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Clinical Trial Results:
A phase I/II study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) antibody-radionuclide-conjugate for treatment of relapsed non-Hodgkin lymphoma.

Summary
EudraCT number	2011-000033-36
Trial protocol	SE GB IT CZ AT FR ES HR HU IE DK FI DE NL BE
Global end of trial date	27 Oct 2022

Results information
Results version number	v1(current)
This version publication date	16 Apr 2023
First version publication date	16 Apr 2023
Other versions

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

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Trial information

Top of page

Sponsor protocol code

LYMRIT-37-01

ISRCTN number

US NCT number

NCT01796171

WHO universal trial number (UTN)

Sponsor organisation name

Nordic Nanovector

Sponsor organisation address

Kjelsåsveien 168B, N-0884 , Oslo, Norway,

Public contact

Information Desk, Nordic Nanovector ASA, +47 22183301, mail@nordicnanovector.com

Scientific contact

Information Desk, Nordic Nanovector ASA, +47 22183301, mail@nordicnanovector.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

31 Jan 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Oct 2022

Global end of trial reached?

Yes

Global end of trial date

27 Oct 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

Part A: Phase I (Arms 1, 2, 3, 4, and 5): To define MTD of Betalutin Phase IIa: To explore tumour response rates in patients receiving Betalutin. Part B Phase IIb Overall response rate

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. A Safety Review Committee reviewed and monitored the safety of participants on on ongoing basis and at pre-defined timepoints, to recommend appropriate actions at the pre-defined timepoints of dose adjustment and to support the identification of the MTD

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Dec 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Norway: 39

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

United Kingdom: 45

Country: Number of subjects enrolled

Croatia: 3

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Czechia: 13

Country: Number of subjects enrolled

Denmark: 4

Country: Number of subjects enrolled

Finland: 5

Country: Number of subjects enrolled

France: 13

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Hungary: 6

Country: Number of subjects enrolled

Ireland: 8

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Israel: 2

Country: Number of subjects enrolled

Turkey: 3

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

United States: 7

Country: Number of subjects enrolled

Singapore: 1

Worldwide total number of subjects

191

EEA total number of subjects

125

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

124

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Participants were screened in the 2-4 weeks before receiving rituximab (according to protocol version). They received rituximab on Days -28 and -21 or Day -14 prior to treatment with lilotomab and Betalutin on Day 0.

Period 1 title

Enrolled

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

Note: Parts A and C were non-randomised and open label . Part B was blinded for the first 47 participants, participants were randomly allocated to 40/15 or 100/20. Following an interim analysis, dosing with 100/20 was stopped and all subsequent dosing was non randomised.

All participants enrolled

Arm description

Arm type

Pre-treatment

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	All participants enrolled
Started	191
Completed	190
Not completed	1
Death	1

Period 2 title

Received rituximab

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

All participants treated

Arm description

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 375 mg/m2 rituximab pre-treatment by intravenous infusion either 28 and 21 days or 14 days prior to lilotomab and Betalutin on Day 0

Number of subjects in period 2	All participants treated
Started	190
Completed	187
Not completed	3
Consent withdrawn by subject	1
Adverse event, non-fatal	2

Period 3 title

Received lilotomab and Betalutin

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Part A Arm 1 40 mg/10 MBq

Arm description

10 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 10 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 40 mg lilotomab by intravenous infusion

Part A Arm 1 40 mg/15 MBq

Arm description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 15 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 40 mg lilotomab by intravenous infusion

Part A Arm 1 40 mg/20 MBq

Arm description

20 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 20 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 40 mg lilotomab by intravenous infusion

Part A Arm 2 No pre-dosing/10 MBq

Arm description

10 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 10 MBq/kg Betalutin by slow bolus intravenous injection

Part A Arm 2 No pre-dosing/15 MBq

Arm description

15 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 15 MBq/kg Betalutin by slow bolus intravenous injection

Part A Arm 3 RTX pre-dosing/15 MBq

Arm description

15 MBq/kg Betalutin with rituximab pre-dosing. Participants were also pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 15 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 375 mg/m2 based on body surface area

Part A Arm 4 100mg/m2/15 MBq

Arm description

15 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 15 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 100 mg/m2 lilotomab by intravenous infusion

Part A Arm 4 100mg/m2/20 MBq

Arm description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 20 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 100 mg/m2 lilotomab by intravenous infusion

Part A Arm 5 60 mg/m2/20 MBq

Arm description

20 MBq/kg Betalutin with 60 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 20 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 60 mg/m2 lilotomab by intravenous infusion

Part B 40 mg/15 MBq

Arm description

15 MBq/kg Betalutin with 40 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 15 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 40 mg lilotomab by intravenous infusion

Part B 100 mg/m2/20 MBq

Arm description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 20 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 100 mg/m2 lilotomab by intravenous infusion

Part B 40 mg/12.5 MBq

Arm description

12.5 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 12.5 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 40 mg lilotomab by intravenous infusion

Part C 40 mg/15 MBq

Arm description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Arm type

Experimental

Investigational medicinal product name

Betalutin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Participants received 15 MBq/kg Betalutin by slow bolus intravenous injection

Investigational medicinal product name

Lilotomab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 40 mg lilotomab by intravenous infusion

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: The baseline period for reporting demographics and baseline variables is the patients who received lilotomab and Betalutin. Rituximab pre-treatment was also given. The number enrolled includes all patients allocated to treatment. One was randomised but not treated and 3 received rituximab pre-treatment but not lilotomab and Betalutin so these 4 are not in the baseline period

