Trial Outcomes & Findings for Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Participants With Recurrent Gliomas (NCT NCT01986348)

NCT ID: NCT01986348

Last Updated: 2023-01-26

Results Overview

The analysis of 6mPFS was performed by calculating the estimated survival probability of having PFS ≥ 6 months based on Kaplan-Meier method, where PFS was defined as the time from the start of study treatment until first documented progression based on Response Assessment in Neuro-Oncology (RANO) criteria, or death from any cause. Progressive disease occurs when either of the criteria was present: greater than or equal to (≥) 25 percentage (%) increase in T1 gadolinium enhancing disease, increase in T2/ Fluid-attenuated inversion recovery (FLAIR), detection of new lesions, or decreased clinical status.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

76 participants

Primary outcome timeframe

From start of study treatment up to disease progression or death, whichever occurred first (assessed up to Month 6)

Results posted on

2023-01-26

Participant Flow

This study was conducted at 6 sites across the United States of America, Denmark and Netherland between 03 March 2014 and 23 January 2020.

A total of 76 participants were enrolled, randomized and treated in this study.

Participant milestones

Participant milestones
Measure	Arm A: Selinexor 60 mg and Surgery Participants who required surgery received up to 3 doses of oral selinexor tablets 60 milligrams (mg) twice weekly (BIW) on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until progression of disease (PD) or development of unacceptable toxicities.	Arm B: Selinexor 50 mg/m^2 Participants who were not eligible for surgery received selinexor tablets 50 mg per square meter (mg/m\^2) BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg Participants who were not eligible for surgery received selinexor tablets 80 mg once weekly (QW) during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Overall Study STARTED	8	24	14	30
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	8	24	14	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: Selinexor 60 mg and Surgery Participants who required surgery received up to 3 doses of oral selinexor tablets 60 milligrams (mg) twice weekly (BIW) on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until progression of disease (PD) or development of unacceptable toxicities.	Arm B: Selinexor 50 mg/m^2 Participants who were not eligible for surgery received selinexor tablets 50 mg per square meter (mg/m\^2) BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg Participants who were not eligible for surgery received selinexor tablets 80 mg once weekly (QW) during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Overall Study Death	8	22	10	21
Overall Study Lost to Follow-up	0	0	0	2
Overall Study Physician Decision	0	0	0	1
Overall Study Progressive Disease	0	0	2	0
Overall Study Withdrawal by Participant	0	1	2	1
Overall Study Study Terminated by Sponsor	0	0	0	3
Overall Study Other-unspecified	0	1	0	2

Baseline Characteristics

Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Participants With Recurrent Gliomas

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Selinexor 60 mg and Surgery n=8 Participants Participants who required surgery received up to 3 doses of oral selinexor tablets 60 mg BIW on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until PD or development of unacceptable toxicities.	Arm B: Selinexor 50 mg/m^2 n=24 Participants Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=14 Participants Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Total n=76 Participants Total of all reporting groups
Sex: Female, Male Female	1 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants	11 Participants n=4 Participants	22 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	19 Participants n=7 Participants	9 Participants n=5 Participants	19 Participants n=4 Participants	54 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	3 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=5 Participants	20 Participants n=7 Participants	8 Participants n=5 Participants	24 Participants n=4 Participants	60 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	3 Participants n=4 Participants	13 Participants n=21 Participants
Age, Continuous	56.6 Years STANDARD_DEVIATION 6.70 • n=5 Participants	51.1 Years STANDARD_DEVIATION 13.04 • n=7 Participants	49.5 Years STANDARD_DEVIATION 12.36 • n=5 Participants	54.3 Years STANDARD_DEVIATION 11.98 • n=4 Participants	52.7 Years STANDARD_DEVIATION 11.99 • n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	24 Participants n=7 Participants	8 Participants n=5 Participants	25 Participants n=4 Participants	65 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	6 Participants n=5 Participants	4 Participants n=4 Participants	10 Participants n=21 Participants

PRIMARY outcome

Timeframe: From start of study treatment up to disease progression or death, whichever occurred first (assessed up to Month 6)

Population: Modified intent-to-treat (mITT) population consisted of all enrolled participants in Arms B, C and D who had received at least 1 dose of study medication and have at least 1 post-baseline efficacy follow-up assessment, unless the participant discontinued treatment prior to the first post baseline assessment due to death, toxicity, or PD. Data for this outcome measure was not planned to be collected and analyzed for Arm A: Selinexor 60 mg and Surgery.

Outcome measures

Outcome measures
Measure	Arm B: Selinexor 50 mg/m^2 n=24 Participants Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=13 Participants Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
6-Month Progression-Free Survival (PFS) Rate	9.72 percentage of participants Interval 2.67 to 35.39	7.69 percentage of participants Interval 1.17 to 50.57	17.24 percentage of participants Interval 7.77 to 38.27	—

SECONDARY outcome

Timeframe: Up to 71 months

Population: mITT population consisted of all enrolled participants in Arms B, C and D who had received at least 1 dose of study medication and have at least 1 post-baseline efficacy follow-up assessment, unless the participant discontinued treatment prior to the first post baseline assessment due to death, toxicity, or disease progression. Data for this outcome measure was not planned to be collected and analyzed for Arm A: Selinexor 60 mg and Surgery.

The ORR was determined as percentage of participants who had either complete response (CR) or partial response (PR) using the RANO criteria. CR: No T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, no corticosteroid use and stable, or increasing clinical status. PR: ≥50% decrease in T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, stable or decreased use of corticosteroids, and stable or increased clinical status.

