
Units: Score on a Scale
arithmetic mean (standard deviation)
TOI Score: Baseline (n=107)	67.5 ± 19.20
TOI Score: Change at C2D1 (n=76)	-6.1 ± 18.43
TOI Score: Change at C3D1 (n=50)	-8.5 ± 15.50
TOI Score: Change at C4D1 (n=31)	-9.1 ± 16.79
TOI Score: Change at C5D1 (n=26)	-6.9 ± 12.06
TOI Score: Change at C6D1 (n=19)	-8.3 ± 15.07
TOI Score: Change at C7D1 (n=13)	-7.5 ± 19.26
TOI Score: Change at C8D1 (n=5)	-15.4 ± 24.59
TOI Score: Change at C9D1 (n=3)	-4.7 ± 14.84
TOI Score: Change at C10D1 (n=3)	-4.0 ± 5.29
TOI Score: Change at C11D1 (n=1)	3.0 ± 99999
TOI Score: Change at C12D1 (n=1)	3.0 ± 99999
TOI Score: Change at C13D1 (n=1)	-23.0 ± 99999
TOI Score: Change at C14D1 (n=1)	14.0 ± 99999
TOI Score: Change at C15D1 (n=1)	1.0 ± 99999
TOI Score: Change at C16D1 (n=1)	4.0 ± 99999
TOI Score: Change at C17D1 (n=0)	9999 ± 9999
TOI Score: Change at C18D1 (n=0)	9999 ± 9999
TOI Score: Change at C19D1 (n=0)	9999 ± 9999
TOI Score: Change at C20D1 (n=0)	9999 ± 9999

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. TEAE are events between first dose of study drug and up to last dose of study treatment + 30 days (inclusive) that were absent before treatment or that worsened relative to pre-treatment state. Safety population set .

End point type

Secondary

End point timeframe

Baseline to 30 days after last dose of study treatment (maximum duration of 18 months)

End point values	Part 1	Part 2
Number of subjects analysed	79	123
Units: Subjects	75	115

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (TEAEs) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

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End point title

Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (TEAEs) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. A treatment related AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event had a causal relationship with the treatment or usage. Safety population set.

End point type

Secondary

End point timeframe

Baseline to 30 days after last dose of study treatment (maximum duration of 18 months)

End point values	Part 1	Part 2
Number of subjects analysed	79	123
Units: Subjects	69	110

No statistical analyses for this end point

Secondary: Part 1: Apparent Clearance (CL/F) of Selinexor in Plasma

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End point title

Part 1: Apparent Clearance (CL/F) of Selinexor in Plasma ^[19]

End point description

CL/F of selinexor in plasma was reported. Pharmacokinetic (PK) set included all subjects in Part 1 who received at least 1 dose of investigational product in this study.

End point type

Secondary

End point timeframe

Cycle 1: Day 1: Pre-dose, 1, 2 and 4 hours post-dose; Day 8 and 15: Pre-dose and 1 hour post-dose; Cycle 2: Day 1: Pre-dose, 1, 2 and 4 hours post-dose

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was not planned to be collected and analyzed for Part 2.

End point values	Part 1
Number of subjects analysed	79
Units: Liters per Hour
arithmetic mean (standard deviation)	16.6 ± 2.8

No statistical analyses for this end point

Secondary: Part 1: Volume of Distribution (V/F) of Selinexor in Plasma

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End point title

Part 1: Volume of Distribution (V/F) of Selinexor in Plasma ^[20]

End point description

Vz/F of selinexor in plasma was reported. PK set included all subjects in Part 1 who received at least 1 dose of investigational product in this study.

End point type

Secondary

End point timeframe

Cycle 1: Day 1: Pre-dose, 1, 2 and 4 hours post-dose; Day 8 and 15: Pre-dose and 1 hour post-dose; Cycle 2: Day 1: Pre-dose, 1, 2 and 4 hours post-dose

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was not planned to be collected and analyzed for Part 2.