Number of subjects in period 3 ^[2]	Part A Arm 1 40 mg/10 MBq	Part A Arm 1 40 mg/15 MBq	Part A Arm 1 40 mg/20 MBq	Part A Arm 2 No pre-dosing/10 MBq	Part A Arm 2 No pre-dosing/15 MBq	Part A Arm 3 RTX pre-dosing/15 MBq	Part A Arm 4 100mg/m2/15 MBq	Part A Arm 4 100mg/m2/20 MBq	Part A Arm 5 60 mg/m2/20 MBq	Part B 40 mg/15 MBq	Part B 100 mg/m2/20 MBq	Part B 40 mg/12.5 MBq	Part C 40 mg/15 MBq
Started	4	36	3	1	2	3	3	18	4	72	28	9	4
Completed	4	35	3	1	2	3	3	18	3	61	25	8	4
Not completed	0	1	0	0	0	0	0	0	1	11	3	1	0
Physician decision	-	-	-	-	-	-	-	-	-	5	1	1	-
Consent withdrawn by subject	-	-	-	-	-	-	-	-	-	1	1	-	-
Death	-	-	-	-	-	-	-	-	-	2	-	-	-
Start of further anticancer therapy	-	-	-	-	-	-	-	-	1	1	1	-	-
Progressive disease	-	1	-	-	-	-	-	-	-	-	-	-	-
Sponsor decision	-	-	-	-	-	-	-	-	-	2	-	-	-

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The baseline period for reporting demographics and baseline variables is the patients who received lilotomab and Betalutin. Rituximab pre-treatment was also given. The number enrolled includes all patients allocated to treatment. One was randomised but not treated and 3 received rituximab pre-treatment but not lilotomab and Betalutin so these 4 are not in the baseline period

Period 4 title

Follow-up period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A Arm 1 40 mg/10 MBq

Arm description

Follow-up of participants receiving 40 mg lilotomab and 10 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 1 40 mg/15 MBq

Arm description

Follow-up of participants receiving 40 mg lilotomab and 15 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 1 40 mg/20 MBq

Arm description

Follow-up of participants receiving 40 mg lilotomab and 20 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 2 10 MBq No pre-dosing

Arm description

Follow-up of participants receiving 10 MBq/kg Betalutin with no pre-dosing

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 2 15 MBq/No pre-dosing

Arm description

Follow-up of participants receiving 15 MBq/kg Betalutin with no pre-dosing

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 3 RTX pre-dosing/15 MBq

Arm description

Follow-up of participants receiving rituximab pre-dosing and 15 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 4 100mg/m2/15 MBq

Arm description

Follow-up of participants receiving 100 mg/m2 lilotomab and 15 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 4 100 mg/m2/20 MBq

Arm description

Follow-up of participants receiving 100 mg/m2 lilotomab and 20 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A Arm 5 60 mg/m2/20 MBq

Arm description

Follow-up of participants receiving 60 mg/m2 lilotomab and 20 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part B 40 mg/15 MBq

Arm description

Follow-up of participants receiving 40 mg lilotomab and 15 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part B 100 mg/m2/20 MBq

Arm description

Follow-up of participants receiving 100 mg/m2 lilotomab and 20 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part B 40 mg/12.5 MBq

Arm description

Follow-up of participants receiving 40 mg lilotomab and 12.5 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part C 40 mg/15 MBq

Arm description

Follow-up of participants receiving 40 mg lilotomab and 15 MBq/kg Betalutin

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 4	Part A Arm 1 40 mg/10 MBq	Part A Arm 1 40 mg/15 MBq	Part A Arm 1 40 mg/20 MBq	Part A Arm 2 10 MBq No pre-dosing	Part A Arm 2 15 MBq/No pre-dosing	Part A Arm 3 RTX pre-dosing/15 MBq	Part A Arm 4 100mg/m2/15 MBq	Part A Arm 4 100 mg/m2/20 MBq	Part A Arm 5 60 mg/m2/20 MBq	Part B 40 mg/15 MBq	Part B 100 mg/m2/20 MBq	Part B 40 mg/12.5 MBq	Part C 40 mg/15 MBq
Started	4	35	3	1	2	3	3	18	3	61	25	8	4
Completed	0	5	1	0	0	0	1	0	1	0	0	0	0
Not completed	4	30	2	1	2	3	2	18	2	61	25	8	4
Physician decision	-	2	-	-	-	-	-	-	-	4	-	-	1
Consent withdrawn by subject	-	1	-	-	-	1	-	-	-	3	1	-	-
Death	-	-	-	-	-	-	1	-	-	17	9	1	-
Participant transferred to other hospital	-	1	-	-	-	-	-	-	-	-	-	-	-
Start of further anticancer therapy	4	25	2	1	2	2	1	15	2	-	-	-	-
Progressive disease	-	1	-	-	-	-	-	3	-	-	-	-	-
Sponsor decision	-	-	-	-	-	-	-	-	-	37	15	7	3

Baseline characteristics

Top of page

Reporting group title

Part A Arm 1 40 mg/10 MBq

Reporting group description

10 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 1 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 1 40 mg/20 MBq

Reporting group description

20 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 2 No pre-dosing/10 MBq

Reporting group description

10 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 2 No pre-dosing/15 MBq

Reporting group description

15 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 3 RTX pre-dosing/15 MBq

Reporting group description

15 MBq/kg Betalutin with rituximab pre-dosing. Participants were also pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 4 100mg/m2/15 MBq

Reporting group description

15 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 4 100mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 5 60 mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 60 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part B 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part B 100 mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part B 40 mg/12.5 MBq

