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Clinical Trial Results:
A Phase II Clinical Trial of MK-3475 (Pembrolizumab) in Subjects with Relapsed or Refractory (R/R) Classical Hodgkin Lymphoma (cHL)

Summary
EudraCT number	2014-004482-24
Trial protocol	SE NO ES NL DE AT HU IE FR GB GR
Global end of trial date	18 Sep 2023

Results information
Results version number	v1(current)
This version publication date	28 Sep 2024
First version publication date	28 Sep 2024
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

3475-087

ISRCTN number

-

US NCT number

NCT02453594

WHO universal trial number (UTN)

-

Sponsor organisation name

Merck Sharp & Dohme LLC

Sponsor organisation address

126 East Lincoln Avenue, Rahway, NJ, United States, P.O. Box 2000

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

18 Sep 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Sep 2023

Global end of trial reached?

Yes

Global end of trial date

18 Sep 2023

Was the trial ended prematurely?

No

Main objective of the trial

This is a study of pembrolizumab (MK-3475) for participants with relapsed/refractory classical Hodgkin Lymphoma (RRcHL) who: 1) have failed to achieve a response or progressed after autologous stem cell transplant (auto-SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT or 2) were unable to achieve a Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV or 3) have failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

10 Jun 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

France: 25

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Greece: 9

Country: Number of subjects enrolled

Hungary: 5

Country: Number of subjects enrolled

Israel: 12

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Japan: 10

Country: Number of subjects enrolled

Norway: 3

Country: Number of subjects enrolled

Russian Federation: 14

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

Sweden: 11

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

United States: 51

Country: Number of subjects enrolled

Netherlands: 1

Worldwide total number of subjects

211

EEA total number of subjects

94

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

193

From 65 to 84 years

18

85 years and over

0

Subject disposition

Top of page

Recruitment details

-

Screening details

Males and females with relapsed or refractory de novo classical Hodgkin lymphoma (RRcHL) of at least 18 years of age were enrolled in this study.

Period 1 title

Randomized

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Participants with RRcHL who failed to achieve a response or progressed after auto-stem cell transplant (SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT received pembrolizumab, 200 mg, intravenously (IV) every 3 weeks (Q3W) on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

KEYTRUDA®

Pharmaceutical forms

Infusion

Routes of administration

Intracavernous use

Dosage and administration details

200 mg every 3 weeks (Q3W) on Day 1 of each 21-day cycle for up to 24 months.

Cohort 2

Arm description

Participants with RRcHL who were unable to achieve Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

KEYTRUDA®

Pharmaceutical forms

Infusion

Routes of administration

Intracavernous use

Dosage and administration details

200 mg Q3W on Day 1 of each 21-day cycle for up to 24 months.

Cohort 3

Arm description

Participants with RRcHL who failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle, up to 35 cycles for up to 24 months. These participants may or may not have received BV as part of primary treatment or salvage treatment.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

KEYTRUDA®

Pharmaceutical forms

Infusion

Routes of administration

Intracavernous use

Dosage and administration details

200 mg Q3W on Day 1 of each 21-day cycle for up to 24 months.

Number of subjects in period 1	Cohort 1	Cohort 2	Cohort 3
Started	69	81	61
Treated	69	81	60
Completed	69	81	60
Not completed	0	0	1
Protocol deviation	-	-	1

Period 2 title

Treated

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Participants with RRcHL who failed to achieve a response or progressed after auto-stem cell transplant (SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT received pembrolizumab, 200 mg, intravenously (IV) every 3 weeks (Q3W) on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

KEYTRUDA®

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg Q3W on Day 1 of each 21-day cycle for up to 24 months.

Cohort 2

Arm description

Participants with RRcHL who were unable to achieve Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

KEYTRUDA®

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg Q3W on Day 1 of each 21-day cycle for up to 24 months.

Cohort 3

Arm description

Participants with RRcHL who failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle, up to 35 cycles for up to 24 months. These participants may or may not have received BV as part of primary treatment or salvage treatment.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

KEYTRUDA®

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg Q3W on Day 1 of each 21-day cycle for up to 24 months.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 was enrolled participants which was not the baseline period. The baseline period was treated participants.