End point values	Part 1
Number of subjects analysed	79
Units: Liter
arithmetic mean (standard deviation)	145.6 ± 28.2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline to 30 days after last dose of study treatment (maximum duration of 18 months)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Part 1

Reporting group description

Subjects with quad-exposed, double-class-refractory (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, but not an anti-CD38 mAb) and penta-exposed, triple-class-refractory MM (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, and refractory to prior treatment with glucocorticoids, an IMiD, a PI, and the anti-CD38 mAb daratumumab) received, two dosing schedules (1) Selinexor 80mg plus low-dose dexamethasone 20mg (Sd) twice-weekly on Days 1 and 3 for 3 weeks of each 4-week cycle; (2) Selinexor 80mg plus low-dose dexamethasone 20mg (Sd) twice-weekly continuously in 4-week cycles; until disease progression, death, or unacceptable toxicity (maximum duration of approximately 13 months).

Reporting group title

Part 2

Reporting group description

Subjects who previously had received more than 3 anti-MM regimens and had penta-exposed, triple class-refractory MM (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, and refractory to prior treatment with glucocorticoids, an IMiD, a PI, and the anti-CD38 mAb daratumumab) received, Selinexor 80mg post oral (PO) plus low-dose dexamethasone 20mg Sd twice-weekly on Days 1 and 3 until disease progression, death, or unacceptable toxicity (maximum duration of approximately 17 months).