Outcome measures

Outcome measures
Measure	Arm B: Selinexor 50 mg/m^2 n=24 Participants Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=13 Participants Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Overall Response Rate (ORR)	8.3 percentage of participants Interval 1.0 to 27.0	7.7 percentage of participants Interval 0.2 to 36.0	10.0 percentage of participants Interval 2.1 to 26.5	—

SECONDARY outcome

Timeframe: From date of study treatment up to date of death (assessed up to 71 months)

The OS was calculated from the date of start of study treatment to the date of death. Participants who were still alive prior to the data cut-off for final efficacy analysis, or who dropout prior to study end, were censored on the day they were last known to be alive. The OS was estimated using Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Arm B: Selinexor 50 mg/m^2 n=24 Participants Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=13 Participants Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Overall Survival (OS)	10.51 months Interval 4.93 to 16.95	8.48 months Interval 7.29 to Data could not be estimated due to higher number (\>50%) of censored participants.	10.15 months Interval 7.03 to 15.38	—

SECONDARY outcome

Timeframe: From start of study treatment up to disease progression (assessed up to 71 months)

The PFS was calculated from the date of start of study treatment to the date of disease progression based on RANO criteria, or date of death should progression not have occurred. Progressive disease occurs when either of the criteria was present: ≥25% increase in T1 gadolinium enhancing disease, increased T2/FLAIR, detection of new lesions, or decreased clinical status.

Outcome measures

Outcome measures
Measure	Arm B: Selinexor 50 mg/m^2 n=24 Participants Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=13 Participants Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Progression-free Survival (PFS)	1.64 months Interval 1.18 to 3.15	1.87 months Interval 1.84 to 14.88	1.87 months Interval 1.81 to 3.02	—

SECONDARY outcome

Timeframe: From start of study treatment administration up to 71 months

Population: Safety population consisted of all participants who had received any amount of study treatment.

An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as an AE that was fatal; life threatening (places the participant at immediate risk of death); requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; and other important medical events. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study medication through 30 days following last dose or any event considered drug-related by the Investigator through the end of the study. TEAEs included both serious and non-serious TEAEs.

Outcome measures

Outcome measures
Measure	Arm B: Selinexor 50 mg/m^2 n=8 Participants Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=24 Participants Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=14 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 Participants Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Participants with TEAEs	8 Participants	24 Participants	14 Participants	30 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Participants with TESAEs	5 Participants	7 Participants	7 Participants	7 Participants

Adverse Events

Arm A: Selinexor 60 mg and Surgery

Serious events: 5 serious events

Other events: 8 other events

Deaths: 8 deaths

Arm B: Selinexor 50 mg/m^2

Serious events: 7 serious events

Other events: 24 other events

Deaths: 22 deaths

Arm C: Selinexor 60 mg

Serious events: 7 serious events

Other events: 14 other events

Deaths: 10 deaths

Arm D: Selinexor 80 mg

Serious events: 7 serious events

Other events: 30 other events

Deaths: 21 deaths

Serious adverse events

Other adverse events

Additional Information

Jatin Shah, MD

Karyopharm Therapeutics Inc.

Phone: (617) 658-0600

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm A: Selinexor 60 mg and Surgery n=8 participants at risk Participants who required surgery received up to 3 doses of oral selinexor tablets 60 mg BIW on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until PD or development of unacceptable toxicities.	Arm B: Selinexor 50 mg/m^2 n=24 participants at risk Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm C: Selinexor 60 mg n=14 participants at risk Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.	Arm D: Selinexor 80 mg n=30 participants at risk Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Gastrointestinal disorders Diarrhoea	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
General disorders Fatigue	0.00% 0/8 • From start of study treatment administration up to 71 months	8.3% 2/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
General disorders Asthenia	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	3.3% 1/30 • From start of study treatment administration up to 71 months
General disorders General physical health deterioration	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	3.3% 1/30 • From start of study treatment administration up to 71 months
Infections and infestations Urinary tract infection	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	6.7% 2/30 • From start of study treatment administration up to 71 months
Infections and infestations Meningitis bacterial	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Infections and infestations Pneumonia	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Infections and infestations Staphylococcal infection	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Injury, poisoning and procedural complications Acetabulum fracture	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Injury, poisoning and procedural complications Concussion	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Injury, poisoning and procedural complications Shunt malfunction	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Metabolism and nutrition disorders Decreased appetite	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Metabolism and nutrition disorders Hyperlipasaemia	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	3.3% 1/30 • From start of study treatment administration up to 71 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intracranial tumour haemorrhage	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Nervous system disorders Seizure	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	21.4% 3/14 • From start of study treatment administration up to 71 months	6.7% 2/30 • From start of study treatment administration up to 71 months
Nervous system disorders Syncope	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	10.0% 3/30 • From start of study treatment administration up to 71 months
Nervous system disorders Headache	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Nervous system disorders Brain oedema	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	3.3% 1/30 • From start of study treatment administration up to 71 months
Nervous system disorders Cerebrospinal fluid leakage	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Nervous system disorders Cerebrovascular accident	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Nervous system disorders Dizziness	0.00% 0/8 • From start of study treatment administration up to 71 months	4.2% 1/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Nervous system disorders Pneumocephalus	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Psychiatric disorders Confusional state	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	7.1% 1/14 • From start of study treatment administration up to 71 months	3.3% 1/30 • From start of study treatment administration up to 71 months
Vascular disorders Embolism	12.5% 1/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	0.00% 0/30 • From start of study treatment administration up to 71 months
Vascular disorders Hypertension	0.00% 0/8 • From start of study treatment administration up to 71 months	0.00% 0/24 • From start of study treatment administration up to 71 months	0.00% 0/14 • From start of study treatment administration up to 71 months	3.3% 1/30 • From start of study treatment administration up to 71 months