Number of subjects in period 2 ^[2]	Cohort 1	Cohort 2	Cohort 3
Started	69	81	60
Second Course Pembrolizumab	10	7	3
Completed	0	0	0
Not completed	69	81	60
Adverse event, serious fatal	20	24	16
Consent withdrawn by subject	7	9	11
Physician decision	2	4	-
Cohort Was Closed	17	21	14
Site Terminated by Sponsor	1	-	1
Study Terminated by Sponsor	16	9	16
Lost to follow-up	6	14	2

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The baseline period was not the worldwide number enrolled; but rather the number treated.

Baseline characteristics

Top of page

Reporting group title

Cohort 1

Reporting group description

Participants with RRcHL who failed to achieve a response or progressed after auto-stem cell transplant (SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT received pembrolizumab, 200 mg, intravenously (IV) every 3 weeks (Q3W) on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 2

Reporting group description

Participants with RRcHL who were unable to achieve Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 3

Reporting group description

Participants with RRcHL who failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle, up to 35 cycles for up to 24 months. These participants may or may not have received BV as part of primary treatment or salvage treatment.

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Total
Number of subjects	69	81	60	210
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	69	66	57	192
From 65-84 years	0	15	3	18
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	37.0 ( 10.9 )	42.3 ( 17.4 )	36.8 ( 13.4 )	-
Sex: Female, Male
Units: Participants
Female	33	38	26	97
Male	36	43	34	113
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	0	1
Asian	7	4	1	12
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	2	2	3	7
White	57	73	55	185
More than one race	2	0	0	2
Unknown or Not Reported	1	1	1	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	7	5	3	15
Not Hispanic or Latino	43	63	48	154
Unknown or Not Reported	19	13	9	41

End points

Top of page

Reporting group title

Cohort 1

Reporting group description

Participants with RRcHL who failed to achieve a response or progressed after auto-stem cell transplant (SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT received pembrolizumab, 200 mg, intravenously (IV) every 3 weeks (Q3W) on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 2

Reporting group description

Participants with RRcHL who were unable to achieve Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 3

Reporting group description

Participants with RRcHL who failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle, up to 35 cycles for up to 24 months. These participants may or may not have received BV as part of primary treatment or salvage treatment.

Reporting group title

Cohort 1

Reporting group description

Participants with RRcHL who failed to achieve a response or progressed after auto-stem cell transplant (SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT received pembrolizumab, 200 mg, intravenously (IV) every 3 weeks (Q3W) on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 2

Reporting group description

Participants with RRcHL who were unable to achieve Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 3

Reporting group description

Participants with RRcHL who failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle, up to 35 cycles for up to 24 months. These participants may or may not have received BV as part of primary treatment or salvage treatment.

Primary: Percentage of Participants Experiencing at Least One Adverse Event (AE)

Top of page

End point title

Percentage of Participants Experiencing at Least One Adverse Event (AE) ^[1]

End point description

An adverse event (AE) is any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 27 months

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: Statistical analyses between treatment groups were neither planned nor performed for this primary endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of Participants
number (not applicable)	98.6	98.8	95.0

No statistical analyses for this end point

Primary: Overall Response Rate (ORR) by BICR based on IWG criteria

Top of page

End point title

Overall Response Rate (ORR) by BICR based on IWG criteria ^[2]

End point description

ORR is the percentage of participants who had a complete response (CR) or partial response (PR) prior to disease progression based on the International Working Group (IWG) criteria using blinded independent central review (BICR). CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. The point estimate and 95% 2-sided exact confidence interval (CI) used the Clopper-Pearson method. An exact binomial test was conducted for each cohort versus a fixed control rate for each cohort. It is hypothesized that ORR will be greater than 20% in each of the 3 cohorts. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to approximately 99 months

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: Statistical analyses between treatment groups were neither planned nor performed for this primary endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of participants
number (confidence interval 95%)	78.3 (66.7 to 87.3)	64.2 (52.8 to 74.6)	73.3 (60.3 to 83.9)

No statistical analyses for this end point

Primary: Percentage of Participants Discontinuing Study Drug Due to AEs

Top of page

End point title

Percentage of Participants Discontinuing Study Drug Due to AEs ^[3]