Serious adverse events	Part 1	Part 2
Total subjects affected by serious adverse events
subjects affected / exposed	45 / 79 (56.96%)	78 / 123 (63.41%)
number of deaths (all causes)	20	28
number of deaths resulting from adverse events	8	12
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ascites
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Plasma cell leukaemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 8	0 / 12
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 79 (2.53%)	4 / 123 (3.25%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 79 (3.80%)	3 / 123 (2.44%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 79 (1.27%)	3 / 123 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 79 (0.00%)	4 / 123 (3.25%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 79 (1.27%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	1 / 8	1 / 12
Hyperthermia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Strangulated hernia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 8	1 / 12
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	3 / 79 (3.80%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	1 / 8	0 / 12
Epistaxis
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 79 (1.27%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 8	1 / 12
Respiratory failure
subjects affected / exposed	1 / 79 (1.27%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	1 / 8	0 / 12
Acute pulmonary oedema
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumopathy
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 8	1 / 12
Psychiatric disorders
Confusional state
subjects affected / exposed	4 / 79 (5.06%)	4 / 123 (3.25%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 79 (1.27%)	4 / 123 (3.25%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Agitation
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mania
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Ejection fraction decreased
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus test positive
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	2 / 79 (2.53%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 79 (1.27%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	1 / 8	1 / 12
Compression fracture
subjects affected / exposed	2 / 79 (2.53%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin abrasion
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	2 / 79 (2.53%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	2 / 8	0 / 12
Cardiac disorder
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 12
Cardiac failure
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 79 (1.27%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral neuropathy
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	5 / 79 (6.33%)	3 / 123 (2.44%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 79 (2.53%)	4 / 123 (3.25%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	3 / 79 (3.80%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	3 / 79 (3.80%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 79 (2.53%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 79 (2.53%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 79 (1.27%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis haemorrhagic
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	4 / 79 (5.06%)	3 / 123 (2.44%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal vein thrombosis
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 79 (1.27%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	2 / 79 (2.53%)	14 / 123 (11.38%)
occurrences causally related to treatment / all	0 / 2	0 / 14
deaths causally related to treatment / all	0 / 8	2 / 12
Sepsis
subjects affected / exposed	1 / 79 (1.27%)	12 / 123 (9.76%)
occurrences causally related to treatment / all	0 / 1	0 / 12
deaths causally related to treatment / all	0 / 8	4 / 12
Bacteraemia
subjects affected / exposed	2 / 79 (2.53%)	3 / 123 (2.44%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	4 / 79 (5.06%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	1 / 8	0 / 12
Parainfluenzae virus infection
subjects affected / exposed	1 / 79 (1.27%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 79 (0.00%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 79 (1.27%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenovirus infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	3 / 79 (3.80%)	3 / 123 (2.44%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 79 (2.53%)	4 / 123 (3.25%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	4 / 79 (5.06%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 79 (1.27%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 79 (1.27%)	2 / 123 (1.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	1 / 79 (1.27%)	0 / 123 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 79 (0.00%)	1 / 123 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Part 1	Part 2
Total subjects affected by non serious adverse events
subjects affected / exposed	79 / 79 (100.00%)	123 / 123 (100.00%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	55 / 79 (69.62%)	77 / 123 (62.60%)
occurrences all number	55	77
Pyrexia
subjects affected / exposed	10 / 79 (12.66%)	18 / 123 (14.63%)
occurrences all number	10	18
Asthenia
subjects affected / exposed	5 / 79 (6.33%)	19 / 123 (15.45%)
occurrences all number	5	19
Oedema peripheral
subjects affected / exposed	5 / 79 (6.33%)	14 / 123 (11.38%)
occurrences all number	5	14
Chills
subjects affected / exposed	6 / 79 (7.59%)	4 / 123 (3.25%)
