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Clinical Trial Results:
A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)

Summary
EudraCT number	2018-002625-38
Trial protocol	BE GB IT
Global end of trial date	08 Nov 2022

Results information
Results version number	v1(current)
This version publication date	07 Dec 2023
First version publication date	07 Dec 2023
Other versions

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

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Trial information

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Sponsor protocol code

ADCT-402-103

ISRCTN number

US NCT number

NCT03684694

WHO universal trial number (UTN)

Sponsor organisation name

ADC Therapeutics SA

Sponsor organisation address

Route de la Corniche, 3B, Epalinges, Switzerland, 1066

Public contact

Clinical Trials Information, ADC Therapeutics SA, clinicaltrials@adctherapeutics.com

Scientific contact

Clinical Trials Information, ADC Therapeutics SA, clinicaltrials@adctherapeutics.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

08 Nov 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Nov 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

Phase 1: To characterize the safety and tolerability of loncastuximab tesirine in combination with ibrutinib, and to identify the maximum tolerated dose (MTD) /recommended dose and schedule for future studies. Phase 2: To evaluate the efficacy of loncastuximab tesirine in combination with ibrutinib in participants with relapsed or refractory diffuse large B-Cell lymphoma (DLBCL).

Protection of trial subjects

The study was conducted in accordance with the principles of the Declaration of Helsinki in place at the time of study conduct. The study was conducted in compliance with the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) (Committee for Proprietary Medicinal Products [CPMP] guideline CPMP/ICH/135/95) and the European Union Clinical Trial Directive (EU CTD): Directive 2001/20/EC.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Dec 2018

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

Belgium: 24

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Italy: 58

Country: Number of subjects enrolled

United States: 30

Worldwide total number of subjects

136

EEA total number of subjects

106

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

136 participants were enrolled into sites in the United States, Belgium, France, Italy, and Spain.

Screening details

Participants were screened for eligibility to enroll within 28 days prior to the start of treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Arm description

Participants with advanced diffuse large B-Cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) were enrolled to receive 60 µg/kg of loncastuximab tesirine via intravenous (IV) infusion once every 3 weeks (Q3W) for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart.

Arm type

Experimental

Investigational medicinal product name

Loncastuximab Tesirine

Investigational medicinal product code

ADCT-402

Other name

Zynlonta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Loncastuximab tesirine was received as 60, 75 or 90 µg/kg via intravenous (IV) infusion once every 3 weeks (Q3W) for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) in Phase 1 arms. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart. In Phase 2 arms, loncastuximab tesirine was received at the recommended phase 2 dose (RP2D) of 60 µg/kg on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2). Participants who had a response of complete response (CR), partial response (PR), and stable disease (SD) received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10 (cycle is 4 weeks for Cycles 3 onwards).

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib was received as 560 mg oral capsules once daily.

Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib

Arm description

Participants with advanced DLBCL or MCL were enrolled to receive 75 µg/kg of loncastuximab tesirine via IV infusion Q3W for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart.

Arm type

Experimental

Investigational medicinal product name

Loncastuximab Tesirine

Investigational medicinal product code

ADCT-402

Other name

Zynlonta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib was received as 560 mg oral capsules once daily.

Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib

Arm description

Participants with advanced DLBCL or MCL were enrolled to receive 90 µg/kg of loncastuximab tesirine via IV infusion Q3W for 2 treatment cycles (cycle is 3 weeks for Cycles 1 and 2) with concurrent 560 mg ibrutinib orally via capsules once daily. Participants who had a response of partial response (PR) or stable disease (SD) at the 14-week assessment may have received 2 additional doses of loncastuximab tesirine given 4 weeks apart.

Arm type

Experimental

Investigational medicinal product name

Loncastuximab Tesirine

Investigational medicinal product code

ADCT-402

Other name

Zynlonta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib was received as 560 mg oral capsules once daily.

Phase 2: Non-Germinal Center B-cell (GCB) DLBCL

Arm description

Participants with non-germinal center B-cell (GCB) DLBCL received the recommended phase 2 dose (RP2D) of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of complete response (CR), partial response (PR), and stable disease (SD) received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Arm type

Experimental

Investigational medicinal product name

Loncastuximab Tesirine

Investigational medicinal product code

ADCT-402

Other name

Zynlonta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib was received as 560 mg oral capsules once daily.

Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL

Arm description

Participants with GCB DLBCL received the RP2D of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of CR, PR, and SD received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Arm type

Experimental

Investigational medicinal product name

Loncastuximab Tesirine

Investigational medicinal product code

ADCT-402

Other name

Zynlonta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib was received as 560 mg oral capsules once daily.

Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL

Arm description

Participants with MCL received the RP2D of 60 µg/kg loncastuximab tesirine via IV infusion with concurrent 560 mg ibrutinib orally via capsules once daily. Loncastuximab tesirine was administered on Day 1 of Cycles 1 and 2 (cycle is 3 weeks for Cycles 1 and 2, and 4 weeks for Cycles 3 onwards). Participants who had a response of CR, PR, and SD received additional doses of loncastuximab tesirine on Day 1 of Cycles 5, 6, 9 and 10.

Arm type

Experimental

Investigational medicinal product name

Loncastuximab Tesirine

Investigational medicinal product code

ADCT-402

Other name

Zynlonta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib was received as 560 mg oral capsules once daily.

Number of subjects in period 1	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 2: Non-Germinal Center B-cell (GCB) DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL
Started	37	4	6	49	30	10
Completed	0	1	1	0	0	0
Not completed	37	3	5	49	30	10
Consent withdrawn by subject	1	-	-	-	-	1
Investigator/Sponsor Decision	12	2	1	17	16	6
Death	24	-	3	28	14	3
Miscellaneous	-	1	-	3	-	-
Lost to follow-up	-	-	1	1	-	-

Baseline characteristics

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Reporting group title

Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 2: Non-Germinal Center B-cell (GCB) DLBCL

Reporting group description

Reporting group title

Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL

Reporting group description

Reporting group title

Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL

Reporting group description

Reporting group values	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 2: Non-Germinal Center B-cell (GCB) DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL	Total
Number of subjects	37	4	6	49	30	10	136
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	11	1	3	13	10	5	43
From 65-84 years	23	3	3	36	18	4	87
85 years and over	3	0	0	0	2	1	6
Gender categorical
Units: Subjects
Female	10	2	2	19	9	3	45
Male	27	2	4	30	21	7	91
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	2	0	0	2
Not Hispanic or Latino	37	4	6	47	27	9	130
Unknown or Not Reported	0	0	0	0	3	1	4
Race (NIH/OMB)
Units: Subjects
Asian	0	0	0	1	0	0	1
Black or African American	1	0	0	1	0	0	2
White	35	4	6	43	26	10	124
Unknown or Not Reported	1	0	0	4	4	0	9

End points

Top of page

Reporting group title

Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 2: Non-Germinal Center B-cell (GCB) DLBCL

Reporting group description

Reporting group title

Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL

Reporting group description

Reporting group title

Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL

Reporting group description

Subject analysis set title

Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Phase 2: Non-GCB DLBCL

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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End point title

Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) ^[1]

End point description

A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy, whichever is earlier. Any clinically significant changes form baseline in safety laboratory values, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, and 12-lead electrocardiograms (ECGs) which occurred after first dose of study drug were recorded as TEAEs.

End point type

Primary

End point timeframe

Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)

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: No statistical analyses were pre-specified for this endpoint. Descriptive statistics are presented.

End point values	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib
Number of subjects analysed	37	4	6
Units: participants	37	4	6

No statistical analyses for this end point

Primary: Phase 1: Number of Participants With Serious TEAEs

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End point title

Phase 1: Number of Participants With Serious TEAEs ^[2]

End point description

A serious TEAE was defined as any AE which occurred after the first dose of study drug that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance was not considered a serious adverse event), resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or important medical events that did not meet the preceding criteria but based on appropriate medical judgement may have jeopardized the participant or may have required medical or surgical intervention to prevent any of the outcomes listed above.

End point type

Primary

End point timeframe

Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were pre-specified for this endpoint. Descriptive statistics are presented.

