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Clinical Trial Results:
A prospective, open-label, multicenter phase-II-trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by GA101 (obinutuzumab) and CAL-101 (idelalisib) followed by CAL-101 and GA101 maintenance in CLL patients (CLL2-BCG-trial of the GCLLSG)

Summary
EudraCT number	2014-000582-47
Trial protocol	DE
Global end of trial date	09 May 2022

Results information
Results version number	v2(current)
This version publication date	01 Dec 2023
First version publication date	28 Mar 2023
Other versions	v1
Version creation reason	Correction of full data set Corrections of reasons for end of treatment need to be done.

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

CLL2-BCG

ISRCTN number

US NCT number

NCT02445131

WHO universal trial number (UTN)

Other trial identifiers

PEI: 2331, Uni Köln: UNI-KOELN-1758

Sponsor organisation name

University of Cologne

Sponsor organisation address

Albertus-Magnus-Platz, Cologne, Germany, 50923

Public contact

Angelina Glatt, Department I of Internal Medicine, Cologne University Hospital, Kerpener Strasse 62, 50937 Cologne, +49 0221-478-88220, angelina.glatt@uk-koeln.de

Scientific contact

PD Dr. med. Paula Cramer, Department I of Internal Medicine, Cologne University Hospital, Kerpener Strasse 62, 50937 Cologne, +49 0221-478-88220, paula.cramer@uk-koeln.de

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

01 Sep 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 May 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the study is to evaluate the efficacy of a sequential regimen of two cycles of bendamustine, followed by a combination therapy of GA101 (obinutuzumab) and CAL-101 (idelalisib) followed by CAL-101 and GA101 maintenance in CLL patients.

Protection of trial subjects

Chapter 8.8 of the most current version of the study protocol includes extended warnings for cytopenias, infections, worsening of cardiac conditions, teratogenicity and mutagenicity, Stevens-Johnson-Syndrome, infusion related reactions, tumor lysis syndrome, hepatitis reactivation, progressive multifocal leukencephalopathy, immunogenicity, gastrointestinal perforation, diarrhea,elevated liver transaminadses, skinreactions,pneumonitis, associated with at least one of the three study drug. The chapters 8.5. include recommendation for concomitant medication, chapter 8.6. include recommendations for dose and schedule modifications.

Background therapy

The PI3K-inhibitor CAL-101 (idelalisib), was tested in phase-II and III-studies and showed very promising efficacy and a favorable toxicity profile. CAL-101 inhibits the migration and adhesion of CLL cells to the protecting microenvironment and thereby lead to a redistribution and mobilization of these cells to peripheral blood and cause a lymphocytosis. All antibodies, especially the highly effective GA101 may lead to early infusion-related side effects, such as cytokine-release- and tumor lysis-syndromes. In order to avoid additional, overlapping toxicities due to these distinctive features, these two drugs should be started sequentially and a debulking treatment with a mild chemotherapy could reduce the tumor load before the start of these two effective targeted agents. On the other hand, the combination of a drug that leads to a lymphocytosis through a redistribution of leukemic cells to the peripheral blood and a very effective antibody that acts predominantly in the peripheral blood and targets the redistributed cells, is a very attractive treatment approach with a synergistic mechanism of action and might have the potential to eradicate the residual CLL cells. Previous preclinical data raised concerns that CAL-101 (idelalisib) might have antagonistic effects on rituximab, due to an inhibitory effect of the kinase inhibitors on the immune effector mediated activity. This effect appeared to be less relevant for the combination of CAL-101 and the glycoengineered type-II antibody GA101 (obinutuzumab) as PI3K inhibition with CAL-101 had only minimal impact on the immune effector function of GA101 in vitro as measured in NK cell-mediated ADCC, macrophage-mediated ADCP and whole blood B-cell depletion.The toxicity profile of the combination of idelalisib and obinutuzumab is expected to be similar to the one observed with idelalisib and rituximab and to compare favorably to those of the chemotherapies currently used in the treatment of CLL.

Evidence for comparator

not applicable

Actual start date of recruitment

02 Mar 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 48

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Initially, it was planned to enroll 62 eligible patients . With the entry into force of amendment 2 the first-line stratum was closed after enrolment of 16 previously untreated patients. Due to a slow recruitment rate, the recruitment was closed early after 48 patients were enrolled .

Screening details

A total of 52 pts were screened and 48 pts were enrolled. Screening procedures include central testing , especially immunophenotyping for confirmation of CLL diagnosis. 4 Pts were not enrolled because of missing inclusion or present exclusion criteria.