occurrences all number	6	4
Malaise
subjects affected / exposed	2 / 79 (2.53%)	8 / 123 (6.50%)
occurrences all number	2	8
Gait disturbance
subjects affected / exposed	0 / 79 (0.00%)	7 / 123 (5.69%)
occurrences all number	0	7
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	23 / 79 (29.11%)	28 / 123 (22.76%)
occurrences all number	23	28
Cough
subjects affected / exposed	12 / 79 (15.19%)	18 / 123 (14.63%)
occurrences all number	12	18
Epistaxis
subjects affected / exposed	11 / 79 (13.92%)	13 / 123 (10.57%)
occurrences all number	11	13
Productive cough
subjects affected / exposed	4 / 79 (5.06%)	3 / 123 (2.44%)
occurrences all number	4	3
Psychiatric disorders
Insomnia
subjects affected / exposed	11 / 79 (13.92%)	22 / 123 (17.89%)
occurrences all number	11	22
Confusional state
subjects affected / exposed	9 / 79 (11.39%)	11 / 123 (8.94%)
occurrences all number	9	11
Anxiety
subjects affected / exposed	4 / 79 (5.06%)	8 / 123 (6.50%)
occurrences all number	4	8
Investigations
Weight decreased
subjects affected / exposed	39 / 79 (49.37%)	61 / 123 (49.59%)
occurrences all number	39	61
Alanine aminotransferase increased
subjects affected / exposed	6 / 79 (7.59%)	13 / 123 (10.57%)
occurrences all number	6	13
Aspartate aminotransferase increased
subjects affected / exposed	3 / 79 (3.80%)	11 / 123 (8.94%)
occurrences all number	3	11
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	4 / 79 (5.06%)	13 / 123 (10.57%)
occurrences all number	4	13
Cardiac disorders
Tachycardia
subjects affected / exposed	9 / 79 (11.39%)	4 / 123 (3.25%)
occurrences all number	9	4
Nervous system disorders
Dizziness
subjects affected / exposed	12 / 79 (15.19%)	19 / 123 (15.45%)
occurrences all number	12	19
Headache
subjects affected / exposed	10 / 79 (12.66%)	11 / 123 (8.94%)
occurrences all number	10	11
Dysgeusia
subjects affected / exposed	10 / 79 (12.66%)	10 / 123 (8.13%)
occurrences all number	10	10
Peripheral neuropathy
subjects affected / exposed	7 / 79 (8.86%)	8 / 123 (6.50%)
occurrences all number	7	8
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	58 / 79 (73.42%)	91 / 123 (73.98%)
occurrences all number	58	91
Anaemia
subjects affected / exposed	37 / 79 (46.84%)	80 / 123 (65.04%)
occurrences all number	37	80
Neutropenia
subjects affected / exposed	23 / 79 (29.11%)	49 / 123 (39.84%)
occurrences all number	23	49
Leukopenia
subjects affected / exposed	20 / 79 (25.32%)	41 / 123 (33.33%)
occurrences all number	20	41
Lymphopenia
subjects affected / exposed	11 / 79 (13.92%)	20 / 123 (16.26%)
occurrences all number	11	20
Eye disorders
Vision blurred
subjects affected / exposed	10 / 79 (12.66%)	13 / 123 (10.57%)
occurrences all number	10	13
Gastrointestinal disorders
Nausea
subjects affected / exposed	60 / 79 (75.95%)	88 / 123 (71.54%)
occurrences all number	60	88
Diarrhoea
subjects affected / exposed	35 / 79 (44.30%)	57 / 123 (46.34%)
occurrences all number	35	57
Vomiting
subjects affected / exposed	37 / 79 (46.84%)	47 / 123 (38.21%)
occurrences all number	37	47
Constipation
subjects affected / exposed	21 / 79 (26.58%)	27 / 123 (21.95%)
occurrences all number	21	27
Abdominal pain
subjects affected / exposed	7 / 79 (8.86%)	12 / 123 (9.76%)
occurrences all number	7	12
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	4 / 79 (5.06%)	3 / 123 (2.44%)
occurrences all number	4	3
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	9 / 79 (11.39%)	10 / 123 (8.13%)
occurrences all number	9	10
Bone pain
subjects affected / exposed	7 / 79 (8.86%)	11 / 123 (8.94%)
occurrences all number	7	11
Hypercreatinaemia
subjects affected / exposed	9 / 79 (11.39%)	6 / 123 (4.88%)
occurrences all number	9	6
Arthralgia
subjects affected / exposed	6 / 79 (7.59%)	6 / 123 (4.88%)
occurrences all number	6	6
Muscle spasms
subjects affected / exposed	4 / 79 (5.06%)	8 / 123 (6.50%)
occurrences all number	4	8
Muscular weakness
subjects affected / exposed	6 / 79 (7.59%)	4 / 123 (3.25%)
occurrences all number	6	4
Pain in extremity
subjects affected / exposed	4 / 79 (5.06%)	4 / 123 (3.25%)
occurrences all number	4	4
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	10 / 79 (12.66%)	17 / 123 (13.82%)
occurrences all number	10	17
Pneumonia
subjects affected / exposed	3 / 79 (3.80%)	10 / 123 (8.13%)
occurrences all number	3	10
Urinary tract infection
subjects affected / exposed	6 / 79 (7.59%)	4 / 123 (3.25%)
occurrences all number	6	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	43 / 79 (54.43%)	68 / 123 (55.28%)
occurrences all number	43	68
Hyponatraemia
subjects affected / exposed	34 / 79 (43.04%)	45 / 123 (36.59%)
occurrences all number	34	45
Hyperglycaemia
subjects affected / exposed	16 / 79 (20.25%)	15 / 123 (12.20%)
occurrences all number	16	15
Hypokalaemia
subjects affected / exposed	5 / 79 (6.33%)	24 / 123 (19.51%)
occurrences all number	5	24
Dehydration
subjects affected / exposed	15 / 79 (18.99%)	10 / 123 (8.13%)
occurrences all number	15	10
Hypocalcaemia
subjects affected / exposed	7 / 79 (8.86%)	13 / 123 (10.57%)
occurrences all number	7	13
Hypomagnesaemia
subjects affected / exposed	10 / 79 (12.66%)	10 / 123 (8.13%)
occurrences all number	10	10
Hypophosphataemia
subjects affected / exposed	6 / 79 (7.59%)	8 / 123 (6.50%)
occurrences all number	6	8
Hypercreatininaemia
subjects affected / exposed	6 / 79 (7.59%)	6 / 123 (4.88%)
occurrences all number	6	6
Hypercalcaemia
subjects affected / exposed	6 / 79 (7.59%)	5 / 123 (4.07%)
occurrences all number	6	5
Hyperkalaemia
subjects affected / exposed	1 / 79 (1.27%)	10 / 123 (8.13%)
occurrences all number	1	10