End point values	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib
Number of subjects analysed	37	4	6
Units: participants	19	0	3

No statistical analyses for this end point

Primary: Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)

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End point title

Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs) ^[3]

End point description

A DLT was defined as any of the following events which occur during the DLT Period (first 21 days of ibrutinib treatment), except those that are clearly due to underlying disease or extraneous causes: a hematologic DLT (grade ≥3 anaemia, grade 4/febrile neutropenia, grade ≥3 thrombocytopenia), a non-hematologic DLT (including aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3× upper limit of normal (ULN) and bilirubin >2× ULN), any other non-hematologic toxicities ≥ Grade 3, with exceptions.

End point type

Primary

End point timeframe

21 days

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: No statistical analyses were pre-specified for this endpoint. Descriptive statistics are presented.

End point values	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib
Number of subjects analysed	37	4	6
Units: participants	0	0	2

No statistical analyses for this end point

Primary: Phase 1: Number of Participants With Dose Interruptions

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End point title

Phase 1: Number of Participants With Dose Interruptions ^[4]

End point description

Measured in the safety population, which included all participants who received study drug.

End point type

Primary

End point timeframe

Up to a maximum of 686 days

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were pre-specified for this endpoint. Descriptive statistics are presented.

End point values	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib
Number of subjects analysed	37	4	6
Units: participants	1	0	0

No statistical analyses for this end point

Primary: Phase 1: Number of Participants With Dose Reductions

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End point title

Phase 1: Number of Participants With Dose Reductions ^[5]

End point description

Measured in the safety population, which included all participants who received study drug.

End point type

Primary

End point timeframe

Up to a maximum of 686 days

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were pre-specified for this endpoint. Descriptive statistics are presented.

End point values	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib
Number of subjects analysed	37	4	6
Units: participants	0	0	0

No statistical analyses for this end point

Primary: Phase 2: Complete Response Rate (CRR)

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End point title

Phase 2: Complete Response Rate (CRR) ^[6]

End point description

CRR according to the 2014 Lugano classifications determined by Independent Review Committee (IRC). CRR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR). Measured in the efficacy analysis set, which included all participants who received at least 1 dose of study drug, who had valid baseline disease assessment(s), and who had at least one valid post-baseline disease assessment. Participants who did not have a post-baseline assessment due to early clinical progression or death (after receiving study drug) were also included.

End point type

Primary

End point timeframe

Up to approximately 38 months

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were pre-specified for this endpoint. Descriptive statistics are presented.

End point values	Phase 2: Non-GCB DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL
Number of subjects analysed	48	30	10
Units: percentage of participants
number (confidence interval 95%)	27.1 (15.3 to 41.8)	26.7 (12.3 to 45.9)	90.0 (55.5 to 99.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-cause mortality from enrollment until approx. 4 years. For serious adverse events and other adverse events, from Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib

