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Clinical Trial Results:
A PHASE 1/2 STUDY TO INVESTIGATE THE SAFETY, PHARMACOKINETICS AND EFFICACY OF EDO-S101, A FIRST-IN-CLASS ALKYLATING HISTONE DEACETYLASE INHIBITION (HDACI) FUSION MOLECULE, IN PATIENTS WITH ADVANCED SOLID TUMORS. SUB-STUDY TO CHARACTERIZE THE EFFECTS OF TINOSTAMUSTINE AT A DOSE OF 60 MG/M2 ADMINISTERED DURING A 60-MINUTE INFUSION ON CARDIAC REPOLARIZATION IN PATIENTS WITH ADVANCED SOLID TUMORS. SUB-STUDY TO CHARACTERIZE THE EFFECTS OF TINOSTAMUSTINE AT A DOSE OF 80 MG/M2 ADMINISTERED DURING A 80-MINUTE INFUSION ON CARDIAC REPOLARIZATION IN PATIENTS WITH ADVANCED SOLID TUMORS

Summary
EudraCT number	2020-004246-11
Trial protocol	NL IT
Global end of trial date	29 Mar 2023

Results information
Results version number	v1(current)
This version publication date	14 Jul 2024
First version publication date	14 Jul 2024
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

EDO-S101-1002

ISRCTN number

US NCT number

NCT03345485

WHO universal trial number (UTN)

Other trial identifiers

IND: 125180

Sponsor organisation name

Mundipharma Research Limited

Sponsor organisation address

Cambridge Science Park, Milton Road, Cambridge , United Kingdom, CB4 0AB

Public contact

Elizabeth Chong, Mundipharma Research Limited, 0044 01223 424900, elizabeth.chong@mundipharma-rd.eu

Scientific contact

Elizabeth Chong, Mundipharma Research Limited, 0044 01223 424900, elizabeth.chong@mundipharma-rd.eu

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

29 Mar 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Jul 2022

Global end of trial reached?

Yes

Global end of trial date

29 Mar 2023

Was the trial ended prematurely?

Main objective of the trial

Phase 1: To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of tinostamustine as a single agent in subjects with solid tumours who have progressed after at least one (1) line of therapy and no other standard therapy with proven clinical benefit is available. Phase 2: To determine the objective response rate (ORR) of any duration, plus the rate of subjects with stable disease (SD) of at least 12-week duration at a dose of 80 mg/m2 administered over 1 hour on Day 1 and Day 15 of each 4-week treatment cycle. Substudies: To characterize the effect of tinostamustine at a dose of 60 or 80 mg/m2 on cardiac repolarization (QTcF) and other electrocardiogram (ECG) parameters in 6 -12 subjects with solid tumours who have progressed after at least 1 line of therapy and for whom no other standard therapy with proven clinical benefit is available.

Protection of trial subjects

The study protocol was approved by relevant regulatory authorities and ethics committees, and clinical trial agreements signed prior to site initiation and activation. All amendments were submitted for relevant approvals before implementation. Only site staff who were delegated by the Principal investigator on the study delegation log and had received training could work on the study. Potential subjects were provided with the ethics approved informed consent form and had the opportunity to discuss the study with delegated investigators before providing consent to take part. Only subjects who meet the eligible criteria were enrolled. The protocol included numerous safety assessments including physical examinations, measurement of vital signs, hematology and clinical chemistry tests, urinalysis, assessment of ECOG performance status and cardiac monitoring. Subjects had to agree to follow contraception requirements, and women of child-bearing potential are required to undergo pregnancy test with negative test results prior to every treatment. Subjects were asked about any adverse events (AE) and use of concomitant medications including herbal supplements, vitamins and minerals, and all were recorded in the study database. Beyond cycle 1 day 1, the re-treatment criteria must be met. During treatment, subjects will be closely monitored for any QTc prolongations. Additional ECGs are taken if the QTcF value is >500ms or represents an increase >60ms from baseline. If the average QTcF is grade 3 or higher, tinostamustine infusion must be stopped and QTcF prolongation reported as a serious adverse event. All AEs must be reported from the time of ICF signature through the point of tinostamustine discontinuation, and followed to resolution or stabilization of event. Tinostamustine must be stored at 2 to 8°C in a secure area with access limited to the Investigator and authorized site staff, and with appropriate temperature monitoring.

Background therapy

Evidence for comparator

There is no comparator in this study.

Actual start date of recruitment

18 Oct 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

United States: 58

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

P1: First Subject First Dose: 08-Nov-2017; Date of last subject enrolled: 11-Oct-2018 P2: First Subject First Dose: 26-Dec-2018; Date of last subject enrolled: 14-Dec-2021 SS1: First Subject First Dose: 09-June-2020; Date of last subject enrolled: 08-Oct-2020 SS2: First Subject First Dose: 30-Dec-2021; Date of last subject enrolled: 30-June-2022

Screening details

Adults with histologically confirmed diagnosis of advanced or metastatic solid tumors, disease should have progressed during or following at least 1 previous line of therapy and no other standard therapy with proven clinical benefit is available or recommended based on the investigator’s individual risk-benefit assessment for the patient.

Period 1 title

Tinostamustine treatment

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 - 60mg/m2 (30 Min). Cohort 1

Arm description

This is dose level 1 of the dose escalation phase (Phase 1) of the study. Tinostamustine at dose of 60mg/m2 administered i.v. over 30min on D1 and D15 of each 4-week cycle. The decision to escalate to the next dose level occurred after all 3 subjects completed the Dose-limiting toxicity (DLT) observation time and were evaluated for safety and toxicity.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 1 - 80mg/m2 (30 Min). Cohort 2

Arm description

This is dose level 2 of the dose escalation phase (Phase 1) of the study. Tinostamustine at dose of 80mg/m2 administered i.v. over 30min on D1 and D15 of each 4-week cycle. The decision to escalate to the next dose level occurred after all 3 subjects completed the Dose-limiting toxicity (DLT) observation time and were evaluated for safety and toxicity.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent administered at doses of 80mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 1 - 100mg/m2 (30 Min). Cohort 3.

Arm description

This is dose level 3 of the dose escalation phase (Phase 1) of the study. Tinostamustine at dose of 100mg/m2 administered i.v. over 30min on D1 and D15 of each 4-week cycle. In the 30-minute infusion study drug dosing had to be delayed in subsequent cycles due to thrombocytopenia, which was associated with an extremely high Cmax of Tinostamustine. To ensure that subjects continue the study treatment safely, the Sponsor decided to stop the investigation of the 30-minute infusion time and open cohorts with the 60-minute infusion in 3 subjects with relapse/refractory solid tumors.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 100mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 1 - 60mg/m2 (60 Min). Cohort 4

Arm description

This is dose level 4 of the dose escalation phase (Phase 1) of the study. Tinostamustine at dose of 60mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle. The decision to escalate to the nextdose level occurred after all 3 subjects completed the Dose-limiting toxicity (DLT) observation time and were evaluated for safety and toxicity.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 1 - 80mg/m2 (60 Min). Cohort 5