Number of subjects started

52 ^[1]

Number of subjects completed

Reason: Number of subjects

missing inclusion or present exclusion criteria: 4

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 52 pts were screened and 48 pts were enrolled. Screening procedures include central testing, especially immunophenotyping for confirmation of CLL diagnosis. 4 Pts were not enrolled because of missing inclusion or present exclusion criteria.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

not applicable

Bendamustine (optional), idelalisib and obinutuzumab

Arm description

Two cycles of bendamustine were administered before induction with obinutuzumab and idelalisib unless the patient had a contraindication or a debulking was not clinically indicated. The induction treatment consisted of 6 cycles, each with a duration of 28 days; during the first cycle obinutuzumab was administered intravenously on days 1 (and 2), 8 and 15 as well as on day 1 of the following cycles. The continuous daily administration of idelalisib started in cycle two. On days with administration of both, idelalisib and obinutuzumab, oral intake of idelalisib was followed by intravenous administration of obinutuzumab. Patients received the first dosage of idelalisib on day 1 of the second cycle in clinic/outpatient clinic/private practice before the administration of obinutuzumab was started. Maintenance consisted of a maximum of 8 cycles idelalisib and 3monthly administered obinutuzumab until - 3 months after confirmation of MRD negativity or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

bendamustine

Investigational medicinal product code

Other name

ribomustin

Pharmaceutical forms

Powder for concentrate and solution for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bendamustine i.v. infusion: Cycles 1-2: Day 1: bendamustine 70 mg/m² i.v. Day 2: bendamustine 70 mg/m² i.v.

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

GA 101

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

GA101 (obinutuzumab) i.v. infusion: Cycles 1: Day 1: GA101 100 mg i.v. Day 1 (or 2): GA101 900 mg i.v. Day 8: GA101 1000 mg i.v. Day 15: GA101 1000 mg i.v. Cycles 2-6: Day 1: GA101 1000 mg i.v.

Investigational medicinal product name

Idelalisib

Investigational medicinal product code

CAL 101

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

CAL-101 (idelalisib) p.o.: Cycle 1: -- Cycles 2-6: Days 1-28: CAL-101 150 mg (1 tabl.) p.o. 1-0-1 CAL-101 tablets with a strength of 100 mg will be used in case of AEs (as described in the protocol, section 8.6.3 Dose and schedule modifications for CAL-101 (idelalisib).

Number of subjects in period 1	Bendamustine (optional), idelalisib and obinutuzumab
Started	48
Completed	16
Not completed	32
Consent withdrawn by subject	1
Patient refused treatment / did not cooperate	3
Adverse event, non-fatal	6
Death	3
Progressive disease	9
Novel safety data (Amendment 2)	10

Baseline characteristics

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Reporting group title

Overall Trial

Reporting group description

All patients enrolled in this trial and who have received at least one dose of study medication are included in the characteristics analysis.

Reporting group values	Overall Trial	Total
Number of subjects	48	48
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	23	23
From 65-84 years	25	25
85 years and over	0	0
Age continuous
median age
Units: years
median (inter-quartile range (Q1-Q3))	66 (58.0 to 74.8)	-
Gender categorical
Units: Subjects
Female	9	9
Male	39	39
Presence of del(17p)
Cytogenetic risk factor
Units: Subjects
Yes	11	11
No	37	37
IGHV mutational status
cytogenetic risk factor
Units: Subjects
unmutated	33	33
mutated	14	14
missing information	1	1
CLL-IPI risk group
International Prognostic Index used for CLL
Units: Subjects
low	2	2
intermediate	7	7
high	20	20
very high	18	18
missing	1	1
TP53 mutational status
cytogenetic risk factor
Units: Subjects
unmutated	31	31
mutated	17	17
Binet stage
Status of the disease
Units: Subjects
Binet A	14	14
Binet B	12	12
Binet C	22	22
Cumulative Illness Rating Scale.
Validated score to evaluate the comorbidity of included patients
Units: scores
median (inter-quartile range (Q1-Q3))	2 (1 to 5)	-
median of previous lines of treatment
Median number of previous lines of treatment
Units: numbers
median (inter-quartile range (Q1-Q3))	2 (1.0 to 3.8)	-
Observation time
The observation time is defined as time between date of enrolment and time point of last observation or death.
Units: months
median (inter-quartile range (Q1-Q3))	36.9 (19.3 to 39.3)	-

Subject analysis set title

First-line safety analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 16 patients included in the trial without previous line of treatment and one dose of any study treatment.

Subject analysis set title

Refractory/relapsed safety analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 32 patients included in the trial with at least one previous line of treatment and at least one dose of any study treatment

Subject analysis set title

Full analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The primary dataset for efficacy analyses is derived from the full analysis set (FAS). This dataset includes all patients enrolled to the trial who received at least one dose of induction treatment, whether withdrawn prematurely or not. The allocation to the FAS will be determined for every patient according to the previously defined criteria.

Subject analysis set title

First-line analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 10 patients included in the trial without previous line of treatment who have received at least one dose of induction treatment.

Subject analysis set title

Refractory/relapsed analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 30 patients included in the trial with at least one previous line of treatment and at least one dose of induction treatment