Reporting group description

Reporting group title

Phase 2: Non-Germinal Center B-cell (GCB) DLBCL

Reporting group description

Reporting group title

Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL

Reporting group description

Reporting group title

Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL

Reporting group description

Serious adverse events	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 2: Non-Germinal Center B-cell (GCB) DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL
Total subjects affected by serious adverse events
subjects affected / exposed	19 / 37 (51.35%)	0 / 4 (0.00%)	3 / 6 (50.00%)	27 / 49 (55.10%)	5 / 30 (16.67%)	5 / 10 (50.00%)
number of deaths (all causes)	24	0	3	28	14	3
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	4 / 49 (8.16%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Transaminases increased
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial disease
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic disorder
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node pain
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumatosis intestinalis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone swelling
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Citrobacter infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Corona virus infection
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Enterococcal infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Folliculitis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii infection
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia parainfluenzae viral
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	5 / 49 (10.20%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 8	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1
Progressive multifocal leukoencephalopathy
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1: 60 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 75 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 1: 90 µg/kg Loncastuximab Tesirine and Ibrutinib	Phase 2: Non-Germinal Center B-cell (GCB) DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in GCB DLBCL	Phase 2: Loncastuximab Tesirine and Ibrutinib in MCL
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 37 (100.00%)	4 / 4 (100.00%)	6 / 6 (100.00%)	48 / 49 (97.96%)	30 / 30 (100.00%)	10 / 10 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0
Haematoma
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	4	0	0	2	3	0
Hypertension
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	1 / 30 (3.33%)	3 / 10 (30.00%)
occurrences all number	4	0	0	2	2	3
Phlebitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	6 / 37 (16.22%)	1 / 4 (25.00%)	0 / 6 (0.00%)	5 / 49 (10.20%)	2 / 30 (6.67%)	3 / 10 (30.00%)
occurrences all number	7	1	0	8	2	4
Chest pain
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	2
Chills
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0	0
Early satiety
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	1	0
Fatigue
subjects affected / exposed	9 / 37 (24.32%)	0 / 4 (0.00%)	2 / 6 (33.33%)	14 / 49 (28.57%)	2 / 30 (6.67%)	3 / 10 (30.00%)
occurrences all number	10	0	3	20	3	3
Generalised oedema
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Malaise
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	1	1	0
Oedema peripheral
subjects affected / exposed	6 / 37 (16.22%)	1 / 4 (25.00%)	1 / 6 (16.67%)	12 / 49 (24.49%)	3 / 30 (10.00%)	1 / 10 (10.00%)
occurrences all number	10	2	1	16	3	1
Pain
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	2	2	0
Peripheral swelling
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	2	1
Pyrexia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	2 / 6 (33.33%)	10 / 49 (20.41%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	3	11	1	0
Sensation of foreign body
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Immune system disorders
Hypogammaglobulinaemia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	1	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	6 / 37 (16.22%)	1 / 4 (25.00%)	0 / 6 (0.00%)	6 / 49 (12.24%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	9	1	0	6	1	0
Dry throat
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	6 / 49 (12.24%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0	9	0	0
Epistaxis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	1	0	1
Hiccups
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0
Oropharyngeal pain
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	1	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	2	0	0
Anxiety
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	4	0	0	2	2	0
Confusional state
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	1	1
Depression
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Insomnia
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	4 / 49 (8.16%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	3	0	0	4	1	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	3 / 6 (50.00%)	4 / 49 (8.16%)	3 / 30 (10.00%)	1 / 10 (10.00%)
occurrences all number	9	0	5	8	4	1
Amylase increased
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	4 / 49 (8.16%)	3 / 30 (10.00%)	1 / 10 (10.00%)
occurrences all number	2	0	0	6	3	2
Aspartate aminotransferase increased
subjects affected / exposed	2 / 37 (5.41%)	1 / 4 (25.00%)	2 / 6 (33.33%)	5 / 49 (10.20%)	3 / 30 (10.00%)	0 / 10 (0.00%)
occurrences all number	3	1	3	9	3	0
Blood bilirubin increased
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 6 (16.67%)	3 / 49 (6.12%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	1	0	1	3	1	0
Blood creatinine increased
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0	2	0	0
Blood iron decreased
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0	0