Reporting group description

12.5 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part C 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group values	Part A Arm 1 40 mg/10 MBq	Part A Arm 1 40 mg/15 MBq	Part A Arm 1 40 mg/20 MBq	Part A Arm 2 No pre-dosing/10 MBq	Part A Arm 2 No pre-dosing/15 MBq	Part A Arm 3 RTX pre-dosing/15 MBq	Part A Arm 4 100mg/m2/15 MBq	Part A Arm 4 100mg/m2/20 MBq	Part A Arm 5 60 mg/m2/20 MBq	Part B 40 mg/15 MBq	Part B 100 mg/m2/20 MBq	Part B 40 mg/12.5 MBq	Part C 40 mg/15 MBq	Total
Number of subjects	4	36	3	1	2	3	3	18	4	72	28	9	4	187
Age categorical
Age at the time of informed consent
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	2	11	1	0	0	0	1	4	1	26	9	4	3	62
From 65-84 years	2	25	2	1	2	2	2	14	3	45	19	4	1	122
85 years and over	0	0	0	0	0	1	0	0	0	1	0	1	0	3
Gender categorical
Units: Subjects
Female	1	19	0	0	1	2	0	8	2	43	16	3	3	98
Male	3	17	3	1	1	1	3	10	2	29	12	6	1	89

End points

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Reporting group title

All participants enrolled

Reporting group description

Reporting group title

All participants treated

Reporting group description

Reporting group title

Part A Arm 1 40 mg/10 MBq

Reporting group description

10 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 1 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 1 40 mg/20 MBq

Reporting group description

20 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 2 No pre-dosing/10 MBq

Reporting group description

10 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 2 No pre-dosing/15 MBq

Reporting group description

15 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 3 RTX pre-dosing/15 MBq

Reporting group description

15 MBq/kg Betalutin with rituximab pre-dosing. Participants were also pre-treated with rituximab on Days -28 and -21 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 4 100mg/m2/15 MBq

Reporting group description

15 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 4 100mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 5 60 mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 60 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part B 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part B 100 mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part B 40 mg/12.5 MBq

Reporting group description

12.5 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part C 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14 prior to lilotomab and Betalutin on Day 0

Reporting group title

Part A Arm 1 40 mg/10 MBq

Reporting group description

Follow-up of participants receiving 40 mg lilotomab and 10 MBq/kg Betalutin

Reporting group title

Part A Arm 1 40 mg/15 MBq

Reporting group description

Follow-up of participants receiving 40 mg lilotomab and 15 MBq/kg Betalutin

Reporting group title

Part A Arm 1 40 mg/20 MBq

Reporting group description

Follow-up of participants receiving 40 mg lilotomab and 20 MBq/kg Betalutin

Reporting group title

Part A Arm 2 10 MBq No pre-dosing

Reporting group description

Follow-up of participants receiving 10 MBq/kg Betalutin with no pre-dosing

Reporting group title

Part A Arm 2 15 MBq/No pre-dosing

Reporting group description

Follow-up of participants receiving 15 MBq/kg Betalutin with no pre-dosing

Reporting group title

Part A Arm 3 RTX pre-dosing/15 MBq

Reporting group description

Follow-up of participants receiving rituximab pre-dosing and 15 MBq/kg Betalutin

Reporting group title

Part A Arm 4 100mg/m2/15 MBq

Reporting group description

Follow-up of participants receiving 100 mg/m2 lilotomab and 15 MBq/kg Betalutin

Reporting group title

Part A Arm 4 100 mg/m2/20 MBq

Reporting group description

Follow-up of participants receiving 100 mg/m2 lilotomab and 20 MBq/kg Betalutin

Reporting group title

Part A Arm 5 60 mg/m2/20 MBq

Reporting group description

Follow-up of participants receiving 60 mg/m2 lilotomab and 20 MBq/kg Betalutin

Reporting group title

Part B 40 mg/15 MBq

Reporting group description

Follow-up of participants receiving 40 mg lilotomab and 15 MBq/kg Betalutin

Reporting group title

Part B 100 mg/m2/20 MBq

Reporting group description

Follow-up of participants receiving 100 mg/m2 lilotomab and 20 MBq/kg Betalutin

Reporting group title

Part B 40 mg/12.5 MBq

Reporting group description

Follow-up of participants receiving 40 mg lilotomab and 12.5 MBq/kg Betalutin

Reporting group title

Part C 40 mg/15 MBq

Reporting group description

Follow-up of participants receiving 40 mg lilotomab and 15 MBq/kg Betalutin

Primary: Part A Phase I: To define the Maximum Tolerated Dose (MTD)

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End point title

Part A Phase I: To define the Maximum Tolerated Dose (MTD) ^[1] ^[2]

End point description

To define the MTD of Betalutin as assessed by the number of participants with dose limiting toxicities (DLTs) in Part A Phase I Note: the DLT in reporting group 7 (40 mg lilotomab/15 MBq/kg Betalutin) meeting the criterion ‘failure of platelets or neutrophils to recover to Grade 1 by 12 weeks after treatment’ was identified retrospectively after dose escalation had occurred

End point type

Primary

End point timeframe

12 weeks after Betalutin

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: The study followed a standard 3+3 design to determine the MTD of Betalutin. No statistical analysis was appropriate in this small number of participants
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for all participants in Phase Ia are reported. This part of the study assessed the MTD for expansion in Phase IIa

End point values	Part A Arm 1 40 mg/10 MBq	Part A Arm 1 40 mg/15 MBq	Part A Arm 1 40 mg/20 MBq	Part A Arm 2 No pre-dosing/10 MBq	Part A Arm 2 No pre-dosing/15 MBq	Part A Arm 3 RTX pre-dosing/15 MBq	Part A Arm 4 100mg/m2/15 MBq	Part A Arm 4 100mg/m2/20 MBq	Part A Arm 5 60 mg/m2/20 MBq
Number of subjects analysed	4	6	3	1	2	3	3	6	3
Units: Number of participants	0	1	3	0	2	1	1	1	0

No statistical analyses for this end point

Primary: Part A Phase IIa: To explore tumour response rates in FL

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End point title

Part A Phase IIa: To explore tumour response rates in FL ^[3] ^[4]

End point description

To explore tumour response rates in Phase IIa patients with follicular lymphoma receiving Betalutin according to Cheson et al, 2007 (combining morphological and metabolic responses) based on evaluation of CT scan images including PET/CT imaging (and bone marrow biopsy if applicable).