Arm description

This is dose level 5 of the dose escalation phase (Phase 1) of the study. Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle. The decision to escalate to the next dose level occurred after all 3 subjects completed the Dose-limiting toxicity (DLT) observation time and were evaluated for safety and toxicity.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 1 - 100mg/m2 (60 Min). Cohort 6

Arm description

This is dose level 6 of the dose escalation phase (Phase 1) of the study. DLT of electrocardiogram QTc prolongation occurred 1 patient. Considering the DLT observed in this cohort and the rapid occurrence of treatment-induced thrombocytopenia (not meeting the DLT definitions), the SRC concluded as follows: The dose of 100 mg/m2 was determined the MAD. The dose level of 80 mg/m2 given i.v. over 60 minutes was determined to be the MTD The dose level of 80 mg/m2 given i.v. over 60 minutes on Day 1 and Day 15 of each 4-week treatment cycle was determined to be the RP2D.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 100mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho

Arm description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort

Arm description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 2 Relapsed/refractory Triple Negative breast Cancer

Arm description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort

Arm description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort

Arm description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Sub study 1 (SS1)

Arm description

Tinostamustine at dose of 60mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Substudy 2 (SS2)

Arm description

Tinostamustine at dose of 80mg/m2 administered i.v. over 80min on D1 and D15 of each 4-week cycle.

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 80 minutes on Days (D) 1 and 15 of each 28-day cycle.

Number of subjects in period 1	Phase 1 - 60mg/m2 (30 Min). Cohort 1	Phase 1 - 80mg/m2 (30 Min). Cohort 2	Phase 1 - 100mg/m2 (30 Min). Cohort 3.	Phase 1 - 60mg/m2 (60 Min). Cohort 4	Phase 1 - 80mg/m2 (60 Min). Cohort 5	Phase 1 - 100mg/m2 (60 Min). Cohort 6	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Substudy 2 (SS2)
Started	3	3	3	3	8	2	4	10	4	12	6	6	7
Completed	3	3	3	3	8	2	3	8	4	12	4	3	4
Not completed	0	0	0	0	0	0	1	2	0	0	2	3	3
Do not have a post-dose tumour assessment	-	-	-	-	-	-	1	2	-	-	2	3	3

Period 2 title

PK cohorts

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 2 all cohorts

Arm description

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Substudy 1

Arm description

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Substudy 2

Arm description

Arm type

Experimental

Investigational medicinal product name

Tinostamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion, Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Tinostamustine powder for injection 100 mg reconstituted with 20 mL of 0.9% saline and then immediately further diluted with 0.9% saline to a final volume of 50 mL. The diluted solution is stored in infusion container (bottle or bag) for a maximum of 10 hours, of which a maximum of 4 hours may be at room temperature including duration of infusion, with the remaining storage period at 2 to 8°C. Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 80 minutes on Days (D) 1 and 15 of each 28-day cycle.

Number of subjects in period 2 ^[1]	Phase 2 all cohorts	Substudy 1	Substudy 2
Started	36	6	7
Completed	31	3	4
Not completed	5	3	3
Do not have a post-dose tumour assessment	5	3	3

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A separate period is entered in order for group results to be provided for PK endpoints. In phase 2 of the study, all patients receive study drug at the same dose with same infusion duration, hence PK data are analysed together.

Baseline characteristics

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Reporting group title

Phase 1 - 60mg/m2 (30 Min). Cohort 1

Reporting group description

Reporting group title

Phase 1 - 80mg/m2 (30 Min). Cohort 2

Reporting group description

Reporting group title

Phase 1 - 100mg/m2 (30 Min). Cohort 3.

Reporting group description

Reporting group title

Phase 1 - 60mg/m2 (60 Min). Cohort 4

Reporting group description

Reporting group title

Phase 1 - 80mg/m2 (60 Min). Cohort 5

Reporting group description

Reporting group title

Phase 1 - 100mg/m2 (60 Min). Cohort 6

Reporting group description

Reporting group title

Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Triple Negative breast Cancer

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Sub study 1 (SS1)

Reporting group description

Tinostamustine at dose of 60mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Substudy 2 (SS2)

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 80min on D1 and D15 of each 4-week cycle.

Reporting group values	Phase 1 - 60mg/m2 (30 Min). Cohort 1	Phase 1 - 80mg/m2 (30 Min). Cohort 2	Phase 1 - 100mg/m2 (30 Min). Cohort 3.	Phase 1 - 60mg/m2 (60 Min). Cohort 4	Phase 1 - 80mg/m2 (60 Min). Cohort 5	Phase 1 - 100mg/m2 (60 Min). Cohort 6	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Substudy 2 (SS2)	Total
Number of subjects	3	3	3	3	8	2	4	10	4	12	6	6	7	71
Age categorical
Demographic information included age, sex, ethnicity, race, height, weight and BMI. Demographics and baseline characteristics were summarised descriptively. Subject demographics (sex, ethnicity, race, and age category) were presented using discrete summary statistics. Age, height, weight and BMI were presented using continuous summary statistics
Units: Subjects
Adults (18-64 years)	1	1	2	3	4	2	2	8	2	8	3	6	6	48
From 65-74	2	2	1	0	4	0	2	2	1	3	3	0	0	20
75 years and over	0	0	0	0	0	0	0	0	1	1	0	0	1	3
Gender categorical
Demographics and baseline characteristics are summarised for Safety Population. Demographic information included age, sex, ethnicity, race, height, weight and BMI. Demographics and baseline characteristics were summarised descriptively. Subject demographics (sex, ethnicity, race, and age category) were presented using discrete summary statistics. Age, height, weight and BMI were presented using continuous summary statistics.
Units: Subjects
Female	2	1	2	2	4	2	2	6	4	12	6	5	4	52
Male	1	2	1	1	4	0	2	4	0	0	0	1	3	19
Ethnicity
Unit of measure: participants
Units: Subjects
Hispanic or Latino	1	0	0	2	1	0	0	2	0	0	0	0	0	6
Not Hispanic or Latino	2	3	3	1	7	2	4	7	4	12	6	4	7	62
Unknown or Not Reported	0	0	0	0	0	0	0	1	0	0	0	2	0	3
Race
Demographics and baseline characteristics are summarised for Safety Population. Demographic information included age, sex, ethnicity, race, height, weight and BMI. Demographics and baseline characteristics were summarised descriptively. Subject demographics (sex, ethnicity, race, and age category) were presented using discrete summary statistics. Age, height, weight and BMI were presented using continuous summary statistics.
Units: Subjects
Asian	0	1	2	0	2	0	0	2	0	2	2	1	0	12
Black or African American	0	0	0	0	0	0	0	0	1	0	0	0	1	2
White	3	2	1	3	6	2	4	8	3	10	4	5	6	57
Height at Screening
Demographics and baseline characteristics are summarised for Safety Population. Demographic information included age, sex, ethnicity, race, height, weight and BMI. Demographics and baseline characteristics were summarised descriptively. Subject demographics (sex, ethnicity, race, and age category) were presented using discrete summary statistics. Age, height, weight and BMI were presented using continuous summary statistics.
Units: centimetre
median (full range (min-max))	166.6 (158 to 176)	171.5 (166 to 183)	165.5 (148 to 183)	154.9 (154 to 178)	161.8 (156 to 198)	164.8 (161 to 169)	163 (156 to 185)	166.1 (155 to 177)	158.2 (152 to 168)	159.1 (152 to 170)	160.4 (155 to 164)	166.7 (151 to 183)	166.4 (156 to 183)	-
Weight at Screening
Demographics and baseline characteristics are summarised for Safety Population. Demographic information included age, sex, ethnicity, race, height, weight and BMI. Demographics and baseline characteristics were summarised descriptively. Subject demographics (sex, ethnicity, race, and age category) were presented using discrete summary statistics. Age, height, weight and BMI were presented using continuous summary statistics.
Units: kilogram(s)
median (full range (min-max))	75.3 (46 to 102)	95.8 (84 to 98)	75.3 (67 to 84)	95.4 (84 to 102)	69.3 (45 to 112)	87.6 (70 to 106)	54.5 (52 to 130)	71.8 (42 to 142)	58.1 (48 to 85)	65.0 (50 to 96)	59.7 (54 to 86)	93.1 (65 to 142)	72.5 (55 to 105)	-
BMI at screening
Demographics and baseline characteristics are summarised for Safety Population. Demographic information included age, sex, ethnicity, race, height, weight and BMI. Demographics and baseline characteristics were summarised descriptively. Subject demographics (sex, ethnicity, race, and age category) were presented using discrete summary statistics. Age, height, weight and BMI were presented using continuous summary statistics.
Units: kilogra
median (full range (min-max))	31.620 (30.36 to 32.88)	28.610 (28.53 to 35.41)	27.775 (24.96 to 30.59)	35.460 (30.11 to 42.34)	21.920 (18.19 to 36.19)	32.675 (24.40 to 40.95)	21.485 (19.67 to 37.95)	24.060 (17.36 to 50.82)	24.005 (19.70 to 30.22)	25.505 (20.98 to 38.28)	23.255 (20.69 to 34.10)	32.880 (23.23 to 50.99)	23.590 (20.76 to 40.06)	-