Coronavirus test positive
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	2 / 6 (33.33%)	3 / 49 (6.12%)	2 / 30 (6.67%)	2 / 10 (20.00%)
occurrences all number	11	0	3	4	2	11
Lipase increased
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	1 / 6 (16.67%)	2 / 49 (4.08%)	2 / 30 (6.67%)	1 / 10 (10.00%)
occurrences all number	4	0	1	2	4	7
Weight decreased
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	3	0	0	0	1	0
Weight increased
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	0 / 6 (0.00%)	3 / 49 (6.12%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0	3	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	0	1	0	2	0
Fall
subjects affected / exposed	1 / 37 (2.70%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	3	1	0	1	1	0
Limb injury
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Skin abrasion
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	1	0	0	0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Atrial fibrillation
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	4 / 49 (8.16%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	3	0	0	7	1	1
Bradycardia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Palpitations
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	2 / 10 (20.00%)
occurrences all number	2	0	0	0	0	2
Sinus bradycardia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	1	0	0
Sinus tachycardia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	1	1	0	0
Tachycardia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1	1
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	3
Dizziness
subjects affected / exposed	1 / 37 (2.70%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	1	1	0	1	1	1
Headache
subjects affected / exposed	2 / 37 (5.41%)	1 / 4 (25.00%)	0 / 6 (0.00%)	4 / 49 (8.16%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	2	1	0	4	1	1
Neuropathy peripheral
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	2 / 10 (20.00%)
occurrences all number	1	0	0	0	1	2
Paraesthesia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	2	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	9 / 37 (24.32%)	2 / 4 (50.00%)	4 / 6 (66.67%)	13 / 49 (26.53%)	4 / 30 (13.33%)	1 / 10 (10.00%)
occurrences all number	14	4	8	15	5	2
Leukopenia
subjects affected / exposed	2 / 37 (5.41%)	1 / 4 (25.00%)	1 / 6 (16.67%)	4 / 49 (8.16%)	4 / 30 (13.33%)	1 / 10 (10.00%)
occurrences all number	3	4	1	7	11	1
Lymphadenopathy
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0
Lymphopenia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	3	0
Neutropenia
subjects affected / exposed	5 / 37 (13.51%)	3 / 4 (75.00%)	1 / 6 (16.67%)	18 / 49 (36.73%)	7 / 30 (23.33%)	4 / 10 (40.00%)
occurrences all number	26	4	3	36	13	11
Thrombocytopenia
subjects affected / exposed	17 / 37 (45.95%)	2 / 4 (50.00%)	4 / 6 (66.67%)	22 / 49 (44.90%)	12 / 30 (40.00%)	4 / 10 (40.00%)
occurrences all number	38	3	8	56	21	14
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0	2	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Ocular hyperaemia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	2	0
Swelling of eyelid
subjects affected / exposed	0 / 37 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Vision blurred
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	2	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 6 (16.67%)	3 / 49 (6.12%)	3 / 30 (10.00%)	0 / 10 (0.00%)
occurrences all number	2	0	2	4	5	0
Abdominal pain upper
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	3 / 30 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	3	0
Constipation
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	0 / 6 (0.00%)	6 / 49 (12.24%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	4	0	0	6	2	0
Diarrhoea
subjects affected / exposed	9 / 37 (24.32%)	2 / 4 (50.00%)	1 / 6 (16.67%)	9 / 49 (18.37%)	7 / 30 (23.33%)	5 / 10 (50.00%)
occurrences all number	13	2	1	16	8	10
Dry mouth
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	2	0	0
Dyspepsia
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	1 / 6 (16.67%)	3 / 49 (6.12%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	3	0	2	4	2	0
Dysphagia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	1	0	0	1	1	1
Faeces soft
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	1	0
Gastritis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Nausea
subjects affected / exposed	9 / 37 (24.32%)	1 / 4 (25.00%)	1 / 6 (16.67%)	5 / 49 (10.20%)	4 / 30 (13.33%)	0 / 10 (0.00%)
occurrences all number	9	1	1	6	5	0
Odynophagia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	0	1
Oral pain
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Pancreatitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	1
Stomatitis
subjects affected / exposed	1 / 37 (2.70%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	1	0	1	0	1
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0
Vomiting
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	5 / 49 (10.20%)	3 / 30 (10.00%)	1 / 10 (10.00%)
occurrences all number	6	0	0	6	7	1
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Cholecystocholangitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Hepatocellular injury
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	1	0	7
Hyperbilirubinaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	4	0	0	0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	0	0	1	0	1
Blood blister
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	2
Dermatitis bullous
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	4	0	0	1	0	1
Dry skin
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	2 / 10 (20.00%)
occurrences all number	4	0	0	0	0	2
Ecchymosis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	0	1
Erythema
subjects affected / exposed	2 / 37 (5.41%)	1 / 4 (25.00%)	0 / 6 (0.00%)	5 / 49 (10.20%)	5 / 30 (16.67%)	3 / 10 (30.00%)