End point type

Primary

End point timeframe

3 months to 5 years

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The purpose of Part IIa was to select doses for further investigation in Part B. Both doses were selected, therefore a statistical analysis was not considered appropriate in this small number of participants
[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: The study was conducted in several parts. The endpoint reports results for all participants in Part IIa with FL as encouraging efficacy was seen in these participants. Data in Phase IIa participants without FL were not summarised

End point values	Part A Arm 1 40 mg/15 MBq	Part A Arm 4 100mg/m2/20 MBq
Number of subjects analysed	18	9
Units: Number of participants
Complete remission	7	2
Partial remission	5	6
Stable disease	3	1
Progressive disease	3	0

No statistical analyses for this end point

Primary: Part B: Phase IIb

Top of page

End point title

Part B: Phase IIb ^[5] ^[6]

End point description

Overall response rate defined as the number of participants with a best response of complete remission or partial remission at any time according to Cheson, 2014.

End point type

Primary

End point timeframe

3 months to 5 years

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: Following an interim analysis, the 40/15 dose only was selected for evaluation, therefore no statistical analysis was deemed appropriate
[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: The study was conducted in several parts. The endpoint reports results for all participants in Part B

End point values	Part B 40 mg/15 MBq	Part B 100 mg/m2/20 MBq
Number of subjects analysed	72	28
Units: Number of participants	28	9

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All adverse events were collected up to 12 weeks after Betalutin administration. Treatment-related adverse events were collected up to 5 years (end of the study)

Adverse event reporting additional description

Adverse events are reported for all participants who received rituximab, lilotomab and Betalutin from the time of lilotomab and Betalutin administration (Day 0) onwards

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Part A Arm 1 40 mg/10 MBq

Reporting group description

10 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21

Reporting group title

Part A Arm 1 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21

Reporting group title

Part A Arm 1 40 mg/20 MBq

Reporting group description

20 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21

Reporting group title

Part A Arm 2 No pre-dosing/10 MBq

Reporting group description

10 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21

Reporting group title

Part A Arm 2 No pre-dosing/15 MBq

Reporting group description

15 MBq/kg Betalutin with no pre-dosing. Participants were pre-treated with rituximab on Days -28 and -21

Reporting group title

Part A Arm 3 RTX pre-dosing/15 MBq

Reporting group description

15 MBq/kg Betalutin with rituximab pre-dosing. Participants were also pre-treated with rituximab on Days -28 and -21

Reporting group title

Part A Arm 4 100mg/m2/15 MBq

Reporting group description

15 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14

Reporting group title

Part A Arm 4 100mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14

Reporting group title

Part A Arm 5 60 mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 60 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14

Reporting group title

Part B and C 40 mg/15 MBq

Reporting group description

15 MBq/kg Betalutin with 40 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14

Reporting group title

Part B 100 mg/m2/20 MBq

Reporting group description

20 MBq/kg Betalutin with 100 mg/m2 lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14

Reporting group title

Part B 40 mg/12.5 MBq

Reporting group description

12.5 MBq/kg Betalutin with 40 mg lilotomab pre-dosing. Participants were pre-treated with rituximab on Day - 14

Part A Arm 1 40 mg/10 MBq

Part A Arm 1 40 mg/15 MBq

Part A Arm 1 40 mg/20 MBq

Part A Arm 2 No pre-dosing/10 MBq

Part A Arm 2 No pre-dosing/15 MBq

Part A Arm 3 RTX pre-dosing/15 MBq

Part A Arm 4 100mg/m2/15 MBq

Part A Arm 4 100mg/m2/20 MBq

Part A Arm 5 60 mg/m2/20 MBq

Part B and C 40 mg/15 MBq

Part B 100 mg/m2/20 MBq

Part B 40 mg/12.5 MBq

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 4 (25.00%)

6 / 36 (16.67%)

2 / 3 (66.67%)

0 / 1 (0.00%)

2 / 2 (100.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

0 / 4 (0.00%)

12 / 76 (15.79%)

7 / 28 (25.00%)

0 / 9 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Chronic myelomonocytic leukaemia

Additional description: Occurrences related to treatment have been recorded as those related to Betalutin

subjects affected / exposed

1 / 4 (25.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

deaths causally related to treatment / all

1 / 1

0 / 0

Non-Hodgkin's lymphoma

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Lung adenocarcinoma

subjects affected / exposed

0 / 4 (0.00%)

1 / 36 (2.78%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peritoneal neoplasm

subjects affected / exposed

0 / 4 (0.00%)

1 / 36 (2.78%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Prostate cancer

subjects affected / exposed

0 / 4 (0.00%)

1 / 36 (2.78%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Basal cell carcinoma

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lentigo maligna

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of skin

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Adenocarcinoma pancreas

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Breast cancer

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myelodysplastic syndrome

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Endometrial cancer

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

1 / 28 (3.57%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Malaise

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

1 / 28 (3.57%)