End point description

An AE is any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Up to 24 months

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: Statistical analyses between treatment groups were neither planned nor performed for this primary endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of Participants
number (not applicable)	11.6	6.2	8.3

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) by BICR based on Lugano criteria

Top of page

End point title

Overall Response Rate (ORR) by BICR based on Lugano criteria

End point description

ORR is the percentage of participants who had a CR or PR prior to disease progression based on the Lugano criteria using BICR. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. The point estimate and 95% 2-sided exact confidence interval (CI) used the Clopper-Pearson method. An exact binomial test was conducted for each cohort versus a fixed control rate for each cohort. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of participants
number (confidence interval 95%)	82.6 (71.6 to 90.7)	67.9 (56.6 to 77.8)	68.3 (55.0 to 79.7)

No statistical analyses for this end point

Secondary: Complete Remission Rate (CRR) by BICR based on IWG criteria

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End point title

Complete Remission Rate (CRR) by BICR based on IWG criteria

End point description

CRR is the percentage of participants with complete remission as demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes based on the IWG criteria using BICR. The analysis consisted of the point estimate and 95% 2-sided exact CI, separately by Cohort using the Clopper-Pearson method. Additional analyses were based on site assessment and by central review using the Lugano (2014) criteria. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of participants
number (not applicable)	24.6	25.9	33.3

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) assessed by investigator based on IWG criteria

Top of page

End point title

Overall Response Rate (ORR) assessed by investigator based on IWG criteria

End point description

ORR is the percentage of participants who had a CR or PR prior to disease progression assessed by the investigator using IWG criteria. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. The point estimate and 95% 2-sided exact confidence interval (CI) used the Clopper-Pearson method. An exact binomial test was conducted for each cohort versus a fixed control rate for each cohort. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of participants
number (confidence interval 95%)	72.5 (60.4 to 82.5)	66.7 (55.3 to 76.8)	71.7 (58.6 to 82.5)

No statistical analyses for this end point

Secondary: Complete Remission Rate (CRR) by BICR based on Lugano criteria

Top of page

End point title

Complete Remission Rate (CRR) by BICR based on Lugano criteria

End point description

CRR is the percentage of participants with complete remission as demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes based on the Lugano criteria using BICR. The analysis consisted of the point estimate and 95% 2-sided exact CI, separately by Cohort using the Clopper-Pearson method. Additional analyses were based on site assessment and by central review using the Lugano (2014) criteria. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of participants
number (not applicable)	34.8	28.4	35.0

No statistical analyses for this end point

Secondary: Complete Remission Rate (CRR) assessed by investigator based on IWG criteria

Top of page

End point title

Complete Remission Rate (CRR) assessed by investigator based on IWG criteria

End point description

CRR is the percentage of participants with complete remission as demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes assessed by the investigator using IWG criteria. The analysis consisted of the point estimate and 95% 2-sided exact CI, separately by Cohort using the Clopper-Pearson method. Additional analyses were based on site assessment and by central review using the Lugano (2014) criteria. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Percentage of participants
number (not applicable)	42.0	32.1	43.3

No statistical analyses for this end point

Secondary: Progression-free Survival (PFS) based on BICR

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End point title

Progression-free Survival (PFS) based on BICR

End point description

PFS is the time from first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurs first based on BICR. For those who have PD, the true date of disease progression was approximated by the date of the first assessment at which PD is objectively documented per IWG criteria, regardless of discontinuation of study drug. Death is always considered as a confirmed PD event. The non-parametric Kaplan-Meier method was used to estimate the PFS curve with missing data censored at last assessment. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Months
median (confidence interval 95%)	16.5 (12.0 to 30.3)	11.1 (7.5 to 13.7)	19.7 (10.8 to 32.9)