occurrences all number	4	1	0	11	5	7
Lividity
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	2
Macule
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Night sweats
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	2	0	1
Onychoclasis
subjects affected / exposed	0 / 37 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Palmar erythema
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Petechiae
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	3 / 30 (10.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0	0	2	0
Photosensitivity reaction
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 6 (16.67%)	2 / 49 (4.08%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	2	0	1	3	2	3
Pruritus
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	1 / 6 (16.67%)	4 / 49 (8.16%)	1 / 30 (3.33%)	3 / 10 (30.00%)
occurrences all number	5	0	1	7	1	6
Purpura
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	2	0	0
Rash
subjects affected / exposed	7 / 37 (18.92%)	1 / 4 (25.00%)	1 / 6 (16.67%)	6 / 49 (12.24%)	4 / 30 (13.33%)	2 / 10 (20.00%)
occurrences all number	12	1	2	9	4	3
Rash macular
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	4
Rash maculo-papular
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	3	1
Rash vesicular
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	2
Skin hyperpigmentation
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Skin ulcer
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	0	3
Renal and urinary disorders
Dysuria
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 49 (4.08%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	3	0	0	2	4	0
Back pain
subjects affected / exposed	1 / 37 (2.70%)	1 / 4 (25.00%)	0 / 6 (0.00%)	6 / 49 (12.24%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	8	0	0
Muscle spasms
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	6 / 49 (12.24%)	2 / 30 (6.67%)	2 / 10 (20.00%)
occurrences all number	3	0	0	6	3	3
Myalgia
subjects affected / exposed	0 / 37 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	3	0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	1	0	1
Clostridium difficile colitis
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	0	1
Conjunctivitis
subjects affected / exposed	6 / 37 (16.22%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	2 / 10 (20.00%)
occurrences all number	7	0	0	1	2	2
Corona virus infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	3 / 49 (6.12%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	0	0	0	8	1	4
Erysipelas
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Eye infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	1
Furuncle
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0	0	0	0
Genital infection fungal
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1
Herpes zoster
subjects affected / exposed	0 / 37 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0
Lung infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 49 (0.00%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	1	0
Oral candidiasis
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	3	0	0	1	1	0
Oral fungal infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0
Oral herpes
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	1	1
Pharyngitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	1 / 30 (3.33%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	1	2
Pneumonia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	4	0	0	0	2	0
Rhinitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	1	1
Sinusitis
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	2	0	0	1	3	0
Upper respiratory tract infection
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	0	0	1
Urinary tract infection
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	3 / 30 (10.00%)	2 / 10 (20.00%)
occurrences all number	4	0	0	3	3	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 37 (13.51%)	0 / 4 (0.00%)	1 / 6 (16.67%)	4 / 49 (8.16%)	0 / 30 (0.00%)	2 / 10 (20.00%)
occurrences all number	5	0	1	5	0	2
Hypercalcaemia
subjects affected / exposed	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	1	4	0	0
Hyperglycaemia
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	1 / 30 (3.33%)	3 / 10 (30.00%)
occurrences all number	2	0	0	1	1	3
Hyperkalaemia
subjects affected / exposed	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0	0	0	0
Hypermagnesaemia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 49 (0.00%)	3 / 30 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	3	0
Hyperuricaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 49 (2.04%)	0 / 30 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 49 (2.04%)	2 / 30 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	0	1	4	1
Hypocalcaemia
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	0 / 6 (0.00%)	5 / 49 (10.20%)	4 / 30 (13.33%)	0 / 10 (0.00%)
occurrences all number	8	0	0	8	6	0
Hypokalaemia
subjects affected / exposed	6 / 37 (16.22%)	1 / 4 (25.00%)	1 / 6 (16.67%)	6 / 49 (12.24%)	3 / 30 (10.00%)	1 / 10 (10.00%)
occurrences all number	8	1	1	7	3	2
Hypomagnesaemia
subjects affected / exposed	5 / 37 (13.51%)	0 / 4 (0.00%)	0 / 6 (0.00%)	6 / 49 (12.24%)	2 / 30 (6.67%)	0 / 10 (0.00%)
occurrences all number	5	0	0	10	2	0
Hyponatraemia
subjects affected / exposed	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 6 (0.00%)	3 / 49 (6.12%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	3	0	0	3	1	0
Hypophosphataemia
subjects affected / exposed	4 / 37 (10.81%)	0 / 4 (0.00%)	1 / 6 (16.67%)	7 / 49 (14.29%)	6 / 30 (20.00%)	0 / 10 (0.00%)
occurrences all number	5	0	1	8	12	0
Musculoskeletal pain
subjects affected / exposed	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 6 (0.00%)	4 / 49 (8.16%)	1 / 30 (3.33%)	0 / 10 (0.00%)
occurrences all number	2	0	0	4	1	0