0 / 9 (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

Epistaxis

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

1 / 3 (33.33%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

1 / 4 (25.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

2 / 76 (2.63%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Platelet count decreased

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

1 / 3 (33.33%)

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (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

Neutrophil count decreased

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (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

Sternal fracture

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Radiation pneumonitis

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Atrial fibrillation

subjects affected / exposed

0 / 4 (0.00%)

2 / 36 (5.56%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Presyncope

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

1 / 28 (3.57%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Febrile neutropenia

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenia

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Ileal perforation

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

1 / 28 (3.57%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Nephrolithiasis

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Pharyngitis

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (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

1 / 4 (25.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

1 / 28 (3.57%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (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

Urinary tract infection

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenic sepsis

subjects affected / exposed

0 / 4 (0.00%)

1 / 36 (2.78%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

1 / 28 (3.57%)

0 / 9 (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

Pleural infection bacterial

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fungaemia

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Rhinovirus infection

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tooth abscess

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

1 / 28 (3.57%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Herpes zoster

alternative dictionary used: MedDRA 25.1

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

0 / 4 (0.00%)

1 / 76 (1.32%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 4 (0.00%)

0 / 36 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

0 / 4 (0.00%)

0 / 76 (0.00%)

0 / 28 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Part A Arm 1 40 mg/10 MBq	Part A Arm 1 40 mg/15 MBq	Part A Arm 1 40 mg/20 MBq	Part A Arm 2 No pre-dosing/10 MBq	Part A Arm 2 No pre-dosing/15 MBq	Part A Arm 3 RTX pre-dosing/15 MBq	Part A Arm 4 100mg/m2/15 MBq	Part A Arm 4 100mg/m2/20 MBq	Part A Arm 5 60 mg/m2/20 MBq	Part B and C 40 mg/15 MBq	Part B 100 mg/m2/20 MBq	Part B 40 mg/12.5 MBq
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 4 (75.00%)	36 / 36 (100.00%)	3 / 3 (100.00%)	0 / 1 (0.00%)	2 / 2 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	16 / 18 (88.89%)	4 / 4 (100.00%)	61 / 76 (80.26%)	22 / 28 (78.57%)	9 / 9 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's lymphoma
subjects affected / exposed	1 / 4 (25.00%)	3 / 36 (8.33%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)	2 / 4 (50.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	3	0	0	0	0	0	2	2	0	0	0
Follicular lymphoma
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0	0	0
Basal cell carcinoma
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Vascular disorders
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	3 / 76 (3.95%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	3	1	0
Haematoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	1 / 76 (1.32%)	1 / 28 (3.57%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	2	1
Hot flush
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 4 (25.00%)	2 / 36 (5.56%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)	0 / 4 (0.00%)	8 / 76 (10.53%)	3 / 28 (10.71%)	2 / 9 (22.22%)
occurrences all number	1	2	1	0	0	0	0	2	0	8	3	2
Influenza like illness
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	1 / 76 (1.32%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	1	1	0
Asthenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	4 / 76 (5.26%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	5	1	0
Axillary pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	3	3	0
Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	1	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)	0 / 4 (0.00%)	3 / 76 (3.95%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	3	2	0
Dysphonia
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	2	0	0
Rales
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0
Productive cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	2 / 76 (2.63%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	2	1	0
Dyspnoea
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	5 / 76 (6.58%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	5	0	0
Dyspnoea exertional
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	1 / 28 (3.57%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	1
Investigations
White blood cell count decreased
subjects affected / exposed	0 / 4 (0.00%)	5 / 36 (13.89%)	3 / 3 (100.00%)	0 / 1 (0.00%)	2 / 2 (100.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	3 / 18 (16.67%)	2 / 4 (50.00%)	2 / 76 (2.63%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	0	5	3	0	2	3	3	3	2	2	2	0
Neutrophil count decreased
subjects affected / exposed	0 / 4 (0.00%)	3 / 36 (8.33%)	3 / 3 (100.00%)	0 / 1 (0.00%)	1 / 2 (50.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	3 / 18 (16.67%)	1 / 4 (25.00%)	5 / 76 (6.58%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	3	3	0	1	3	2	3	1	7	1	0
Platelet count decreased
subjects affected / exposed	0 / 4 (0.00%)	4 / 36 (11.11%)	2 / 3 (66.67%)	0 / 1 (0.00%)	1 / 2 (50.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	4 / 18 (22.22%)	0 / 4 (0.00%)	8 / 76 (10.53%)	3 / 28 (10.71%)	0 / 9 (0.00%)
occurrences all number	0	4	2	0	1	2	1	4	0	8	3	0
Lymphocyte count decreased
subjects affected / exposed	0 / 4 (0.00%)	2 / 36 (5.56%)	3 / 3 (100.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 18 (22.22%)	1 / 4 (25.00%)	3 / 76 (3.95%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	2	3	0	0	1	1	4	2	3	1	0
Blood creatine increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1	1	0	0	0	0	0	0	2	0	1
Blood lactate dehydrogenase decreased
subjects affected / exposed	0 / 4 (0.00%)	2 / 36 (5.56%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	2	0	0
Cardiac murmur
subjects affected / exposed	0 / 4 (0.00%)	2 / 36 (5.56%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	1	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 4 (0.00%)	2 / 36 (5.56%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	2	0	0
Road traffic accident
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0
Dose calculation error
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	3 / 36 (8.33%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	3 / 76 (3.95%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	0	3	1	0
Dysgeusia
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	3 / 76 (3.95%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	4	1	0
Hypersomnia
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	2 / 4 (50.00%)	20 / 36 (55.56%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 18 (27.78%)	0 / 4 (0.00%)	12 / 76 (15.79%)	3 / 28 (10.71%)	3 / 9 (33.33%)
occurrences all number	2	23	0	0	0	0	0	5	0	16	3	4
Thrombocytopenia
subjects affected / exposed	1 / 4 (25.00%)	19 / 36 (52.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 18 (22.22%)	0 / 4 (0.00%)	13 / 76 (17.11%)	3 / 28 (10.71%)	3 / 9 (33.33%)
occurrences all number	1	19	0	0	0	0	0	4	0	13	4	3
Leukopenia
subjects affected / exposed	1 / 4 (25.00%)	14 / 36 (38.89%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	15	0	0	0	0	0	1	0	0	0	0
Lymphopenia
subjects affected / exposed	1 / 4 (25.00%)	9 / 36 (25.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)	0 / 4 (0.00%)	4 / 76 (5.26%)	1 / 28 (3.57%)	1 / 9 (11.11%)
occurrences all number	1	10	0	0	0	0	0	2	0	6	1	1
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	3 / 36 (8.33%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 18 (0.00%)	0 / 4 (0.00%)	11 / 76 (14.47%)	5 / 28 (17.86%)	2 / 9 (22.22%)
occurrences all number	0	3	0	0	0	1	1	0	0	12	5	2
Leukocytosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Lymphocytosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 4 (25.00%)	4 / 36 (11.11%)	1 / 3 (33.33%)	0 / 1 (0.00%)	2 / 2 (100.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)	2 / 4 (50.00%)	9 / 76 (11.84%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	1	4	1	0	2	0	1	0	3	9	2	0
Diarrhoea
subjects affected / exposed	1 / 4 (25.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)	1 / 4 (25.00%)	7 / 76 (9.21%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	0	0	0	2	1	7	2	0
Mouth haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	2 / 3 (66.67%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	2	0	0	0	0	1	0	1	0	0
Abdominal pain
subjects affected / exposed	1 / 4 (25.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	5 / 76 (6.58%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	5	2	0
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0
Constipation
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	4 / 76 (5.26%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	4	1	0
Tongue coated
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	2 / 28 (7.14%)	1 / 9 (11.11%)
occurrences all number	0	1	0	0	0	0	0	0	0	2	2	1
Paraesthesia oral
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	3	0	0
Erythema multiforme
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Pruritus
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	5 / 76 (6.58%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	6	0	0
Skin burning sensation
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Alopecia
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Eczema
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Vertigo positional
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Renal impairment
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 4 (0.00%)	2 / 36 (5.56%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	2 / 76 (2.63%)	4 / 28 (14.29%)	1 / 9 (11.11%)
occurrences all number	0	2	0	0	0	0	0	1	0	2	5	1
Back pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	5 / 76 (6.58%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	6	2	0
Pain in extremity
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	3	0	0
Hypermobility syndrome
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Myalgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	4 / 36 (11.11%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 18 (11.11%)	0 / 4 (0.00%)	3 / 76 (3.95%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	5	0	0	0	0	1	2	0	3	0	0
Nasopharyngitis
subjects affected / exposed	1 / 4 (25.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 18 (16.67%)	0 / 4 (0.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	0	0	0	3	0	1	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	3 / 36 (8.33%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	2 / 76 (2.63%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	4	0	0	0	0	0	0	0	2	0	0
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 36 (2.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	2 / 36 (5.56%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)	0 / 4 (0.00%)	1 / 76 (1.32%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	1	1	0
Oral candidiasis
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	1 / 76 (1.32%)	0 / 28 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0
COVID-19
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	4 / 76 (5.26%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	0	1
Infection
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	1 / 4 (25.00%)	0 / 76 (0.00%)	1 / 28 (3.57%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0	1	0
Decreased appetite
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	3 / 76 (3.95%)	2 / 28 (7.14%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	3	2	0
Gout
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	0 / 4 (0.00%)	0 / 36 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)	0 / 4 (0.00%)	0 / 76 (0.00%)	0 / 28 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