No statistical analyses for this end point

Secondary: Progression-free Survival (PFS) assessed by the investigator

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End point title

Progression-free Survival (PFS) assessed by the investigator

End point description

PFS is the time from first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurs first assessed by the investigator based on the IWG criteria. For those who have PD, the true date of disease progression was approximated by the date of the first assessment at which PD is objectively documented per IWG criteria, regardless of discontinuation of study drug. Death is always considered as a confirmed PD event. The non-parametric Kaplan-Meier method was used to estimate the PFS curve with missing data censored at last assessment. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69	81	60
Units: Months
median (confidence interval 95%)	24.9 (13.9 to 33.9)	13.9 (10.9 to 22.4)	22.0 (11.1 to 30.3)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) based on BICR

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End point title

Duration of Response (DOR) based on BICR

End point description

DOR for the subgroup of participants who achieved a CR or PR by independent central review, is the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first based on BICR. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. The analysis used the Kaplan-Meier method, with participants with response censored at their last assessment, and there was no progressive disease at the time of the last disease assessment. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	54	52	44
Units: Months
median (full range (min-max))	25.0 (0.0 to 88.8)	11.1 (0.0 to 86.2)	24.4 (0.0 to 88.3)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) assessed by the investigator

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End point title

Duration of Response (DOR) assessed by the investigator

End point description

DOR for the subgroup of participants who achieved a CR or PR by independent central review, is the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first assessed by the investigator based on the IWG criteria. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. The analysis used the Kaplan-Meier method, with participants with response censored at their last assessment, and there was no progressive disease at the time of the last disease assessment. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	50	54	43
Units: Months
median (full range (min-max))	25.0 (0.0 to 88.8)	16.4 (0.0 to 86.1)	24.7 (2.8 to 91.2)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is the time from the first dose to death due to any cause. The Kaplan-Meier method was used to estimate the survival curve, separately by Cohort with missing data censored at last assessment. The population analyzed was all allocated participants who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Up to approximately 99 months

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	69 ^[4]	81 ^[5]	60 ^[6]
Units: Months
median (full range (min-max))	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)

Notes
[4] - 9999 means median, upper limit, and lower limit not reached at time of data cut-off.
[5] - 9999 means median, upper limit, and lower limit not reached at time of data cut-off.
[6] - 9999 means median, upper limit, and lower limit not reached at time of data cut-off.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Up to approximately 99 months.

Adverse event reporting additional description

The population analyzed for all-cause mortality consisted of all allocated participants. The population for AEs consisted of all allocated participants who received at least 1 dose of study treatment. The following AE preferred terms not related to the drug were excluded: Neoplasm progression, Malignant neoplasm progression and Disease progression.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Cohort 1 (First Course)

Reporting group description

Participants with RRcHL who failed to achieve a response or progressed after auto-stem cell transplant (SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT received pembrolizumab, 200 mg, intravenously (IV) every 3 weeks (Q3W) on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 2 (First Course)

Reporting group description

Participants with RRcHL who were unable to achieve Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months.

Reporting group title

Cohort 3 (First Course)

Reporting group description

Participants with RRcHL who failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT received pembrolizumab, 200 mg, IV Q3W on Day 1 of each 21-day cycle up to 35 cycles, for up to 24 months. These participants may or may not have received BV as part of primary treatment or salvage treatment.

Reporting group title

Cohort 1 (Second Course)

Reporting group description

Eligible participants allocated to the pembrolizumab first course in Cohort 1 who stopped (or completed) initial treatment with pembrolizumab after attaining confirmed CR, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 of each 3 week cycle (Q3W) for up to 17 cycles up to approximately an additional year.

Reporting group title

Cohort 2 (Second Course)

Reporting group description

Eligible participants allocated to the pembrolizumab first course in Cohort 2 who stopped (or completed) initial treatment with pembrolizumab after attaining confirmed CR, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 Q3W for up to 17 cycles up to approximately an additional year.

Reporting group title

Cohort 3 (Second Course)

Reporting group description

Eligible participants allocated to the pembrolizumab first course in Cohort 3 who stopped (or completed) initial treatment with pembrolizumab after attaining confirmed CR, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg on Day 1 Q3W for up to 17 cycles up to approximately an additional year.