Subject analysis sets values	First-line safety analysis set	Refractory/relapsed safety analysis set	Full analysis set	First-line analysis set	Refractory/relapsed analysis set
Number of subjects	16	32	40	10	30
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	7	16	18	3	15
From 65-84 years	9	16	22	7	15
85 years and over	0	0	0	0	0
Age continuous
median age
Units: years
median (inter-quartile range (Q1-Q3))	66.5 (58.3 to 72.8)	65.5 (56.3 to 75.0)	67 (57 to 75)	71 (60 to 74)	66 (56 to 75)
Gender categorical
Units: Subjects
Female	2	7	8	1	7
Male	14	25	32	9	23
Presence of del(17p)
Cytogenetic risk factor
Units: Subjects
Yes	0	11	11	0	11
No	16	21	29	10	19
IGHV mutational status
cytogenetic risk factor
Units: Subjects
unmutated	8	25	28	4	24
mutated	8	6	11	6	5
missing information	0	1	1	0	1
CLL-IPI risk group
International Prognostic Index used for CLL
Units: Subjects
low	1	1	0	0	0
intermediate	5	2	5	3	2
high	10	10	16	7	9
very high	0	18	18	0	18
missing	0	1	1	0	1
TP53 mutational status
cytogenetic risk factor
Units: Subjects
unmutated	16	15	23	10	13
mutated	0	17	17	0	17
Binet stage
Status of the disease
Units: Subjects
Binet A	5	9	9	1	8
Binet B	5	7	10	4	6
Binet C	6	16	21	5	16
Cumulative Illness Rating Scale.
Validated score to evaluate the comorbidity of included patients
Units: scores
median (inter-quartile range (Q1-Q3))	2 (1.0 to 2.8)	3 (1.3 to 5.8)	3 (1 to 6)	2 (1 to 4)	3 (1 to 6)
median of previous lines of treatment
Median number of previous lines of treatment
Units: numbers
median (inter-quartile range (Q1-Q3))	0 (0 to 0)	2 (1.0 to 3.8)	0 (0 to 0)	0 (0 to 0)	2 (1 to 4)
Observation time
The observation time is defined as time between date of enrolment and time point of last observation or death.
Units: months
median (inter-quartile range (Q1-Q3))	32.5 (17.1 to 39.6)	37.4 (19.3 to 38.7)	37.4 (28.1 to 39.6)	39.3 (32.5 to 39.7)	37.4 (19.3 to 39.0)

End points

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Reporting group title

Bendamustine (optional), idelalisib and obinutuzumab

Reporting group description

Subject analysis set title

First-line safety analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 16 patients included in the trial without previous line of treatment and one dose of any study treatment.

Subject analysis set title

Refractory/relapsed safety analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 32 patients included in the trial with at least one previous line of treatment and at least one dose of any study treatment

Subject analysis set title

Full analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

First-line analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 10 patients included in the trial without previous line of treatment who have received at least one dose of induction treatment.

Subject analysis set title

Refractory/relapsed analysis set

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set consists of 30 patients included in the trial with at least one previous line of treatment and at least one dose of induction treatment

Primary: Response at end of induction treatment

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End point title

Response at end of induction treatment ^[1]

End point description

Overall response rate (ORR) at final restaging (RE) 12 weeks after start of the last cycle of induction therapy (end of induction treatment response = EOIT) will be used as primary parameter of efficacy. In the ORR all patients achieving a (clinical) complete response (CR) / (clinical) complete response with incomplete recovery of the bone marrow (CRi), partial response (PR) and PR with lymphocytosis will be included. The response will be assessed according to the iwCLL criteria. In 6 patients the response at final restaging was not available at data cut-off: response from interim staging was used for one patient who discontinued treatment early due to adverse event. Initial response was used for 4 patients who discontinued treatment due to progressive disease (n=2) or death (n=2). One patient discontinued treatment due to adverse event before interim staging, so that no response assesment was available.

End point type

Primary

End point timeframe

12 weeks after start of the last cycle of induction therapy (end of induction treatment response = EOIT)

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 evaluation of the primary efficacy variable ORR will be based on the estimation of the ORR and its corresponding exact confidence interval based on the FAS. No inferential test will be performed. The goal is to obtain preliminary estimates. Exact confidence intervals will be calculated using the Clopper-Pearson method. Pairwise comparisons of the strata will be performed descriptively only.

End point values	Full analysis set	First-line analysis set	Refractory/relapsed analysis set
Number of subjects analysed	40	10	30
Units: Patients
Clinical complete remission	6	3	3
Clinical CR with incomplete bone marrow recovery	1	0	1
Partial remission	25	7	18
Stable disease	1	0	1
Progressive disease	6	0	6
Missing	1	0	1

No statistical analyses for this end point

Primary: Overall response rate at end of induction

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End point title

Overall response rate at end of induction ^[2]

End point description

End point type

Primary

End point timeframe

12 weeks after start of the last cycle of induction therapy (end of induction treatment response = EOIT).

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: The evaluation of the primary efficacy variable ORR will be based on the estimation of the ORR and its corresponding exact confidence interval based on the FAS. No inferential test will be performed. The goal is to obtain preliminary estimates. Exact confidence intervals will be calculated using the Clopper-Pearson method. Pairwise comparisons of the strata will be performed descriptively only.

End point values	Full analysis set	First-line analysis set	Refractory/relapsed analysis set
Number of subjects analysed	40	10	30
Units: Percentage
number (not applicable)
Overall response rate	80.0	100.0	73.3
95% Confidence interval: lower bound	64.4	69.2	54.1
95% Confidence interval: upper bound	90.9	100.0	87.7

No statistical analyses for this end point

Secondary: Minimal residual disease at end of induction treatment

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End point title

Minimal residual disease at end of induction treatment

End point description

The rate of MRD responses is assessed with four-color-flow cytometry (FACS) and MRD negativity is arbitrarily defined as one CLL cell per 10,000 leukocytes [0.01 %], i.e. <10-4 [1E-4] and patients are defined as MRD negative if their disease burden is below this threshold. MRD in peripheral blood will be analyzed in patients responding to induction treatment at the time point of final restaging.