14 Sep 2012

Version 4.0 In the Phase I part of the study, participants were to receive two infusions of 250 mg/m2 rituximab (the first on Day -7 and the second within 4 hours before Betalutin injection on Day 0). The first participant was to receive a sentinel dose of 10 MBq/kg Betalutin; subsequent participants were to be enrolled following a ‘3+3’ design with escalating doses of Betalutin. Dose expansion at the maximum tolerated dose (MTD) was then to be performed in the Phase IIa part of the study (referred to as Phase IIa Arm 1).

25 Mar 2013

Version 5.0 • The pre-treatment/pre-dosing regimen was amended to two pre-treatment infusions of 375 mg/m2 rituximab (the first on Day -28 and the second on Day -21) plus pre-dosing with 40 mg lilotomab within 4 hours of Betalutin injection on Day 0) • Additional participants were included at the 10 MBq/kg Betalutin dose level

11 Mar 2014

Version 6.0 • Smaller dose de-escalation steps of 5 MBq/kg were implemented (i.e. from 20 MBq/kg to 15 MBq/kg based on the study status at the time of implementation of this amendment) • A Quality of Life assessment (FACT-Lym) was introduced in Part A Phase IIa

18 Feb 2015

Version 6B • Phase I Arm 2 was introduced to investigate the effect of omitting pre-dosing with lilotomab • The Dose Limiting Toxicity (DLT) definition was updated