Serious adverse events	Cohort 1 (First Course)	Cohort 2 (First Course)	Cohort 3 (First Course)	Cohort 1 (Second Course)	Cohort 2 (Second Course)	Cohort 3 (Second Course)
Total subjects affected by serious adverse events
subjects affected / exposed	15 / 69 (21.74%)	18 / 81 (22.22%)	15 / 60 (25.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
number of deaths (all causes)	21	28	19	2	0	0
number of deaths resulting from adverse events	0	2	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Myelodysplastic syndrome
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Basal cell carcinoma
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Squamous cell carcinoma
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	3 / 60 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Acute graft versus host disease
subjects affected / exposed	1 / 69 (1.45%)	1 / 81 (1.23%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	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
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	1 / 69 (1.45%)	1 / 81 (1.23%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 2	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 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Pneumothorax
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Psychiatric disorders
Schizophrenia
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Hip fracture
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Cardiac disorders
Stress cardiomyopathy
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	2 / 69 (2.90%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	2 / 2	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
Myocarditis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Myocardial infarction
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Nervous system disorders
Chronic inflammatory demyelinating polyradiculoneuropathy
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Epilepsy
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Polyneuropathy
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Gastrointestinal disorders
Alcoholic pancreatitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (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
Diarrhoea
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Musculoskeletal and connective tissue disorders
Necrotising myositis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Osteonecrosis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Acute sinusitis
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Escherichia bacteraemia
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Device related infection
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Cystitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Clostridium difficile colitis
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Bronchitis
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Lower respiratory tract infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Influenza
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Herpes zoster
subjects affected / exposed	0 / 69 (0.00%)	2 / 81 (2.47%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	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
Herpes simplex
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Gastroenteritis salmonella
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Myelitis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Gastroenteritis
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Pneumonia
subjects affected / exposed	4 / 69 (5.80%)	1 / 81 (1.23%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	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
Post procedural infection
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Septic shock
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Respiratory syncytial virus infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Varicella zoster virus infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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
Urosepsis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (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