End point type

Secondary

End point timeframe

MRD levels of the peripheral blood will be assessed at final restaging in all patients responding to induction treatment

End point values	Full analysis set	First-line analysis set	Refractory/relapsed analysis set
Number of subjects analysed	40	10	30
Units: Patients
Negative (< 10-4)	9	3	6
Intermediate (>= 10-4 & < 10-2)	15	3	12
Positive (>= 10-2)	5	1	4
Missing	11	3	8

No statistical analyses for this end point

Secondary: Progression-free Survival

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End point title

Progression-free Survival

End point description

Progression-free survival (PFS) will be calculated until first documented disease progression (determined using standard iwCLL guidelines [2008]) or death, whichever occurs first. Patients for whom no documented event for PFS is available at the time of analysis will be censored at the time point of last follow-up information they were assessed to be event-free. Patients are followed for progression-free survival at each study visit. Analyses of time-to-event endpoints will be performed using Kaplan-Meier methods.

End point type

Secondary

End point timeframe

Data for this endpoint will be collected from first study visit until last visit of each study subject.

End point values	Full analysis set	First-line analysis set	Refractory/relapsed analysis set
Number of subjects analysed	40	10	30
Units: percentage/months
number (not applicable)
Median PFS (months)	34.9	44.3	32.3
3-month survival (%)	97.5	100.0	96.7
6-month survival (%)	85.0	90.0	83.3
12-month survival (%)	75.0	90.0	70.0
24-month survival (%)	61.7	68.6	59.5
36-month survival (%)	47.6	68.6	40.9

Cox regression regarding progression-free survival

Statistical analysis description

Progression-free survival was also analyzed separately for first-line patients and refractory/relapsed patients. To compare both groups regarding PFS, a cox regression was performed to test refractory/relapsed patients vs. first-line patients.

Comparison groups

First-line analysis set v Refractory/relapsed analysis set

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

other

Method

Parameter type

Cox proportional hazard

Point estimate

1.964

Confidence interval

level

95%

sides

2-sided

lower limit

0.666

upper limit

5.795

Secondary: Overall survival

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End point title

Overall survival

End point description

Overall survival (OS) will be calculated from the date of enrolment to the date of death due to any cause. Patients who have not yet died at the time of analysis will be censored at the time of last follow-up information they were assessed to be alive. Analyses of time-to-event endpoints will be performed using Kaplan-Meier methods.

End point type

Secondary

End point timeframe

Data for this endpoint will be collected from first study visit until last visit of each study subject.

End point values	Full analysis set	First-line analysis set	Refractory/relapsed analysis set
Number of subjects analysed	40	10 ^[3]	30
Units: percentage/months
number (not applicable)
Median OS	46.4	0	46.4
3-month survival (%)	100.0	100.0	100.0
6-month survival (%)	92.3	90.0	93.1
12-month survival (%)	84.1	90.0	81.9
24-month survival (%)	81.0	90.0	77.6
36-month survival (%)	81.0	90.0	77.6

Notes
[3] - Median overall survival was not reached within this subgroup.

Cox regression regarding overall survival

Statistical analysis description

Overall survival was also analyzed separately for first-line patients and refractory/relapsed patients. To compare both groups regarding OS, a cox regression was performed to test refractory/relapsed patients vs. first-line patients.

Comparison groups

First-line analysis set v Refractory/relapsed analysis set

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

other

Method

Parameter type

Cox proportional hazard

Point estimate

2.585

Confidence interval

level

95%

sides

2-sided

lower limit

0.318

upper limit

21.028

Adverse events

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Timeframe for reporting adverse events