26 Nov 2015

Version 7.0 • The following Phase I arms were introduced: Arm 3 (to investigate pre-dosing with rituximab on Day 0), Arm 4 (pre-dosing with 100 mg/m2 lilotomab on Day 0) and Arm 5 (pre-dosing with a combination of both rituximab and 100 mg/m2 lilotomab on Day 0). The starting dose of Betalutin in all three cohorts was 15 MBq/kg, with the possibility of escalation to 17.5 MBq/kg or 20 MBq/kg. Participants continued to be eligible for enrolment into the 10 MBq/kg cohort of Arm 2 until this version of the protocol was approved given the prolonged partial remission (PR) participants had experienced with this dose of Betalutin in Arm 1 and the likely reduction in haematological toxicities seen in this arm with the 15 MBq/kg dose of Betalutin • The rituximab pre-treatment regimen introduced in Version 5.0 was amended to a single infusion of 375 mg/m2 on Day -14 for Phase I Arms 3, 4 and 5 • The inclusion criterion requiring participants to have CD37 positive tumours was removed. No validated commercial assay of CD37 expression in tumour samples was available (testing of CD37 expression at screening was continued) and a total of 99.5% of the lymphoma tumour tissues tested with the available assay were positive for expression of CD37. Removing this criterion prevented delay in the treatment of participants whilst tumour tissue was tested for little or no potential benefit

04 Jul 2016

Version 8.0 • The dose of Betalutin was capped at the dose corresponding to a body weight of 130 kg

28 Nov 2016

Version 9.0 • Enrolment was continued following the interim analysis in expansion of Phase IIa Arm 1 • A second Phase IIa expansion cohort with a further 10 to 15 participants was added to Arm 4 with the 100/20 treatment regimen and pre-treatment with rituximab on Day -14 (assuming acceptable tolerability in the first three to six participants) • The lilotomab dose to be tested in Phase I Arm 5 was changed to 60 mg/m2. Rituximab pre dosing on Day 0 (in combination with lilotomab) was removed since review of data from Arm 3 showed no benefit of rituximab pre-dosing on Day 0. The intermediate escalation step of 17.5 MBq/kg was also removed from Arm 5 • DLTs in Phase I Arm 1 were re-evaluated using the DLT criteria that were applied for Arms 2, 3, 4, 5 and Phase IIa (under Protocol Version 6B), to harmonise the assessment of the safety data of all enrolled participants/treatment arms • Exclusion criterion 2 was amended to allow the treatment of participants with a screening platelet count of 100 to 150×109/L in the Phase II Arm 4, depending on safety review of participants with a screening platelet count >150×109/L treated with 20 MBq/kg Betalutin and 100 mg/m2 lilotomab by the Safety Review Committee (SRC)

04 Jul 2017

Version 10.0 • The number of participants enrolled in Phase IIa Arm 1 was increased from 24 to 30 as an additional six participants had provided informed consent and started screening procedures at the time the original enrolment target of 24 participants was reached and it was considered unethical by the Sponsor to withhold treatment

27 Oct 2017

Version 11.0 • Following decision by the SRC the dose of Betalutin in Arm 5 was fixed at 20 MBq/kg • Part B (PARADIGME) was added to the study, with a Phase IIb randomised design to compare the two recommended doses for Phase II identified and confirmed in Part A Phase I and Phase IIa, respectively. Up to 130 additional participants were to be treated with either the “40/15” or “100/20” treatment regimens to further delineate the risk: benefit profile of these treatment regimens in a population with relapsed, rituximab/anti CD20 refractory follicular lymphoma (FL) • The primary assessment of tumour responses was updated to Cheson et al, 2014 by Independent review Committee (IRC) • The DLT definition was updated • A clarification was added that survival information and potential long-term toxicity information would continue to be collected on withdrawn participants unless consent was withdrawn • Immunogenicity assessments to measure the anti-drug antibody (ADA) response in Part B were added • Biobanking of tumour samples and peripheral blood samples for future analysis was added

22 Oct 2018

Version 12.0 • Magnetic resonance imaging (MRI) was added as an alternative to contrast enhanced computed tomography (CT) for disease assessments • Statistical methods were updated to include the method for comparing the ORR between the two treatment regimens in Part B • Three country-specific addenda were added: Germany: Additional pregnancy testing was added in the 3 days prior to rituximab administration and also at Months 2, 4, 5, 7, 8, 9 and 11. In-patient hospitalisation for 48 hours after Betalutin injection and confirmation of CD37 antigen positive FL before Betalutin administration, were required France: Clarification was made that the source documentation for the collection of participant ethnic origin and race, would be the electronic case report form (eCRF) (these data would not be recorded in patient medical file) and consent would be taken prior to collection of these data. Further clarifications relating to blood sampling for deoxyribonucleic acid (DNA) extraction and human leukocyte antigen (HLA) typing, clarification of biobanking, analysis and destruction Ireland and Norway: Pregnancy testing was mandated monthly after Betalutin injection until 12 months after Betalutin injection (or withdrawal)

13 Mar 2020

Version 13.0 • The Part B interim analysis information was updated. The overall response rate (ORR) boundary of 40% was made non-binding and for guidance only when deciding whether to terminate treatment regimens. The majority (75%) of the 48 participants enrolled in Part B at the time of the protocol amendment had exhausted all treatment options, and 64% had received prior bendamustine (which had been reported in a Phase II study investigating duvelisib in participants with refractory B-cell indolent NHL to be associated with an ORR of 39% [Flinn et al, 2019]). A number of enrolled participants were also refractory to phosphoinositide 3-kinase (PI3K) inhibitors. Since the participant population appeared more refractory than initially anticipated, the ORR cut-off of 40% was considered too strict