End points

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Reporting group title

Phase 1 - 60mg/m2 (30 Min). Cohort 1

Reporting group description

Reporting group title

Phase 1 - 80mg/m2 (30 Min). Cohort 2

Reporting group description

Reporting group title

Phase 1 - 100mg/m2 (30 Min). Cohort 3.

Reporting group description

Reporting group title

Phase 1 - 60mg/m2 (60 Min). Cohort 4

Reporting group description

Reporting group title

Phase 1 - 80mg/m2 (60 Min). Cohort 5

Reporting group description

Reporting group title

Phase 1 - 100mg/m2 (60 Min). Cohort 6

Reporting group description

Reporting group title

Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Triple Negative breast Cancer

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Sub study 1 (SS1)

Reporting group description

Tinostamustine at dose of 60mg/m2 administered i.v. over 60min on D1 and D15 of each 4-week cycle.

Reporting group title

Substudy 2 (SS2)

Reporting group description

Tinostamustine at dose of 80mg/m2 administered i.v. over 80min on D1 and D15 of each 4-week cycle.

Reporting group title

Phase 2 all cohorts

Reporting group description

Reporting group title

Substudy 1

Reporting group description

Reporting group title

Substudy 2

Reporting group description

Primary: Clinical Benefit Response Rate in Selected Solid Tumor Cohorts on Phase 2

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End point title

Clinical Benefit Response Rate in Selected Solid Tumor Cohorts on Phase 2 ^[1] ^[2]

End point description

The Clinical Benefit Response Rate is calculated as the number of patients with Clinical Benefit Response divided by number of patients in the FAS (in the respective cohort).

End point type

Primary

End point timeframe

Over complete study

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: Due to the nature of the phase 1/2 study, no statistical analysis was to be performed other than summary statistics
[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: This study is designed into various phases. This is not an end point in Phase 1 or for the sub-studies.

End point values	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort
Number of subjects analysed	4	10	4	12	6
Units: percent
number (confidence interval 90%)
Clinical Benefit Response Rate (CR+PR+durable SD)	0 (0 to 52.7)	40 (15.0 to 69.6)	50.0 (9.8 to 90.2)	50.0 (24.5 to 75.5)	50.0 (15.3 to 84.7)

No statistical analyses for this end point

Primary: Highest Change From Baseline in QTcF in Sub-studies

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End point title

Highest Change From Baseline in QTcF in Sub-studies ^[3] ^[4]

End point description

QTcF: corrected QT interval [QTc] using Fridericia's formula) and other electrocardiogram (ECG) parameters in subjects with solid tumours who have progressed after at least 1 line of therapy and for whom no other standard therapy with proven clinical benefit is available. Within each cycle a Change from baseline (CfB) is calculated for QTcF relative to the baseline value of day 1 of the cycle. QTcF CfB= QTcF Post-dose value - QTcF pre-dose value of D1 ECG Parameters: 4-hours ECG holter monitoring in C1 and ECGs during EDO-S101 administration. Continuous variables the mean and standard deviation are presented together with the total number of observations and the number of missing and non-missing values.

End point type

Primary

End point timeframe

QTcF change from baseline over all cycles.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of the phase 1/2 study, no statistical analysis was to be performed other than summary statistics
[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: This study is designed into various phases. This end-point is only applicable to the sub-studies.

End point values	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	6	7
Units: msec
arithmetic mean (standard deviation)	53.33 ( 23.777 )	33.24 ( 12.588 )

No statistical analyses for this end point

Primary: Number of participants with treatment-related adverse events as assessed by CTCAE V4.03 on Phase 1

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End point title

Number of participants with treatment-related adverse events as assessed by CTCAE V4.03 on Phase 1 ^[5] ^[6]

End point description

All TEAEs was reported from the first dose of study drug through the time of study drug discontinuation (at any time or Day 28 of the last treatment Cycle). All treatment-related TEAEs was followed until resolution or stabilization. For the purpose of regulatory reporting requirements, causal relationships of definite, probable, and possible was considered treatment-related. Number of patients experiencing treatment-related adverse events (TEAE) as assessed by CTCAE v4.03. (June 2010).

End point type

Primary

End point timeframe

From start treatment until end of treatment

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of the phase 1/2 study, no statistical analysis was to be performed other than summary statistics
[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: This study is designed into various phases. This end point is a primary endpoint in phase 1, but a secondary endpoint in phase 2 and substudies, hence they are reported separately.