Timeframe for AE

Adverse event reporting additional description

AE additional description

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

RR patient

Reporting group description

Reporting group title

FL patient

Reporting group description

Serious adverse events	RR patient	FL patient
Total subjects affected by serious adverse events
subjects affected / exposed	30 / 32 (93.75%)	10 / 16 (62.50%)
number of deaths (all causes)	8	1
number of deaths resulting from adverse events	7	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acanthoma
Additional description: Acanthoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
Additional description: Basal cell carcinoma
subjects affected / exposed	4 / 32 (12.50%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Benign neoplasm of prostate
Additional description: Benign neoplasm of prostate
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bowen's disease
Additional description: Bowen's disease
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
Additional description: Malignant melanoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal carcinoma
Additional description: Oesophageal carcinoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of head and neck
Additional description: Squamous cell carcinoma of head and neck
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
Additional description: Squamous cell carcinoma
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin papilloma
Additional description: Skin papilloma
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of skin
Additional description: Squamous cell carcinoma of skin
subjects affected / exposed	1 / 32 (3.13%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
Additional description: Hypertensive crisis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
Additional description: Thrombosis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General physical health deterioration
Additional description: General physical health deterioration
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriasis
Additional description: Psoriasis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
Additional description: Hypersensitivity
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Graft versus host disease in lung
Additional description: Graft versus host disease in lung
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea at rest
Additional description: Dyspnoea at rest
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
Additional description: Dyspnoea
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
Additional description: Pneumonitis
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
Additional description: Pulmonary embolism
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
Additional description: Anxiety
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
Additional description: Depression
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
Additional description: Femur fracture
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
Additional description: Infusion related reaction
subjects affected / exposed	0 / 32 (0.00%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
Additional description: Angina pectoris
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
Additional description: Atrial fibrillation
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
Additional description: Cardiac arrest
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
Additional description: Cardiac failure
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
Additional description: Coronary artery disease
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
Additional description: Myocardial infarction
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain hypoxia
Additional description: Brain hypoxia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
Additional description: Ischaemic stroke
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
Additional description: Syncope
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
Additional description: Neutropenia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
Additional description: Pancytopenia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
Additional description: Thrombocytopenia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Autoimmune colitis
Additional description: Autoimmune colitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
Additional description: Faecaloma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
Additional description: Enterocolitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
Additional description: Diarrhoea
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
Additional description: Colitis
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
Additional description: Cholecystitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
Additional description: Hepatic failure
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Actinic keratosis
Additional description: Actinic keratosis
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Guttate psoriasis
Additional description: Guttate psoriasis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Precancerous skin lesion
Additional description: Precancerous skin lesion
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
Additional description: Hydronephrosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
Additional description: Renal impairment
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
Additional description: Renal failure
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
Additional description: Urinary tract obstruction
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Thyroiditis subacute
Additional description: Thyroiditis subacute
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
Additional description: Osteoarthritis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Atypical pneumonia
Additional description: Atypical pneumonia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspergillus infection
Additional description: Aspergillus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
Additional description: Bronchitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
Additional description: Bacterial infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
Additional description: Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
Additional description: Febrile infection
subjects affected / exposed	1 / 32 (3.13%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
Additional description: Escherichia sepsis
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0
Cytomegalovirus infection reactivation
Additional description: Cytomegalovirus infection reactivation
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic sinusitis
Additional description: Chronic sinusitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster infection neurological
Additional description: Herpes zoster infection neurological
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nasopharyngitis
Additional description: Nasopharyngitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
Additional description: Neutropenic sepsis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal candidiasis
Additional description: Oesophageal candidiasis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral herpes
Additional description: Oral herpes
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
Additional description: Pharyngitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural infection
Additional description: Pleural infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
Additional description: Pulmonary sepsis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonia respiratory syncytial viral
Additional description: Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia influenzal
Additional description: Pneumonia influenzal
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumonia
Additional description: Pneumonia
subjects affected / exposed	5 / 32 (15.63%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	4 / 7	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
Additional description: Pneumocystis jirovecii pneumonia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Sepsis
Additional description: Sepsis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
Additional description: Septic shock
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Superinfection
Additional description: Superinfection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic candida
Additional description: Systemic candida
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
Additional description: Urinary tract infection
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella zoster virus infection
Additional description: Varicella zoster virus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
Additional description: Upper respiratory tract infection
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
Additional description: Hyponatraemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperuricaemia
Additional description: Hyperuricaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
Additional description: Tumour lysis syndrome
subjects affected / exposed	4 / 32 (12.50%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	RR patient	FL patient
Total subjects affected by non serious adverse events
subjects affected / exposed	31 / 32 (96.88%)	12 / 16 (75.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acanthoma
Additional description: Acanthoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Skin papilloma
Additional description: Skin papilloma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Vascular disorders
Haematoma
Additional description: Haematoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Hypertension
Additional description: Hypertension
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Hypertensive crisis
Additional description: Hypertensive crisis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Infarction
Additional description: Infarction
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Pelvic venous thrombosis
Additional description: Pelvic venous thrombosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Phlebitis
Additional description: Phlebitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Thrombophlebitis
Additional description: Thrombophlebitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Thrombosis