31 Jul 2020

Version 14.0 • The participant population for Part B was redefined: The platelet threshold for inclusion was reduced from ≥150×109/L to ≥100×109/L to allow enrolment of a more representative population of patients with FL Participants with a prior autologous stem cell transplant (SCT) could be included if at least 2 years had elapsed since transplantation, and they had been without Grade ≥1 graft versus host disease for at least 8 weeks (the requirement relating to graft versus host disease was subsequently removed in Version 15.0) • The 100/20 treatment regimen was terminated at the recommendation of the SRC following the Part B interim analysis. Part B was to continue with the 40/15 treatment regimen only, with a lower Betalutin dose for the sub-populations with the lower platelet threshold and/or prior autologous-SCT: 12.5 MBq/kg for participants with prior autologous-SCT and but platelets ≥150×109/L 12.5 MBq/kg for participants without prior autologous-SCT and platelets 100 to <150×109/L 10 MBq/kg for participants with prior autologous-SCT and platelets 100 to <150×109/L • Additional SRC meetings were included to review the first three participants enrolled in the following sub-populations (i) lower platelet threshold, (ii) autologous-SCT and (iii) lower platelet threshold and autologous-SCT, after all three participants in each sub population had been followed for at least 6 weeks • Single-photon emission computed tomography/computed tomography (SPECT/CT) dosimetry was no longer required at sites collecting pharmacokinetic samples, except for participants entering Part B from sites in Germany and in other agreed sites. The Part B exploratory objectives were updated accordingly • Statistical analysis of pharmacokinetics was added • The country-specific addendum for Germany was amended to clarify that the participants must have confirmed positive CD37 FL before receiving Betalutin

26 Jan 2021

Version 15.0 was not submitted and was superseded by the next amendments Versions 15.1 to 15.4 • Part C was added to better characterise the pharmacokinetics of Betalutin and total lilotomab antibodies of the 40/15 treatment regimen • Specific rules for dose determination following a “3+3” design were added in the three sub populations with the lower platelet threshold and/or prior autologous-SCT introduced in Version 14.0 • The Part B objectives were updated to delineate between the randomised and non randomised sub-parts and additional objectives relating to complete response rate (CRR) and duration of complete response (DoCR) were added. Clarifications that Part B efficacy endpoints would be assessed by IRC and the Investigator were added where required • The Part B sample size was updated to reflect termination of dosing with the 100/20 treatment regimen and set a hypothesis and sample size for assessment of the 40/15 treatment regimen selected for further development • Flexibility was included to the screening period and the possibility of performing study visits without key assessments as non-hospital visits due to the COVID-19 pandemic • The different study periods were better clarified, up to 3 months, from 6 to 12 months and thereafter with clear separation of what is required during follow-up until disease progression or start of further anti-cancer therapy (extensive follow-up involving hospital visits) versus after disease progression or further therapy (limited follow-up which may be conducted by telephone). Starting further therapy was removed as an option for withdrawal from the study as participants were to enter limited (long term) follow-up when they had disease progression or start another cancer treatment (whichever comes first). This follow up allowed for long term toxicities of Betalutin, to be captured and managed • The country-specific addendum for Ireland and Norway was updated for pregnancy tests

19 Feb 2021

Version 15.1 Haematology testing prior to rituximab infusion was added in order to verify the applicable eligibility criteria

06 Apr 2021

Version 15.2 - Specific to US only: The definitions of duration of response (DoR) and duration of complete response (DoCR) were updated at the request of the US Food and Drug Administration (FDA) to include death due to any cause

28 Jul 2021

Version 15.3: Applicable to France only Amendment to Version 15.1 following feedback from the regulatory authority in France: Scheduled safety reviews and dose decision making criteria were added for participants in Part C

28 Jul 2021

Version 15.4: Applicable to US only Amendment to Version 15.2 to remove the requirement for a negative human anti-mouse antibody (HAMA) test result at screening as: The likelihood of a participant having received prior murine antibody therapy was very low given the low number of approved murine-based therapies on the market The recorded screen failure rate in the study due to pre-existing HAMA was low at the time of the amendment Effective mitigation and precautionary measures were in place in the unlikely event of hypersensitivity reactions caused by pre-existing HAMAs reacting with successively administered murine monoclonal antibodies (lilotomab/Betalutin)

Were there any global interruptions to the trial? No

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

Participants were enrolled to protocol Version 4.0 and later. The overall study design of protocol Version 4.0 and the subsequent amendments are identified in the protocol amendments section

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Clinical trials

Clinical Trial Results:
A phase I/II study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) antibody-radionuclide-conjugate for treatment of relapsed non-Hodgkin lymphoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A Phase I: To define the Maximum Tolerated Dose (MTD)

Primary: Part A Phase I: To define the Maximum Tolerated Dose (MTD)

Primary: Part A Phase IIa: To explore tumour response rates in FL

Primary: Part A Phase IIa: To explore tumour response rates in FL

Primary: Part B: Phase IIb

Primary: Part B: Phase IIb

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A phase I/II study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) antibody-radionuclide-conjugate for treatment of relapsed non-Hodgkin lymphoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A Phase I: To define the Maximum Tolerated Dose (MTD)

Primary: Part A Phase I: To define the Maximum Tolerated Dose (MTD)

Primary: Part A Phase IIa: To explore tumour response rates in FL

Primary: Part A Phase IIa: To explore tumour response rates in FL

Primary: Part B: Phase IIb

Primary: Part B: Phase IIb

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase I/II study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) antibody-radionuclide-conjugate for treatment of relapsed non-Hodgkin lymphoma.