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Were there any global substantial amendments to the protocol? Yes

08 Jul 2019

• Schedule of Events revised to for all participants to determine whether they met Exclusion Criterion 10. • Exclusion Criteria was modified to remove the notation from Exclusion Criterion 10. Criterion 15 was modified to add the exclusion of participants with tuberculosis infection. • Packaging and Storage was updated to match the ibrutinib Investigator’s Brochure (IB). • Preparation and Administration was updated to include precautions concerning extravasation of loncastuximab tesirine based on updated safety information. • Loncastuximab Tesirine dosing was revised to clarify the criteria for using sequential dosing. • Dose Escalation Design was revised to specify a minimum of 5 days between dosing the first and second patient at each dose level during dose escalation (Part 1), and was also revised to allow enrollment of additional participants during the dose escalation phase at the discretion of the Dose Escalation Steering Committee (DESC). • Dose-Limiting Toxicity Definition was modified to clarify the non-hematologic DLT definition. • Loncastuximab Tesirine was revised to clarify criteria for dose hold and resumption for non-hematologic and hematologic toxicity. • Premedication for Loncastuximab Tesirine and Treatment and Prophylaxis of Infusion-Related to Hypersensitivity Reactions were modified to allow the use of intravenous (IV) dexamethasone. • Adverse Events of Special Interest (AESIs) was added to provide information regarding reporting the AESI of major hemorrhage. • Laboratory Tests added hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) testing. • Table 9 was revised to show updated PK time points for C5 and C6 • Adverse Events was revised to clarify which treatment-emergent adverse events (TEAEs) were included in the statistical analysis.

09 Jan 2020

• Based on the observed complete response (CR) rate in participants who were enrolled and treated with loncastuximab tesirine and ibrutinib in Part 1, this trial was amended to a Phase 1/2 protocol. • The trial expanded enrollment to allow GCB DLBCL patients on study treatment. • The trial sample size was increased to approximately 161 patients, and Phase 2 evaluated efficacy in non-GCB DLBCL participants as its primary endpoint. • Supplementary secondary endpoints were added.

14 May 2020

• The trial was amended to allow for additional doses of loncastuximab tesirine to be administered on Day 1 of Cycles 5, 6, 9 and 10 in the Phase 2 portion of the study. • In addition, the Sponsor on a case-by-case review could have allowed participants benefitting clinically at 1 year to receive additional doses of study drug(s).

26 Mar 2021

• Extended the contraception duration for applicable participants to align with the current regulatory guidance; to update guidance to investigators regarding loncastuximab tesirine dose delays and modifications as well as prohibited medication for concurrent use with loncastuximab tesirine; and removed the loncastuximab tesirine dose adjustment for participants with a body mass index (BMI) ≥35kg/m^2. • Provided two clarifications: one regarding patient reported outcome (PRO) collection time points during the study follow-up and the other notifying that mantle cell lymphoma (MCL) participants enrolled into the Phase 2 part of the study will have central reviews of their scans. • Incorporated all country specific amendments from the country specific protocols to a global protocol to eliminate country specific protocols going forward.

31 Aug 2021

• Amended the study design for the Phase 2 by enrolling approximately 100 participants with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) to a new treatment cohort in which loncastuximab tesirine will be given every cycle (rather than intermittently) in combination with ibrutinib.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
08 Nov 2022	The study was early terminated before enrolling participants into the new, planned treatment cohort.	-

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

None reported

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Clinical Trial Results:
A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)

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Primary: Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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Clinical trials

Clinical Trial Results: A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)

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Primary: Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Primary: Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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Primary: Phase 1: Number of Participants With Serious TEAEs

Primary: Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)