End point values	Phase 1 - 60mg/m2 (30 Min). Cohort 1	Phase 1 - 80mg/m2 (30 Min). Cohort 2	Phase 1 - 100mg/m2 (30 Min). Cohort 3.	Phase 1 - 60mg/m2 (60 Min). Cohort 4	Phase 1 - 80mg/m2 (60 Min). Cohort 5	Phase 1 - 100mg/m2 (60 Min). Cohort 6
Number of subjects analysed	3	3	3	3	8	2
Units: number of participants
Investigations	3	3	3	3	6	2
Gastrointestinal disorders	3	3	2	1	8	2
Blood and lymphatic system disorders	1	3	2	3	4	1
General disorders and administration site conditio	1	2	2	2	5	1
Nervous system disorders	1	1	2	1	3	2
Skin and subcutaneous tissue disorders	1	2	1	1	2	0
Metabolism and nutrition disorders	1	0	0	1	3	1
Injury, poisoning and procedural complications	0	1	0	0	1	0
Respiratory, thoracic and mediastinal disorders	0	0	1	0	1	0
Cardiac disorders	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders	0	0	0	0	1	0
Vascular disorders	0	0	0	1	0	0

No statistical analyses for this end point

Secondary: Safety Population With Treatment-related Adverse Events on Phase 2 and Sub Studies

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End point title

Safety Population With Treatment-related Adverse Events on Phase 2 and Sub Studies ^[7]

End point description

Number of patients experiencing treatment-related adverse events (TEAE) as assessed by CTCAE v4.03, June 2010, with the exception that assessment of QTc prolongations constituting adverse events (AEs) of special interest were based on NCI CTCAE version 5.0, November 2017. All subjects who received at least 1 dose of study treatment were included in the Safety Population. Safety analyses were performed on data from all subjects in the Safety Population.

End point type

Secondary

End point timeframe

P2: A single dose of 80 mg/m2 over 60 min of EDO-101 on D1 and D15 of each four (4) week treatment cycle. SS: A single dose of 60 mg/m2 over 60 min of EDO-101. SS2: A single dose of 80 mg/m2 over 80 min of EDO-101 on D1 and D15 in cycle 1.

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: This study is designed into various phases. This end point is a primary endpoint in phase 1, but a secondary endpoint in phase 2 and substudies, hence they are reported separately.

End point values	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	4	10	4	12	6	6	7
Units: Patients
Gastrointestinal disorders	2	4	3	12	4	2	2
Investigations	3	3	2	8	5	3	2
Blood and lymphatic system disorders	2	4	2	7	3	3	3
General disorders and administration site conditio	2	3	1	9	5	2	1
Metabolism and nutrition disorders	1	1	1	4	3	1	0
Nervous system disorders	2	2	0	3	3	1	0
Skin and subcutaneous tissue disorders	1	3	0	4	1	0	0
Musculoskeletal and connective tissue disorders	1	1	0	1	0	1	1
Respiratory, thoracic and mediastinal disorders	1	1	1	0	1	1	0
Vascular disorders	0	2	0	2	1	0	0
Cardiac disorders	0	0	1	1	1	0	0
Injury, poisoning and procedural complications	1	0	1	1	0	0	0
Infections and infestations	0	1	0	0	0	0	2

No statistical analyses for this end point

Secondary: Duration of stable disease (SD) that persists for at least 4 months in selected solid tumor cohorts on Sub studies

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End point title

Duration of stable disease (SD) that persists for at least 4 months in selected solid tumor cohorts on Sub studies ^[8]

End point description

Duration of SD, was defined as the number of days between the date of the first dose of treatment and the first date of disease progression or death. SD was regarded as durable if, after observing SD, the first observation of progression disease was at least 84 days after the start of study treatment.

End point type

Secondary

End point timeframe

Every 2 cycles until end of treatment

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: This study is designed into various phases. This end-point is only applicable to the sub-studies.

End point values	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	2	1
Units: participants
<84 days	0	0
≥84 days	2	1

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR) and the clinical benefit rate (CBR) that persists for at least four (4) months in selected solid tumor cohorts on Sub studies

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End point title

Objective Response Rate (ORR) and the clinical benefit rate (CBR) that persists for at least four (4) months in selected solid tumor cohorts on Sub studies ^[9]

End point description

Every 2 cycles until end of treatment

End point type

Secondary

End point timeframe

To determine the objective response rate (ORR), the clinical benefit rate (CBR [CR, PR plus SD]), and Duration of SD on Sub Studies. SD was regarded as durable if, after observing SD, the first observation of PD was at least 84 days after 1st dose.

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: This study is designed into various phases. This end-point is only applicable to the sub-studies.

End point values	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	6	7
Units: day
least squares mean (confidence interval 90%)
Objective Response Rate	16.7 (0.9 to 58.2)	0 (0 to 34.8)
Clinical Benefit Response	50.0 (15.3 to 84.7)	14.3 (0.7 to 52.1)

No statistical analyses for this end point

Secondary: To Determine the Duration of Response (DoR) time for Phase 2 and Sub Studies

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End point title

To Determine the Duration of Response (DoR) time for Phase 2 and Sub Studies ^[10]

End point description

To Determine the Duration of Response (DoR) time for Phase 2 and Sub Studies

End point type

Secondary

End point timeframe

Date of the first tumor response assessment with an Investigator’s Overall Response of CR or PR (whichever status is recorded first) until the date of progression or death.

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: This study is designed into various phases. DoR time is not one of the endpoints in phase 1.

End point values	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	4	10	4	12	6	6	7
Units: day
number (not applicable)	0	51	0	52	0	734	0

No statistical analyses for this end point

Secondary: To Determine the Overall Survival (OS) Time for Phase 2 and Sub Studies

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End point title

To Determine the Overall Survival (OS) Time for Phase 2 and Sub Studies ^[11]

End point description

Phase 2: To determine the overall survival (OS) time for subjects with solid tumours SS1:To determine the overall survival (OS) time for subjects who received 60 mg/m2 of EDO-S101 during a 60-minute Infusion. SS2: To determine the overall survival (OS) time for subjects who received 80 mg/m2 of EDO-S101 during a 80-minute Infusion. NOTE: 999999 is entered for data not presented or not estimable

End point type

Secondary

End point timeframe

On Day 1 and 15 of each 4-week treatment cycle.

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: This study is designed into various phases. OS is not one of the endpoints in phase 1.

End point values	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	4	10	4	12	6	6	7
Units: day
median (inter-quartile range (Q1-Q3))	114.5 (88.5 to 150.0)	346.5 (167.0 to 650.0)	218.5 (92.5 to 999999)	261.0 (121.0 to 1260.0)	127.0 (68.0 to 1058.0)	177.0 (78.0 to 784.0)	139.0 (130.0 to 999999)

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) in Phase 2 and Sub Studies

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End point title

Maximum Plasma Concentration (Cmax) in Phase 2 and Sub Studies

End point description

Cmax (Maximum Plasma Concentration) of EDO-S101 and 2 metabolites M2 and M8. *999999 is entered where data field could not be calculated due to insufficient data.

End point type

Secondary

End point timeframe

Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.