Additional description: Thrombosis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
General disorders and administration site conditions
Chills
Additional description: Chills
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Extravasation
Additional description: Extravasation
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Fatigue
Additional description: Fatigue
subjects affected / exposed	6 / 32 (18.75%)	2 / 16 (12.50%)
occurrences all number	10	2
General physical health deterioration
Additional description: General physical health deterioration
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Hernia
Additional description: Hernia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Malaise
Additional description: Malaise
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Influenza like illness
Additional description: Influenza like illness
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Mucosal inflammation
Additional description: Mucosal inflammation
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Oedema
Additional description: Oedema
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Oedema peripheral
Additional description: Oedema peripheral
subjects affected / exposed	3 / 32 (9.38%)	1 / 16 (6.25%)
occurrences all number	3	1
Pyrexia
Additional description: Pyrexia
subjects affected / exposed	4 / 32 (12.50%)	1 / 16 (6.25%)
occurrences all number	4	1
Immune system disorders
Allergic reaction to excipient
Additional description: Allergic reaction to excipient
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Acute graft versus host disease in skin
Additional description: Acute graft versus host disease in skin
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Allergy to arthropod sting
Additional description: Allergy to arthropod sting
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Drug hypersensitivity
Additional description: Drug hypersensitivity
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Immunodeficiency
Additional description: Immunodeficiency
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Respiratory, thoracic and mediastinal disorders
Cough
Additional description: Cough
subjects affected / exposed	7 / 32 (21.88%)	2 / 16 (12.50%)
occurrences all number	9	2
Bronchospasm
Additional description: Bronchospasm
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dyspnoea
Additional description: Dyspnoea
subjects affected / exposed	2 / 32 (6.25%)	1 / 16 (6.25%)
occurrences all number	2	1
Dyspnoea exertional
Additional description: Dyspnoea exertional
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Epistaxis
Additional description: Epistaxis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Oropharyngeal pain
Additional description: Oropharyngeal pain
subjects affected / exposed	0 / 32 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Pleural effusion
Additional description: Pleural effusion
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Rhinitis allergic
Additional description: Rhinitis allergic
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Disorientation
Additional description: Disorientation
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Depression
Additional description: Depression
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Delirium
Additional description: Delirium
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Insomnia
Additional description: Insomnia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Nervousness
Additional description: Nervousness
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Sleep disorder
Additional description: Sleep disorder
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Investigations
Blood creatinine increased
Additional description: Blood creatinine increased
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Blood bilirubin increased
Additional description: Blood bilirubin increased
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Blood potassium decreased
Additional description: Blood potassium decreased
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Gamma-glutamyltransferase increased
Additional description: Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Immunoglobulins decreased
Additional description: Immunoglobulins decreased
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Hepatic enzyme increased
Additional description: Hepatic enzyme increased
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Pneumocystis test positive
Additional description: Pneumocystis test positive
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Serum ferritin decreased
Additional description: Serum ferritin decreased
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Weight decreased
Additional description: Weight decreased
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Transaminases increased
Additional description: Transaminases increased
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	5	0
Injury, poisoning and procedural complications
Arthropod bite
Additional description: Arthropod bite
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Facial bones fracture
Additional description: Facial bones fracture
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Fall
Additional description: Fall
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Infusion related reaction
Additional description: Infusion related reaction
subjects affected / exposed	12 / 32 (37.50%)	2 / 16 (12.50%)
occurrences all number	13	2
Joint injury
Additional description: Joint injury
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Nail injury
Additional description: Nail injury
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Cardiac disorders
Arrhythmia
Additional description: Arrhythmia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Atrial fibrillation
Additional description: Atrial fibrillation
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Coronary artery disease
Additional description: Coronary artery disease
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Left ventricular failure
Additional description: Left ventricular failure
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Tachycardia
Additional description: Tachycardia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Nervous system disorders
Carpal tunnel syndrome
Additional description: Carpal tunnel syndrome
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dysgeusia
Additional description: Dysgeusia
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Dizziness
Additional description: Dizziness
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Essential tremor
Additional description: Essential tremor
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Headache
Additional description: Headache
subjects affected / exposed	8 / 32 (25.00%)	1 / 16 (6.25%)
occurrences all number	10	1
Parkinson's disease
Additional description: Parkinson's disease
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Polyneuropathy
Additional description: Polyneuropathy
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Post herpetic neuralgia
Additional description: Post herpetic neuralgia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Paraesthesia
Additional description: Paraesthesia
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Sciatica
Additional description: Sciatica
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Taste disorder
Additional description: Taste disorder
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	2	0
Syncope
Additional description: Syncope
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tremor
Additional description: Tremor
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Anaemia
Additional description: Anaemia
subjects affected / exposed	14 / 32 (43.75%)	2 / 16 (12.50%)
occurrences all number	15	2
Eosinophilia
Additional description: Eosinophilia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Febrile neutropenia
Additional description: Febrile neutropenia
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Leukopenia
Additional description: Leukopenia
subjects affected / exposed	3 / 32 (9.38%)	2 / 16 (12.50%)
occurrences all number	6	2
Lymph node pain
Additional description: Lymph node pain
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Neutropenia
Additional description: Neutropenia
subjects affected / exposed	13 / 32 (40.63%)	4 / 16 (25.00%)
occurrences all number	21	4
Thrombocytopenia
Additional description: Thrombocytopenia
subjects affected / exposed	10 / 32 (31.25%)	2 / 16 (12.50%)
occurrences all number	16	2
Ear and labyrinth disorders
Deafness
Additional description: Deafness
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tinnitus
Additional description: Tinnitus
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Vertigo
Additional description: Vertigo
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Eye disorders
Cataract
Additional description: Cataract
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Dry conjunctives
Additional description: Dry conjunctives
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Dry eye
Additional description: Dry eye
subjects affected / exposed	2 / 32 (6.25%)	1 / 16 (6.25%)
occurrences all number	2	1
Eyelid bleeding
Additional description: Eyelid bleeding
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Lacrimation increased
Additional description: Lacrimation increased
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal pain
Additional description: Abdominal pain
subjects affected / exposed	3 / 32 (9.38%)	1 / 16 (6.25%)
occurrences all number	3	1
Abdominal pain upper
Additional description: Abdominal pain upper
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Aphthous ulcer
Additional description: Aphthous ulcer
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Autoimmune colitis
Additional description: Autoimmune colitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Colitis
Additional description: Colitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Constipation
Additional description: Constipation
subjects affected / exposed	3 / 32 (9.38%)	1 / 16 (6.25%)
occurrences all number	4	2
Diarrhoea
Additional description: Diarrhoea
subjects affected / exposed	8 / 32 (25.00%)	1 / 16 (6.25%)
occurrences all number	10	2
Dry mouth
Additional description: Dry mouth
subjects affected / exposed	2 / 32 (6.25%)	2 / 16 (12.50%)
occurrences all number	2	2
Dysbiosis