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

Non-serious adverse events	Cohort 1 (First Course)	Cohort 2 (First Course)	Cohort 3 (First Course)	Cohort 1 (Second Course)	Cohort 2 (Second Course)	Cohort 3 (Second Course)
Total subjects affected by non serious adverse events
subjects affected / exposed	68 / 69 (98.55%)	76 / 81 (93.83%)	56 / 60 (93.33%)	10 / 10 (100.00%)	7 / 7 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour inflammation
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1
Vascular disorders
Hot flush
subjects affected / exposed	1 / 69 (1.45%)	1 / 81 (1.23%)	3 / 60 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	1	3	0	0	1
Hypertension
subjects affected / exposed	1 / 69 (1.45%)	3 / 81 (3.70%)	1 / 60 (1.67%)	1 / 10 (10.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)
occurrences all number	1	3	1	1	2	0
General disorders and administration site conditions
Catheter site erosion
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0
Asthenia
subjects affected / exposed	6 / 69 (8.70%)	9 / 81 (11.11%)	2 / 60 (3.33%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	8	11	2	1	0	0
Chest discomfort
subjects affected / exposed	1 / 69 (1.45%)	1 / 81 (1.23%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	1	0	0
Fatigue
subjects affected / exposed	15 / 69 (21.74%)	17 / 81 (20.99%)	16 / 60 (26.67%)	3 / 10 (30.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)
occurrences all number	16	19	19	3	2	2
Chills
subjects affected / exposed	4 / 69 (5.80%)	5 / 81 (6.17%)	5 / 60 (8.33%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	5	5	1	0	0
Chest pain
subjects affected / exposed	3 / 69 (4.35%)	2 / 81 (2.47%)	5 / 60 (8.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	3	5	0	0	0
Influenza like illness
subjects affected / exposed	7 / 69 (10.14%)	2 / 81 (2.47%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)
occurrences all number	9	3	0	0	1	1
Malaise
subjects affected / exposed	4 / 69 (5.80%)	2 / 81 (2.47%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	3	0	0	0	0
Pyrexia
subjects affected / exposed	27 / 69 (39.13%)	18 / 81 (22.22%)	16 / 60 (26.67%)	4 / 10 (40.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)
occurrences all number	48	22	17	5	1	1
Pain
subjects affected / exposed	3 / 69 (4.35%)	2 / 81 (2.47%)	3 / 60 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	3	2	3	1	0	1
Oedema peripheral
subjects affected / exposed	3 / 69 (4.35%)	4 / 81 (4.94%)	5 / 60 (8.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	4	5	0	0	0
Immune system disorders
Sarcoidosis
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1
Pelvic pain
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	7 / 69 (10.14%)	7 / 81 (8.64%)	9 / 60 (15.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)
occurrences all number	11	8	11	1	1	1
Nasal congestion
subjects affected / exposed	6 / 69 (8.70%)	8 / 81 (9.88%)	8 / 60 (13.33%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	8	8	14	1	1	0
Dyspnoea
subjects affected / exposed	8 / 69 (11.59%)	10 / 81 (12.35%)	7 / 60 (11.67%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)
occurrences all number	19	16	13	0	1	1
Cough
subjects affected / exposed	19 / 69 (27.54%)	22 / 81 (27.16%)	14 / 60 (23.33%)	2 / 10 (20.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)
occurrences all number	26	37	19	3	2	0
Productive cough
subjects affected / exposed	10 / 69 (14.49%)	1 / 81 (1.23%)	4 / 60 (6.67%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	11	1	6	1	1	0
Tonsillar exudate
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0
Rhinorrhoea
subjects affected / exposed	9 / 69 (13.04%)	4 / 81 (4.94%)	3 / 60 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	10	4	3	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	7 / 69 (10.14%)	6 / 81 (7.41%)	7 / 60 (11.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	7	8	7	0	0	1
Depression
subjects affected / exposed	1 / 69 (1.45%)	3 / 81 (3.70%)	3 / 60 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	3	3	1	0	0
Anxiety
subjects affected / exposed	3 / 69 (4.35%)	4 / 81 (4.94%)	4 / 60 (6.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	4	4	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	7 / 69 (10.14%)	3 / 81 (3.70%)	0 / 60 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	12	3	0	4	1	0
Aspartate aminotransferase increased
subjects affected / exposed	6 / 69 (8.70%)	3 / 81 (3.70%)	1 / 60 (1.67%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	12	3	1	4	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	5 / 69 (7.25%)	1 / 81 (1.23%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	6	1	1	0	0	0
Blood creatinine increased
subjects affected / exposed	4 / 69 (5.80%)	2 / 81 (2.47%)	2 / 60 (3.33%)	2 / 10 (20.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	6	2	2	2	1	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	2 / 69 (2.90%)	4 / 81 (4.94%)	1 / 60 (1.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	4	1	1	0	0
Blood uric acid increased
subjects affected / exposed	1 / 69 (1.45%)	1 / 81 (1.23%)	1 / 60 (1.67%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	1	1	1	0	1	0
Platelet count decreased