End point values	Phase 2 all cohorts	Substudy 1	Substudy 2
Number of subjects analysed	35	6	7
Units: nanogram(s)/millilitre
geometric mean (geometric coefficient of variation)
EDO-S101 concentration, Cycle 1 D1	1620 ( 43.3 )	1150 ( 15.8 )	1210 ( 11.3 )
EDO-S101 concentration, Cycle 1 D15	1540 ( 41.5 )	999 ( 38.6 )	1040 ( 21.2 )
M2 metabolite concentration, Cycle 1 D1	1.92 ( 77.9 )	2.18 ( 65.4 )	2.32 ( 65.5 )
M2 metabolite concentration, Cycle 1 D15	1.98 ( 63.3 )	2.31 ( 105 )	2.91 ( 999999 )
M8 metabolite concentration, Cycle 1 D1	47.7 ( 50.2 )	37.4 ( 17.0 )	27.0 ( 36.5 )
M8 metabolite concentration, Cycle 1 D15	49.8 ( 43.7 )	31.2 ( 46.3 )	24.6 ( 33.3 )

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) Time for Phase 2 and Sub Studies

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End point title

Progression Free Survival (PFS) Time for Phase 2 and Sub Studies ^[12]

End point description

PFS was defined as the number of days between the date of the first dose of treatment and the first date of disease progression or death. Phase 2: To determine the PFS time for subjects who received 80 mg/m2 over 60-minute of EDO-S101 infusion. SS1:To determine the PFS time for subjects who received 60 mg/m2 over 60-minute of EDO-S101 infusion. SS2: To determine the PFS time for subjects who received 80 mg/m2over 80-minute of EDO-S101 infusion.

End point type

Secondary

End point timeframe

Date of the first dose of treatment and the first date of disease progression or death.

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: This study is designed into various phases. PFS is not one of the endpoints in phase 1.

End point values	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Substudy 2 (SS2)
Number of subjects analysed	4	10	4	12	6	6	7
Units: day
median (inter-quartile range (Q1-Q3))	54.0 (51.0 to 74.0)	56.0 (52.0 to 236.0)	85.0 (58.0 to 310.0)	63.0 (46.5 to 97.0)	87.0 (52.0 to 107.0)	177.0 (78.0 to 784.0)	65.0 (42.0 to 131.0)

No statistical analyses for this end point

Secondary: Area Under the Curve [AUC(0-t)] in Phase 2 and Sub Studies.

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End point title

Area Under the Curve [AUC(0-t)] in Phase 2 and Sub Studies.

End point description

All enrolled subjects in the Safety Population with at least 1 quantifiable pre-dose and 1 quantifiable post-dose PK plasma concentration in Cycle 1 were included in the PK Population. PK analyses were performed using the PK population. 48 subjects of the Safety Population were included in the PK Population. *999999 is entered for those fields where a value cannot be calculated due to insufficient data.

End point type

Secondary

End point timeframe

Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.

End point values	Phase 2 all cohorts	Substudy 1	Substudy 2
Number of subjects analysed	35	6	7
Units: ng.h/mL
geometric mean (geometric coefficient of variation)
EDO-S101 concentration, Cycle 1 D1	1490 ( 40.9 )	938 ( 41.9 )	1680 ( 22.6 )
EDO-S101 concentration, Cycle 1 D15	1520 ( 41.7 )	943 ( 53.7 )	1390 ( 28.7 )
M2 metabolite concentration, Cycle 1 D1	0.865 ( 248 )	5.19 ( 420 )	12.4 ( 1430 )
M2 metabolite concentration, Cycle 1 D15	1.32 ( 163 )	2.32 ( 9060 )	48.6 ( 999999 )
M8 metabolite concentration, Cycle 1 D1	47.7 ( 48.3 )	36.0 ( 80.5 )	54.4 ( 61.2 )
M8 metabolite concentration, Cycle 1 D15	53.3 ( 44.8 )	40.9 ( 94.1 )	35.2 ( 33.7 )

No statistical analyses for this end point

Secondary: Summary of Tmax in in Phase 2 and Sub Studies.

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End point title

Summary of Tmax in in Phase 2 and Sub Studies.

End point description

End point type

Secondary

End point timeframe

Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.

End point values	Phase 2 all cohorts	Substudy 1	Substudy 2
Number of subjects analysed	35	6	7
Units: hours
median (full range (min-max))
EDO-S101 concentration, Cycle 1 D1	0.750 (0.250 to 1.25)	0.750 (0.250 to 0.750)	1 (0.750 to 1.33)
EDO-S101 concentration, Cycle 1 D15	0.750 (0 to 1.25)	0.750 (0.5 to 0.750)	0.875 (0.167 to 1.33)
M2 metabolite concentration, Cycle 1 D1	1.00 (0.25 to 2.00)	1 (0.250 to 6)	1.58 (0.750 to 24)
M2 metabolite concentration, Cycle 1 D15	1.00 (0 to 6)	1 (0.250 to 24)	3.50 (3.50 to 3.50)
M8 metabolite concentration, Cycle 1 D1	0.750 (0.250 to 1.50)	0.750 (0.250 to 1)	1 (1 to 1.33)
M8 metabolite concentration, Cycle 1 D15	0.750 (0 to 1.25)	0.750 (0.500 to 0.750)	1.33 (1 to 1.33)

No statistical analyses for this end point

Secondary: Clearance of Tinostamustine and Metabolites in Phase 2 and Substudies

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End point title

Clearance of Tinostamustine and Metabolites in Phase 2 and Substudies

End point description

End point type

Secondary

End point timeframe

Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.

End point values	Phase 2 all cohorts	Substudy 1	Substudy 2
Number of subjects analysed	35	6	7
Units: mL/h/m^2
geometric mean (geometric coefficient of variation)
EDO-S101 concentration, Cycle 1 D1	50800 ( 41.1 )	69800 ( 48.7 )	56000 ( 23.9 )
EDO-S101 concentration, Cycle 1 D15	53600 ( 45.2 )	89600 ( 19.5 )	49600 ( 58.3 )
M2 metabolite concentration, Cycle 1 D1	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
M2 metabolite concentration, Cycle 1 D15	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
M8 metabolite concentration, Cycle 1 D1	999999 ( 999999 )	2410000 ( 54.2 )	2270000 ( 22.4 )
M8 metabolite concentration, Cycle 1 D15	999999 ( 999999 )	1240000 ( 14.8 )	1740000 ( 40.8 )

No statistical analyses for this end point

Secondary: Summary of Half-life of Tinostamustine in Phase 2 and Substudies

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End point title

Summary of Half-life of Tinostamustine in Phase 2 and Substudies

End point description

End point type

Secondary

End point timeframe

Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.

End point values	Phase 2 all cohorts	Substudy 1	Substudy 2
Number of subjects analysed	35	6	7
Units: Hour
geometric mean (geometric coefficient of variation)
EDO-S101 concentration, Cycle 1 D1	0.70 ( 54 )	0.919 ( 38 )	2.14 ( 185 )
EDO-S101 concentration, Cycle 1 D15	0.704 ( 51.2 )	0.678 ( 45.8 )	4.03 ( 2150 )
M2 metabolite concentration, Cycle 1 D1	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
M2 metabolite concentration, Cycle 1 D15	999999 ( 999999 )	999999 ( 999999 )	999999 ( 999999 )
M8 metabolite concentration, Cycle 1 D1	0.414 ( 49 )	0.602 ( 30.2 )	1.22 ( 96.8 )
M8 metabolite concentration, Cycle 1 D15	4.43 ( 553 )	2.30 ( 153 )	2.48 ( 99.7 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All TEAEs occurring during the course of the study.