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Were there any global substantial amendments to the protocol? Yes

05 Feb 2015

Protocol Amendment 1: - Extended the Screening Period from 14 days to 21 days prior to first dose. - Added resolution of hematologic toxicities from previous treatments to ≤ Grade 2 in response to a deficiency reported by the FDA. - Clarified that that PFS, QoL, and OS will not be tested for statistical significance, in response to comments from the FDA.

25 Sep 2015

Protocol Amendment 2: - Revised the study target subject population from quad-refractory to dualrefractory as shown in the following modified inclusion criteria: From: Subjects must have “MM refractory to lenalidomide, pomalidomide, bortezomib, and carfilzomib.” To: “Subjects must have been previously exposed to lenalidomide, pomalidomide, bortezomib, and carfilzomib” and have “MM double refractory to previous treatment with both the PI and IMiD drug classes”. - Changed the study treatment (selinexor plus dexamethasone) dose schedule from “twice-weekly for three weeks of every four-week cycle” to “twice weekly for every week of each four-week cycle.” Changed the indication from Multiple myeloma quad-refractory to prior treatment with bortezomib, carfilzomib, lenalidomide, and pomalidomide to Multiple myeloma refractory to prior treatment with an IMiD and a PI. - Moved the following objective from exploratory objectives to secondary objectives: * Determine ORR, DOR, PFS, and OS in the subgroup of subjects with free light chain (FLC) MM” * Added MRD assessment for subjects who achieve sCR to Exploratory Objectives

11 Aug 2016

Protocol Amendment 3: - Expanded the population of subjects with penta-refractory MM by enrolling approximately 130 additional subjects. The overall study population increased to ~210 subjects. - Revised the study design to make the expansion population (Part 2) the mITT population for the primary efficacy analysis (using ORR); ORR for subjects enrolled in Part 1 became a secondary analysis. - Added that the secondary objectives DOR, PFS, DCR, CBR, TTP and OS will be analyzed separately in different subject sub-populations (i.e. Part 1 subjects with quad-refractory MM, Part 1 subjects with penta-refractory MM, and Part 2 subjects with penta-refractory MM). - Modified inclusion criteria 5 (now 4) to include either daratumumab or isatuximab Modified inclusion criteria 6 (now 5) to include subjects with MM refractory to previous treatment with one or more glucocorticoids, parenteral PI (i.e. bortezomib in and/or carfilzomib), IMiD (i.e. lenalidomide and/or pomalidomide), and anti-CD38 mAb (i.e. either daratumumab or isatuximab). - Modified inclusion criteria 7 (now 6) (multiple myeloma that is refractory to the subjects most recent anti-MM regimen). The new wording in 6 states that “documented severe intolerance to the subjects last therapy is allowed upon approval by the Medical Monitor.” - Adjusted inclusion criterion 13 (now 12), requiring adequate platelet count of ≥50,000/mm3 (subjects in whom ≥50% of bone marrow nucleated cells are plasma cells) at baseline. - Added inclusion criteria13, regarding baseline hemoglobin level ≥8.5 g/dL.

28 Apr 2017

Protocol Amendment 4: - Removed blood draws for PDn and PK analysis as PK and PDn blood samples are no longer being collected. - Pregnancy Testing added, with the following text: “For females of childbearing potential, a negative serum human chorionic gonadotropin (hCG) pregnancy test must be obtained within 3 days before the first dose of study treatment. Test sensitivity for hCG must be ≥25 mIU/mL. Pregnancy testing (serum hCG or urine) is also required for females of childbearing potential prior to dosing on Day 1 of Cycles ≥2 during the study and at the EoT Visit (serum hCG). Pregnancy testing may also be performed as clinically indicated during the study.” - Changed volume of Screening bone marrow aspirate from 1x6 mL to 2x10mL to provide sufficient material for PDn tests. Specified that karyotyping and FISH will be performed at a central laboratory.