subjects affected / exposed	3 / 69 (4.35%)	3 / 81 (3.70%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	5	4	0	1	0	0
Weight increased
subjects affected / exposed	3 / 69 (4.35%)	5 / 81 (6.17%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	6	0	0	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 69 (4.35%)	1 / 81 (1.23%)	1 / 60 (1.67%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	3	1	1	0	1	0
Infusion related reaction
subjects affected / exposed	6 / 69 (8.70%)	2 / 81 (2.47%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	6	2	2	0	0	0
Ligament sprain
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Limb injury
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0
Skin laceration
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	4 / 69 (5.80%)	0 / 81 (0.00%)	3 / 60 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	0	3	0	0	0
Pericarditis
subjects affected / exposed	2 / 69 (2.90%)	0 / 81 (0.00%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	12 / 69 (17.39%)	6 / 81 (7.41%)	10 / 60 (16.67%)	2 / 10 (20.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	19	11	11	2	0	0
Disturbance in attention
subjects affected / exposed	4 / 69 (5.80%)	1 / 81 (1.23%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	1	2	0	0	0
Neuropathy peripheral
subjects affected / exposed	3 / 69 (4.35%)	5 / 81 (6.17%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	5	2	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	4 / 69 (5.80%)	4 / 81 (4.94%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	4	1	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 69 (10.14%)	8 / 81 (9.88%)	5 / 60 (8.33%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	8	8	6	0	1	0
Neutropenia
subjects affected / exposed	5 / 69 (7.25%)	4 / 81 (4.94%)	4 / 60 (6.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	6	6	5	0	0	0
Thrombocytopenia
subjects affected / exposed	4 / 69 (5.80%)	3 / 81 (3.70%)	3 / 60 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	5	3	7	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 69 (0.00%)	2 / 81 (2.47%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	2	1	0	0	1
Ear congestion
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0
Eye disorders
Visual impairment
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0
Scleral hyperaemia
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0
Iritis
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	2	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	1	0
Abdominal pain
subjects affected / exposed	5 / 69 (7.25%)	5 / 81 (6.17%)	3 / 60 (5.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	6	5	4	0	1	0
Abdominal pain upper
subjects affected / exposed	3 / 69 (4.35%)	3 / 81 (3.70%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	3	3	1	0	0	1
Constipation
subjects affected / exposed	9 / 69 (13.04%)	11 / 81 (13.58%)	3 / 60 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	12	11	23	1	0	1
Vomiting
subjects affected / exposed	16 / 69 (23.19%)	9 / 81 (11.11%)	13 / 60 (21.67%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	22	11	20	1	1	0
Stomatitis
subjects affected / exposed	4 / 69 (5.80%)	2 / 81 (2.47%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	5	2	2	0	0	0
Nausea
subjects affected / exposed	16 / 69 (23.19%)	11 / 81 (13.58%)	11 / 60 (18.33%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	25	15	32	1	2	0
Dyspepsia
subjects affected / exposed	2 / 69 (2.90%)	2 / 81 (2.47%)	4 / 60 (6.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	3	4	0	0	0
Diarrhoea
subjects affected / exposed	20 / 69 (28.99%)	12 / 81 (14.81%)	11 / 60 (18.33%)	2 / 10 (20.00%)	4 / 7 (57.14%)	2 / 3 (66.67%)
occurrences all number	37	19	17	2	7	2
Skin and subcutaneous tissue disorders
Rash pruritic
subjects affected / exposed	1 / 69 (1.45%)	0 / 81 (0.00%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	0	0
Rash maculo-papular
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	4 / 60 (6.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	4	5	0	0	0
Rash
subjects affected / exposed	12 / 69 (17.39%)	9 / 81 (11.11%)	10 / 60 (16.67%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	15	11	14	1	1	0
Pruritus
subjects affected / exposed	12 / 69 (17.39%)	11 / 81 (13.58%)	7 / 60 (11.67%)	3 / 10 (30.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	16	18	8	3	1	0
Erythema
subjects affected / exposed	4 / 69 (5.80%)	2 / 81 (2.47%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	2	1	0	0	0
Dry skin
subjects affected / exposed	5 / 69 (7.25%)	5 / 81 (6.17%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	6	5	2	0	0	1
Alopecia
subjects affected / exposed	3 / 69 (4.35%)	0 / 81 (0.00%)	4 / 60 (6.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	0	4	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 69 (1.45%)	1 / 81 (1.23%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	8 / 69 (11.59%)	13 / 81 (16.05%)	12 / 60 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	9	14	15	0	0	0
Musculoskeletal and connective tissue disorders
Groin pain
subjects affected / exposed	0 / 69 (0.00%)	1 / 81 (1.23%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Back pain