Adverse event reporting additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Phase 1 - 60mg/m2 (30 Min) Cohort 1

Reporting group description

Patients who received 60mg/m2 over 30 minutes infusion time of EDO-S101

Reporting group title

Phase 1 - 80mg/m2 (30 Min) Cohort 2

Reporting group description

Patients who received 80mg/m2 over 30 minutes infusion time of EDO-S101

Reporting group title

Phase 1 - 100mg/m2 (30 Min) Cohort 3

Reporting group description

Patients who received 100mg/m2 over 30 minutes infusion time of EDO-S101

Reporting group title

Phase 1 - 60mg/m2 (60 Min). Cohort 4

Reporting group description

Patients who received 60mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Phase 1 - 80mg/m2 (60 Min) Cohort 5

Reporting group description

Patients who received who 80mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Phase 1 - 100mg/m2 (60 Min). Cohort 6

Reporting group description

Patients who received who 100mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho

Reporting group description

Patient with relapsed/refractory SCLC who received 80mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort

Reporting group description

Patient with relapsed/refractory STS who received 80mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Phase 2 Relapsed/refractory Triple Negative breast Cancer

Reporting group description

Patient with relapsed/refractory TNBC who received 80mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort

Reporting group description

Reporting group title

Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort

Reporting group description

Patient with relapsed/refractory OC who received 80mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Sub study 1 (SS1)

Reporting group description

Patients who received 60mg/m2 over 60 minutes infusion time of EDO-S101

Reporting group title

Sub study 2 (SS2)

Reporting group description

Patients who received 80mg/m2 over 80 minutes infusion time of EDO-S101

Phase 1 - 60mg/m2 (30 Min) Cohort 1

Phase 1 - 80mg/m2 (30 Min) Cohort 2

Phase 1 - 100mg/m2 (30 Min) Cohort 3

Phase 1 - 60mg/m2 (60 Min). Cohort 4

Phase 1 - 80mg/m2 (60 Min) Cohort 5

Phase 1 - 100mg/m2 (60 Min). Cohort 6

Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho

Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort

Phase 2 Relapsed/refractory Triple Negative breast Cancer

Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort

Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort

Sub study 1 (SS1)

Sub study 2 (SS2)

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 3 (33.33%)

2 / 3 (66.67%)

3 / 3 (100.00%)

5 / 8 (62.50%)

2 / 2 (100.00%)

0 / 4 (0.00%)

6 / 10 (60.00%)

1 / 4 (25.00%)

7 / 12 (58.33%)

4 / 6 (66.67%)

6 / 6 (100.00%)

0 / 7 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Sarcoma

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour pain

subjects affected / exposed

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Deep vein thrombosis

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Multiple organ dysfunction syndrome

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Generalised oedema

subjects affected / exposed

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 4 (25.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Pleural effusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 4 (25.00%)

0 / 12 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Acute respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoxia

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 4 (25.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Pneumothorax

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary alveolar haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Lymphocyte count decreased

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 3 (33.33%)

3 / 8 (37.50%)

1 / 2 (50.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

1 / 4 (25.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

4 / 4

1 / 1

0 / 0

1 / 1

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Platelet count decreased

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 8 (12.50%)

1 / 2 (50.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

1 / 1

0 / 0

1 / 1

3 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Electrocardiogram QT prolonged

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 8 (12.50%)

1 / 2 (50.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Transaminases increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

White blood cell count decreased

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Infusion related reaction

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 4 (25.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute myocardial infarction

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac arrest

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Coronary artery thrombosis

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Syncope

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Thrombocytopenia

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Small intestinal obstruction

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

2 / 12 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ascites

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fistula of small intestine

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhagic ascites

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal perforation

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Intra-abdominal haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Vomiting

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Urinary tract obstruction

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Flank pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Pneumocystis jirovecii pneumonia

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal wall abscess

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Septic shock

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Urinary tract infection

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Failure to thrive

subjects affected / exposed

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase 1 - 60mg/m2 (30 Min) Cohort 1	Phase 1 - 80mg/m2 (30 Min) Cohort 2	Phase 1 - 100mg/m2 (30 Min) Cohort 3	Phase 1 - 60mg/m2 (60 Min). Cohort 4	Phase 1 - 80mg/m2 (60 Min) Cohort 5	Phase 1 - 100mg/m2 (60 Min). Cohort 6	Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) coho	Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort	Phase 2 Relapsed/refractory Triple Negative breast Cancer	Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort	Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort	Sub study 1 (SS1)	Sub study 2 (SS2)
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	8 / 8 (100.00%)	2 / 2 (100.00%)	4 / 4 (100.00%)	10 / 10 (100.00%)	4 / 4 (100.00%)	12 / 12 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 7 (85.71%)
Vascular disorders
Hypotension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	1	0	0
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0
Phlebitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	1	0	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Phlebitis superficial
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Surgical and medical procedures
Sinus operation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	6 / 8 (75.00%)	1 / 2 (50.00%)	1 / 4 (25.00%)	4 / 10 (40.00%)	1 / 4 (25.00%)	3 / 12 (25.00%)	5 / 6 (83.33%)	1 / 6 (16.67%)	2 / 7 (28.57%)
occurrences all number	1	4	2	4	14	1	2	5	2	6	8	1	2
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	2	0	0	1	0	0	1	1	0
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	3 / 12 (25.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	7	0	0	0
Infusion site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	4	0	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	2	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	1	0	0
Face oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0	0	0	0	0	0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0	0
Administration site irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Administration site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Catheter site hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Catheter site related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Infusion site discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Infusion site erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Infusion site reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Injection site discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Mucosal dryness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Catheter site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Pelvic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 7 (28.57%)
occurrences all number	0	0	0	1	2	0	1	1	0	1	1	1	2
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	1	0	3	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	1	0
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1	0
Rhinitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0
Atelectasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Sinus pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 8 (25.00%)	2 / 2 (100.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	2	2	0	1	0	1	1	0	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0	1	1	0	0	0	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	0	0
Anticipatory anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	3 / 12 (25.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	5	3	0	2	3	1	0	0	8	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	1	0	1	0	3	2	1	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	2	0	1	1	0	1	0	1	1
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	2	0	0	0	0	0	0	1	0	1	2	1	2
Blood bilirubin increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	1	0	2	0	0	0	0	1	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	5	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	2	0	0	0	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1	0	0
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Breath sounds abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Respiratory rate increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Weight increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	1	0
Compression fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Radiation necrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Stoma site haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Vulvovaginal injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	2	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Supraventricular tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 8 (25.00%)	1 / 2 (50.00%)	1 / 4 (25.00%)	3 / 10 (30.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	3	2	1	1	2	1	1	3	0	3	2	0	0
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	2	1	0	0	0	0	2	2	0	0
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0	0	0	1	1	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	1	0	0	1	0	0	1	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	0
Ataxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Cerebral haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 8 (37.50%)	1 / 2 (50.00%)	1 / 4 (25.00%)	2 / 10 (20.00%)	2 / 4 (50.00%)	5 / 12 (41.67%)	4 / 6 (66.67%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	4	7	6	16	6	1	1	4	3	7	15	6	0
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	4	0	0	0
Hypereosinophilic syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Cyclic neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0	0	0	0	0	0
Otorrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Tinnitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Eye disorders
Eye swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Exophthalmos
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	1	1	0	0
Diplopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1	0
Retinal detachment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0	0
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Dental caries
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Enteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Gingival pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Large intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Proctalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Retching
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Toothache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Flatulence
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Food poisoning
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	1	0	0
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	1	0	0	0	1	0	0	1	0	0	0	1	1
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	1	1	0	0	0	3	2	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	2 / 10 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	1	1	2	0	0	2	0	0	2	0	0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)	1 / 4 (25.00%)	5 / 12 (41.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	1	1	1	8	1	2	0
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)	2 / 4 (50.00%)	3 / 12 (25.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	2	2	0	0	2	1	1	2	3	4	3	1	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	1	1	1	0	0	0	0	2	0	0	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	1	0	1	0	0	0	1	0	1
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	4	0	0	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	2 / 10 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Dry skin
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Skin discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Swelling face
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0	0	0	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Hydronephrosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 7 (28.57%)
occurrences all number	0	0	0	2	1	0	0	0	0	3	4	1	2
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1	0	0	0	2	0	3	1	1
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	2 / 4 (50.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	4	3	0	0	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	0	0	1	0	1	0	1	1
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	1	0	1	0	0	0	0	0	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	1	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0	0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0	0
Arthritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Limb discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Synovial cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	1	1	0	0	0
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0
Abscess neck
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Chronic sinusitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Clostridium difficile infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Corona virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Enterobacter bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Nail infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Pelvic abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Rhinitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 8 (37.50%)	1 / 2 (50.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)	1 / 4 (25.00%)	2 / 12 (16.67%)	4 / 6 (66.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	1	0	1	3	1	2	1	1	3	4	0	0
Hypokalaemia
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	4	1	1	1	1	1	0	0	0	5	3	2	0
Dehydration
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	3	0	0	0	5	0	0	1	1	1	1	1	0
Hypomagnesaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	4 / 12 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	2	0	0	1	1	0	0	0	0	7	1	1	0
Hypoalbuminaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	3	1	2	0	0	0	0	2	0	0
Hyponatraemia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	3	0	0	1	0	0	0	0	0	0	3	0	0
Hypocalcaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	4	0	0	0	0	0	0	0	0
Hyperglycaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	0	0
Hyperkalaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0	0	0
Hypophosphataemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0
Acidosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