Additional description: Dysbiosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dyspepsia
Additional description: Dyspepsia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dysphagia
Additional description: Dysphagia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Faeces soft
Additional description: Faeces soft
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Gastrointestinal disorder
Additional description: Gastrointestinal disorder
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Gastrointestinal pain
Additional description: Gastrointestinal pain
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Haemorrhoids
Additional description: Haemorrhoids
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Flatulence
Additional description: Flatulence
subjects affected / exposed	2 / 32 (6.25%)	1 / 16 (6.25%)
occurrences all number	2	2
Nausea
Additional description: Nausea
subjects affected / exposed	5 / 32 (15.63%)	3 / 16 (18.75%)
occurrences all number	5	3
Oral discharge
Additional description: Oral discharge
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Tongue discomfort
Additional description: Tongue discomfort
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tongue oedema
Additional description: Tongue oedema
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tooth loss
Additional description: Tooth loss
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Alopecia
Additional description: Alopecia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Angioedema
Additional description: Angioedema
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dry skin
Additional description: Dry skin
subjects affected / exposed	4 / 32 (12.50%)	2 / 16 (12.50%)
occurrences all number	5	2
Drug eruption
Additional description: Drug eruption
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dermatosis
Additional description: Dermatosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dermatitis allergic
Additional description: Dermatitis allergic
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Eczema
Additional description: Eczema
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Erythema
Additional description: Erythema
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Hyperhidrosis
Additional description: Hyperhidrosis
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Night sweats
Additional description: Night sweats
subjects affected / exposed	3 / 32 (9.38%)	1 / 16 (6.25%)
occurrences all number	5	2
Pruritus
Additional description: Pruritus
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Psoriasis
Additional description: Psoriasis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Rash
Additional description: Rash
subjects affected / exposed	4 / 32 (12.50%)	6 / 16 (37.50%)
occurrences all number	4	6
Rash maculo-papular
Additional description: Rash maculo-papular
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Skin fissures
Additional description: Skin fissures
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Urticaria
Additional description: Urticaria
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Acute kidney injury
Additional description: Acute kidney injury
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Calculus bladder
Additional description: Calculus bladder
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Chronic kidney disease
Additional description: Chronic kidney disease
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Haematuria
Additional description: Haematuria
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Prerenal failure
Additional description: Prerenal failure
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Urinary tract obstruction
Additional description: Urinary tract obstruction
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
Additional description: Arthralgia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Back pain
Additional description: Back pain
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Bone pain
Additional description: Bone pain
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Flank pain
Additional description: Flank pain
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Meniscal degeneration
Additional description: Meniscal degeneration
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Muscle spasms
Additional description: Muscle spasms
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Myalgia
Additional description: Myalgia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	3	0
Neck pain
Additional description: Neck pain
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Osteoarthritis
Additional description: Osteoarthritis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	2	0
Spondylitis
Additional description: Spondylitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Infections and infestations
Bacterial infection
Additional description: Bacterial infection
subjects affected / exposed	3 / 32 (9.38%)	0 / 16 (0.00%)
occurrences all number	3	0
Clostridium difficile colitis
Additional description: Clostridium difficile colitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Conjunctivitis
Additional description: Conjunctivitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Candida infection
Additional description: Candida infection
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Bronchopulmonary aspergillosis
Additional description: Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Bronchitis
Additional description: Bronchitis
subjects affected / exposed	6 / 32 (18.75%)	2 / 16 (12.50%)
occurrences all number	6	3
Chronic sinusitis
Additional description: Chronic sinusitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Device related infection
Additional description: Device related infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Epididymitis
Additional description: Epididymitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Erysipelas
Additional description: Erysipelas
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Febrile infection
Additional description: Febrile infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Fungal skin infection
Additional description: Fungal skin infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Gastroenteritis
Additional description: Gastroenteritis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Gingivitis
Additional description: Gingivitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Genital herpes
Additional description: Genital herpes
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Haemophilus infection
Additional description: Haemophilus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Herpes virus infection
Additional description: Herpes virus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Herpes zoster
Additional description: Herpes zoster
subjects affected / exposed	4 / 32 (12.50%)	1 / 16 (6.25%)
occurrences all number	4	1
Infection
Additional description: Infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Influenza
Additional description: Influenza
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Laryngopharyngitis
Additional description: Laryngopharyngitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Lip infection
Additional description: Lip infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Mucosal infection
Additional description: Mucosal infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Nasopharyngitis
Additional description: Nasopharyngitis
subjects affected / exposed	11 / 32 (34.38%)	4 / 16 (25.00%)
occurrences all number	16	6
Oesophageal candidiasis
Additional description: Oesophageal candidiasis
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Oral candidiasis
Additional description: Oral candidiasis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Oral fungal infection
Additional description: Oral fungal infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Oral herpes
Additional description: Oral herpes
subjects affected / exposed	4 / 32 (12.50%)	1 / 16 (6.25%)
occurrences all number	4	1
Pneumonia
Additional description: Pneumonia
subjects affected / exposed	4 / 32 (12.50%)	0 / 16 (0.00%)
occurrences all number	4	0
Pneumonia pneumococcal
Additional description: Pneumonia pneumococcal
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Respiratory tract infection
Additional description: Respiratory tract infection
subjects affected / exposed	1 / 32 (3.13%)	1 / 16 (6.25%)
occurrences all number	1	1
Rhinitis
Additional description: Rhinitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Rhinovirus infection
Additional description: Rhinovirus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Sinusitis
Additional description: Sinusitis
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Upper respiratory tract infection
Additional description: Upper respiratory tract infection
subjects affected / exposed	4 / 32 (12.50%)	3 / 16 (18.75%)
occurrences all number	4	3
Urinary tract infection
Additional description: Urinary tract infection
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	3	0
Varicella zoster virus infection
Additional description: Varicella zoster virus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Decreased appetite
Additional description: Decreased appetite
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Diabetes mellitus
Additional description: Diabetes mellitus
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Dehydration
Additional description: Dehydration
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Folate deficiency
Additional description: Folate deficiency
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Gout
Additional description: Gout
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0
Hypercalcaemia
Additional description: Hypercalcaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	3	0
Hyperkalaemia
Additional description: Hyperkalaemia
subjects affected / exposed	2 / 32 (6.25%)	1 / 16 (6.25%)
occurrences all number	2	1
Hyperuricaemia
Additional description: Hyperuricaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	2	0
Hypokalaemia
Additional description: Hypokalaemia
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	3	0
Iron deficiency
Additional description: Iron deficiency
subjects affected / exposed	2 / 32 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	0
Vitamin D deficiency
Additional description: Vitamin D deficiency
subjects affected / exposed	1 / 32 (3.13%)	0 / 16 (0.00%)
occurrences all number	1	0