13 Dec 2017

Protocol Amendment 5: - Updated definitions of Durations of CBR and DCR. - For consistency with Statistical Analysis Plan: updated the definition of mITT and PP populations; removed presentation of exploratory EE population (details to be provided SAP only). - Updated Sub-Group Efficacy Analyses.

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

Trial information

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Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 2: Percentage of Subjects With Overall Response Rate (ORR) Per International Myeloma Working Group (IMWG) as Assessed by an Independent Review Committee (IRC)

Primary: Part 2: Percentage of Subjects With Overall Response Rate (ORR) Per International Myeloma Working Group (IMWG) as Assessed by an Independent Review Committee (IRC)

Secondary: Part 1: Duration of Response (DoR) Per IMWG as Assessed by IRC

Secondary: Part 1: Duration of Response (DoR) Per IMWG as Assessed by IRC

Secondary: Part 2: Duration of Response (DoR) Per IMWG as Assessed by an IRC

Secondary: Part 2: Duration of Response (DoR) Per IMWG as Assessed by an IRC

Secondary: Part 1: Percentage of Subjects With Clinical Benefit Rate (CBR) ) Per IMWG as Assessed by IRC

Secondary: Part 1: Percentage of Subjects With Clinical Benefit Rate (CBR) ) Per IMWG as Assessed by IRC

Secondary: Part 2: Percentage of Subjects With Clinical Benefit Rate (CBR) Per IMWG as Assessed by IRC

Secondary: Part 2: Percentage of Subjects With Clinical Benefit Rate (CBR) Per IMWG as Assessed by IRC

Secondary: Part 1: Duration of Clinical Benefit Per IMWG as Assessed by IRC

Secondary: Part 1: Duration of Clinical Benefit Per IMWG as Assessed by IRC

Secondary: Part 2: Duration of Clinical Benefit Per IMWG as Assessed by IRC

Secondary: Part 2: Duration of Clinical Benefit Per IMWG as Assessed by IRC

Secondary: Part 2: Disease Control Rate (DCR)

Secondary: Part 2: Disease Control Rate (DCR)

Secondary: Part 1: Progression Free Survival (PFS) Per IMWG as Assessed by IRC

Secondary: Part 1: Progression Free Survival (PFS) Per IMWG as Assessed by IRC

Secondary: Part 2: Progression Free Survival (PFS) Per IMWG as Assessed by IRC

Secondary: Part 2: Progression Free Survival (PFS) Per IMWG as Assessed by IRC

Secondary: Part 1: Time to Progression (TTP) Per IMWG as Assessed by IRC

Secondary: Part 1: Time to Progression (TTP) Per IMWG as Assessed by IRC

Secondary: Part 2: Time to Progression (TTP) Per IMWG as Assessed by IRC

Secondary: Part 2: Time to Progression (TTP) Per IMWG as Assessed by IRC

Secondary: Part 1: Time to Next Treatment (TTNT)

Secondary: Part 1: Time to Next Treatment (TTNT)

Secondary: Part 2: Time to Next Treatment (TTNT)

Secondary: Part 2: Time to Next Treatment (TTNT)

Secondary: Part 1: Overall Survival (OS)

Secondary: Part 1: Overall Survival (OS)

Secondary: Part 2: Overall Survival (OS)

Secondary: Part 2: Overall Survival (OS)

Secondary: Part 2: Change From Baseline in Health-related Quality of Life (HRQL) Score Based on Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) Questionnaire

Secondary: Part 2: Change From Baseline in Health-related Quality of Life (HRQL) Score Based on Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) Questionnaire

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (TEAEs) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (TEAEs) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Part 1: Apparent Clearance (CL/F) of Selinexor in Plasma

Secondary: Part 1: Apparent Clearance (CL/F) of Selinexor in Plasma

Secondary: Part 1: Volume of Distribution (V/F) of Selinexor in Plasma

Secondary: Part 1: Volume of Distribution (V/F) of Selinexor in Plasma

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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