31 Oct 2018

Amendment 1: Protocol version 4.0 Reason for Changes: Added the RP2D determined in Phase 1 and Updated the Phase 2 sections in the protocol. Description of Changes:  Clarified Phase 2 primary objective and efficacy evaluation time points.  Added a fifth subject cohort (endometrial cancer) and eligibility requirements.  Clarified that treatment could continue until progression, intolerable toxicity, or until CR has been achieved.  Changed patient eligibility to allow recovery to ≤ Grade 2 for neuropathy or other endocrinopathies from prior treatment. Clarified the inclusion eligibility for GIST subjects  Added allopurinol as a prohibitive medication. Pre-treatment with allopurinol was contraindicated.  Changed drug preparation instructions to reflect new, higher concentration of the drug product.  Added window of +5 minutes to drug infusion duration.

04 Feb 2019

Amendment 2: Protocol version 5.0 Reason for changes: Updated the Phase 2 sections in the protocol. Description of Changes:  Added a statement (underline text) to the inclusion criteria: Must have received at least one line of chemotherapy and no other standard therapy with proven clinical benefit is available or recommended based on the Investigator’s individual risk-benefit assessment for the subject.  Clarified for TNBC subjects that HER2 negative needed to be proven by immunohistochemistry or in situ hybridization per ASCO-CAP guidelines.  Clarified the timing of the pre-dose ECG assessment and the pre-dose PK sample collection.  Clarified Phase 2 criteria for subjects to receive subsequent treatment after Cycle 1, and the option to dose reduce in case of safety concerns.  Clarified that a second serotonin 5-HT3 receptor antagonist, granisetron (Kytril), was acceptable for the prophylaxis of delayed nausea and vomiting

28 Jan 2020

Amendment 3: Protocol version 6.0 Reason for Changes: Updated the Phase 2 sections in the protocol. Implemented Risk Mitigation Measures related to possible QTc prolongations. Description of Changes:  Limited study treatment to a maximum of 12 cycles.  Implemented strict guidelines on methods of contraception for subjects of childbearing potential.  Specified that the subject population eligible for the study were subjects who have been progressing or relapsing after their previous treatment.  Specified that the subject could withdraw from study for any reason.  Specified that the Sponsor would continuously assess the benefit-risk ratio for subject safety and discontinue treatment if deemed necessary.  Specified that a separate ICF was needed for gene expression sample collection.  Specified that blood samples for laboratory tests were needed to be taken before the start of study drug administration.  Clarified reporting of TEAEs, SAEs and Suspected Unexpected Serious Adverse Reactions.

08 Apr 2020

Amendment 4: Protocol version 6.2. Reason for Changes: Requested by the FDA. Description of Changes: Created a separate protocol for Sub-study 1 to characterize the effect of tinostamustine 60 mg/m2 infused over 60 minutes on cardiac repolarization (QTc) and other ECG parameters.

05 Sep 2020

Amendment 5: Protocol version 7.0. Description of Changes:  Added centres in Europe.  Each cohort could treat an additional 19 subjects (29 in total) if there was evidence of 2 successes in that cohort.  Dose reduction to 60 mg/m2 in case of safety concerns.  Allowed to reintroduce the initial dose if toxicity issues were resolved and specified that a subject must be withdrawn if she/he did not tolerate the reduced dose.  Clarifications to the general inclusion criteria for phase 1 and phase 2 of the trial.  Clarifications to cohort specific eligibility criteria.  Clarifications to the schedule of assessments.  Guidance on IMP administration.  Clarifications on reporting of AEs, SAEs and pregnancies.

27 Sep 2020

Amendment 6: Protocol version 7.1. Reason for Changes: Updated the Phase 2 sections in the protocol. Description of Changes:  Added “Life expectancy > 3 months” to the inclusion criteria.  Exclude subjects being treated with valproic acid from the study.  Excluded MMMT from the study.  Deleted the paragraph on replacement of subjects  Specified that serum potassium and magnesium should be at least at the LLN before the start of study drug infusion.  Specified that clinically significant laboratory findings must be recorded as AEs.  Specified that PD itself and death from PD should not be recorded as an AE.

22 Mar 2021

Amendment 7: Protocol version 7.2. Reason for Changes: Followed the Clinical Trials Facilitation group’s guidance, which was updated in September 2020, on contraception to be used for investigational drugs that have demonstrated genotoxicity. Description of Changes: Contraceptive measures for women of childbearing potential were extended from 90 days to 6 months after the last study drug administration.