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Were there any global substantial amendments to the protocol? Yes

02 Dec 2015

A new version of the investigator's brochure for obinutuzumab was submitted aand consequently the informed consent form was emended. ICF v2.1 12.01.2016, 1st extension ICF 1.1 12.01.2016

08 Jul 2016

Due an unexpected incidence of infections and treatment related mortality in other studies with idelalisib as IMP not under the sponsorship of the university of Cologne, the recruitment for this study was put on hold and competent authority and ethic committees informed about the stopp of recruitment. After evaluation of the new safety information, administration of idelalisib was discontinued in all first-line patients, further recruitment was limited to relapsed/refractory patients with high-risk features (see also chapter 6. Trial population) and a close monitoring with laboratory assessments, including a CMV screening at least every 14 days during the induction treatment with idelalisib (see 7.4.2 Monitoring during treatment with CAL-101 (idelalisib)) was implemented with the second amendment.

18 Aug 2016

New version of the investigator's brochure for idelalisib and consequently amendment of informed consent form Description and comments: ICF v4.1 23.08.2016, 3rd extension ICF (relapsed/refractory patients) v.1.1 23.08.2016

19 Sep 2016

New version of the investigator's brochure for idelalisib

08 Dec 2016

New version of the investigator's brochure for Obinutuzumab and consequently amendment of informed consent form: Description and comments: ICF v5.0 17.11.2016, ICF extension 4. Amendment v1.0 17.11.2016

06 Jun 2017

addendum to Investigator's brochure for obinutuzumab

15 Aug 2019

New Safety Reference Documents: Description and comments: ICF v6.0 16.04.2019, ICF extension Amendment 5 v1.0 04.06.2019

18 May 2020

Early closure of recruitment due to low interest of participating sites and to low recruitment. Recruitment was closed after 48 of 62 planned patienst were recruited.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Mar 2016	Due an unexpected incidence of infections and treatment related mortality in other studies with idelalisib as IMP not under the sponsorship of the university of Cologne, the recruitment for this study was put on hold and competent authority and ethic committees informed about the stopp of recruitment. After evaluation of the new safety information, administration of idelalisib was discontinued in all first-line patients, further recruitment was limited to relapsed/refractory patients with high-risk features (see also chapter 6. Trial population) and a close monitoring with laboratory assessments, including a CMV screening at least every 14 days during the induction treatment with idelalisib (see 7.4.2 Monitoring during treatment with CAL-101 (idelalisib)) was implemented with the second amendment.	08 Jul 2016

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

In this trial with the combination of obinutuzumab and idelalisib, the known idelalisib toxicities were confirmed. Thus, this combination should be used with caution and only if other treatment options cannot be used.

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Clinical Trial Results:
A prospective, open-label, multicenter phase-II-trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by GA101 (obinutuzumab) and CAL-101 (idelalisib) followed by CAL-101 and GA101 maintenance in CLL patients (CLL2-BCG-trial of the GCLLSG)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Response at end of induction treatment

Primary: Response at end of induction treatment

Primary: Overall response rate at end of induction

Primary: Overall response rate at end of induction

Secondary: Minimal residual disease at end of induction treatment

Secondary: Minimal residual disease at end of induction treatment

Secondary: Progression-free Survival

Secondary: Progression-free Survival

Secondary: Overall survival

Secondary: Overall survival

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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