subjects affected / exposed	8 / 69 (11.59%)	12 / 81 (14.81%)	5 / 60 (8.33%)	3 / 10 (30.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	11	13	6	3	0	0
Arthralgia
subjects affected / exposed	14 / 69 (20.29%)	12 / 81 (14.81%)	6 / 60 (10.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	20	14	10	1	1	0
Pain in extremity
subjects affected / exposed	4 / 69 (5.80%)	2 / 81 (2.47%)	2 / 60 (3.33%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)
occurrences all number	5	2	2	0	1	1
Neck pain
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	1	0	0
Myalgia
subjects affected / exposed	6 / 69 (8.70%)	5 / 81 (6.17%)	5 / 60 (8.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	8	7	8	0	0	0
Muscular weakness
subjects affected / exposed	4 / 69 (5.80%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	0	1	0	0	0
Muscle twitching
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	8 / 69 (11.59%)	1 / 81 (1.23%)	5 / 60 (8.33%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	12	2	5	1	0	0
Muscle contracture
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	0	1
Joint swelling
subjects affected / exposed	0 / 69 (0.00%)	2 / 81 (2.47%)	0 / 60 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	1	0	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	3 / 69 (4.35%)	4 / 81 (4.94%)	1 / 60 (1.67%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	3	4	1	0	1	0
Folliculitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1
Conjunctivitis
subjects affected / exposed	4 / 69 (5.80%)	2 / 81 (2.47%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	2	2	0	0	0
Bronchitis
subjects affected / exposed	6 / 69 (8.70%)	4 / 81 (4.94%)	7 / 60 (11.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	6	8	11	1	0	1
Herpes zoster
subjects affected / exposed	2 / 69 (2.90%)	4 / 81 (4.94%)	4 / 60 (6.67%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	4	4	0	0	0
Sinusitis
subjects affected / exposed	7 / 69 (10.14%)	9 / 81 (11.11%)	5 / 60 (8.33%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	11	12	9	1	1	0
Upper respiratory tract infection
subjects affected / exposed	23 / 69 (33.33%)	7 / 81 (8.64%)	12 / 60 (20.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	33	7	22	2	1	0
Urinary tract infection
subjects affected / exposed	4 / 69 (5.80%)	6 / 81 (7.41%)	5 / 60 (8.33%)	1 / 10 (10.00%)	0 / 7 (0.00%)	3 / 3 (100.00%)
occurrences all number	10	6	7	1	0	4
Respiratory tract infection viral
subjects affected / exposed	0 / 69 (0.00%)	0 / 81 (0.00%)	1 / 60 (1.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0
Respiratory tract infection
subjects affected / exposed	5 / 69 (7.25%)	3 / 81 (3.70%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	6	3	2	0	0	0
Pneumonia
subjects affected / exposed	5 / 69 (7.25%)	5 / 81 (6.17%)	1 / 60 (1.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	5	5	2	1	0	0
Nasopharyngitis
subjects affected / exposed	12 / 69 (17.39%)	16 / 81 (19.75%)	7 / 60 (11.67%)	2 / 10 (20.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	15	16	11	3	0	0
Rhinitis
subjects affected / exposed	8 / 69 (11.59%)	0 / 81 (0.00%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	8	0	2	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 69 (4.35%)	6 / 81 (7.41%)	2 / 60 (3.33%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	6	3	0	0	1
Hypomagnesaemia
subjects affected / exposed	2 / 69 (2.90%)	1 / 81 (1.23%)	2 / 60 (3.33%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	2	1	4	2	0	1
Hypokalaemia
subjects affected / exposed	5 / 69 (7.25%)	5 / 81 (6.17%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	7	6	0	0	0	0
Hypocalcaemia
subjects affected / exposed	3 / 69 (4.35%)	0 / 81 (0.00%)	0 / 60 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	0	0	0	0	1
Hyperuricaemia
subjects affected / exposed	1 / 69 (1.45%)	2 / 81 (2.47%)	1 / 60 (1.67%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	2	1	2	0	0
Hypophosphataemia
subjects affected / exposed	2 / 69 (2.90%)	1 / 81 (1.23%)	3 / 60 (5.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)
occurrences all number	5	1	3	2	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

06 Jan 2016

Amendment 3: Revised statistical section and added safety updates.

11 Sep 2016

Amendment 7: Clarified timing of efficacy analyses.

03 Feb 2017

Amendment 8: Added clarification on efficacy interim and posttreatment analyses.

26 Aug 2017

Amendment 10: Added clarification on allostem cell transplant data collection.

19 Apr 2021

Amendment 12: Updated the dose modification and toxicity management guidelines for irAEs.

23 Aug 2022

Amendment 14: Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name change and update to the address.

08 Dec 2022

Amendment 16: To add language allowing eligible participants to enroll in an extension study, if available, following the end of MK-3475-087. To clarify that specific events will be collected as ECIs for 18 months from the date of the allogeneic transplant unless the trial closes earlier.

Were there any global interruptions to the trial? No

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

None reported

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