02 Apr 2021

Amendment 8: Protocol version 8.0. Reason for Changes: Updated the Phase 2 sections in the protocol. Description of Changes:  Noted the halting the recruitment into the cohorts for TNBC and endometrial cancer.  Update the washout period of previous anticancer therapies from 3 weeks to 28 days.  Updated the washout period of other investigational agents from 30 days or 5 half-lives to 28 days prior to first dose of tinostamustine.  Update the allowable elapsed time since prior treatment from at least 3 weeks to at least 28 days.  Added that platelets must be ≥ 100,000 /μL without platelet transfusion within the 14 days before Day 1 of Cycle 1.  Updated the allowable window for the collection of blood samples on Days 1 and 15 from ±2 days to -2 days.  Updated the allowable window for the collection of the 60-minute PK sample from ±5 minutes to -5 minutes  Clarified that all PK sample times should be calculated from the start of the tinostamustine infusion.  Updated the storage instructions for the diluted solution of study drug, in line with the latest Investigator’s Brochure dated 19 March 2021.  Updated the criteria for continuing study drug to reduce the rate of thrombocytopenia leading to study discontinuation.  Clarified the allowable supportive care for subjects.

10 May 2021

Amendment 9: Protocol version 8.1. Reason for Changes: Corrected changes erroneously made in Protocol Version 8.0. Description of Changes: Corrected to revert the removal of the relapsed/refractory TNBC and relapsed/refractory endometrial cancer cohorts from the safety analysis.

12 Jul 2021

Amendment 10: Protocol version 6.3. Reason for Changes: Completed Sub-study 1 safely. Description of Changes:  Created a separate protocol for Sub-study 2 to characterize the effect of tinostamustine 80 mg/m2 infused over 80 minutes on cardiac repolarization (QTc) and other ECG parameters.  Updated some sections to be aligned with the latest protocol for Phase 2 (version 8.1).  Amended the wording of the secondary objective to state more clearly ‘determine plasma concentrations.’  Removed the exploratory objective for gene expression analysis as tumour samples were not collected in Sub-study 2.  Allowed additional subjects to be recruited up to 12 in total.  Amended the stopping rules to be more specific and to separate stopping rules for individual subject’s treatment and those for the whole study.  Clarified that the subject should stay in the unit until the QTcF decreased to ≤ 450ms.  Amended the timepoints for Holter readings and PK sampling to include more timepoints during study drug infusion and to align with a change in infusion duration of 80 minutes

11 Aug 2021

Amendment 11: Protocol version 6.4. Reason for Change: Requested by the FDA. Description of Changes: Amended the stopping rules as per the following FDA comments:  Add to the study stopping rules that for any treatment-related death, the study would be stopped.  Add that for a specified rate or number of Grade 3 or higher QT prolongation (i.e. 2 subjects), the study would be stopped.  Add to the dose modification guidelines, that for Grade 4 non-haematologic toxicity, the subject would be discontinued from further treatment.

18 Aug 2021

Amendment 12: Protocol version 6.5. Reason for Changes: Requested by the FDA. Description of Changes: Amended the inclusion criteria as per the following FDA comments:  Revise the renal function inclusion criterion to specify creatinine clearance (CLcr) is utilized rather than serum creatinine and specify a consistent and appropriately validated prediction equation in adults is used for the estimation of eGFR (e.g., Cockcroft-Gault for CLcr or Modification of Diet in Renal Disease method).  Revise the hepatic function inclusion criterion for total bilirubin to be expressed as multiples of ULN.

14 Feb 2023

Amendment 13: Protocol version 6.7 Reason for Changes: Updated the protocol for Sub-study 2. Description of Changes: Changed the follow-up overall survival period to a maximum of 12 months.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
04 Jun 2019	QTc prolongation was noted in separate study with Tinostamustin administered at high dose ( 180 or 220mg/m2 over 1hr). Although the QTc prolongations were transient and asymptomatic, the Sponsor terminated the EDO-S101-1004 study and decided not to pursue further development of high-dose tinostamustine. The Sponsor decided to conduct an in-depth analysis of clinically relevant ECG findings and a consequential benefit-risk assessment. Subject recruitment in the US sites for the EDO-S101-1002 study (this phase 1/2 study) was set on hold as a consequence of the Partial Clinical Hold Letter issued by the Food and Drug Administration (FDA) on 03 June 2019. The FDA requested that the Sponsor perform additional studies to better characterise the effect of tinostamustine on cardiac repolarization (QTc). After the benefit-risk assessment, the protocol was amended to include more intense ECG and PK collection in order to allow a precise characterization of the effects of tinostamustine on QTc and other ECG parameters, at the dosages being investigated for the treatment of solid tumours. QTc prolongations were also defined as AEs of special interest. Consequently, 2 sub-studies were planned for and conducted. The hold was lifted in the US for the 60mg/m2 over 60min substudy 1 and 80mg/m2 over 80min. The phase 2 of the study could be carried out in non-US sites.	09 Apr 2020

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

No applicable

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Clinical Benefit Response Rate in Selected Solid Tumor Cohorts on Phase 2

Primary: Clinical Benefit Response Rate in Selected Solid Tumor Cohorts on Phase 2

Primary: Highest Change From Baseline in QTcF in Sub-studies

Primary: Highest Change From Baseline in QTcF in Sub-studies

Primary: Number of participants with treatment-related adverse events as assessed by CTCAE V4.03 on Phase 1

Primary: Number of participants with treatment-related adverse events as assessed by CTCAE V4.03 on Phase 1

Secondary: Safety Population With Treatment-related Adverse Events on Phase 2 and Sub Studies

Secondary: Safety Population With Treatment-related Adverse Events on Phase 2 and Sub Studies

Secondary: Duration of stable disease (SD) that persists for at least 4 months in selected solid tumor cohorts on Sub studies

Secondary: Duration of stable disease (SD) that persists for at least 4 months in selected solid tumor cohorts on Sub studies

Secondary: Objective Response Rate (ORR) and the clinical benefit rate (CBR) that persists for at least four (4) months in selected solid tumor cohorts on Sub studies

Secondary: Objective Response Rate (ORR) and the clinical benefit rate (CBR) that persists for at least four (4) months in selected solid tumor cohorts on Sub studies

Secondary: To Determine the Duration of Response (DoR) time for Phase 2 and Sub Studies

Secondary: To Determine the Duration of Response (DoR) time for Phase 2 and Sub Studies

Secondary: To Determine the Overall Survival (OS) Time for Phase 2 and Sub Studies

Secondary: To Determine the Overall Survival (OS) Time for Phase 2 and Sub Studies

Secondary: Maximum Plasma Concentration (Cmax) in Phase 2 and Sub Studies

Secondary: Maximum Plasma Concentration (Cmax) in Phase 2 and Sub Studies

Secondary: Progression Free Survival (PFS) Time for Phase 2 and Sub Studies

Secondary: Progression Free Survival (PFS) Time for Phase 2 and Sub Studies

Secondary: Area Under the Curve [AUC(0-t)] in Phase 2 and Sub Studies.

Secondary: Area Under the Curve [AUC(0-t)] in Phase 2 and Sub Studies.

Secondary: Summary of Tmax in in Phase 2 and Sub Studies.

Secondary: Summary of Tmax in in Phase 2 and Sub Studies.

Secondary: Clearance of Tinostamustine and Metabolites in Phase 2 and Substudies

Secondary: Clearance of Tinostamustine and Metabolites in Phase 2 and Substudies

Secondary: Summary of Half-life of Tinostamustine in Phase 2 and Substudies

Secondary: Summary of Half-life of Tinostamustine in Phase 2 and Substudies

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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