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Clinical Trial Results:
A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer

Summary
EudraCT number	2016-002579-83
Trial protocol	ES HU FR PL
Global end of trial date	26 Sep 2019

Results information
Results version number	v1(current)
This version publication date	11 Oct 2020
First version publication date	11 Oct 2020
Other versions

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

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Trial information

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Sponsor protocol code

CR108256

ISRCTN number

US NCT number

NCT03023423

WHO universal trial number (UTN)

Sponsor organisation name

Janssen Research & Development, LLC

Sponsor organisation address

920 US Highway Route 202 South, Raritan, United States, NJ 08869

Public contact

Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

26 Sep 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Sep 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to compare the overall response rate (ORR) in subjects treated with daratumumab in combination with atezolizumab versus atezolizumab alone.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included adverse events, routine clinical laboratory tests (hematology, chemistry, urinalysis), vital signs (temperature, pulse/heart rate, and blood pressure), physical examination, infusion related reactions and electrocardiogram (ECG).

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Dec 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 49

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Hungary: 15

Country: Number of subjects enrolled

United States: 19

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

Screening details

A total of 100 subjects were enrolled in the study (7 in phase 1b [safety run-in phase], and 93 in Phase 2 [randomized phase]). Among them, 99 subjects (7 in phase 1b [safety run-in phase], and 92 in phase 2 [randomized phase]) were randomized as 1 subject was randomized after the clinical cutoff date (17-May-2018).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Safety Run-in Phase: Daratumumab + Atezolizumab

Arm description

Subjects received daratumumab (Dara) 16 milligram per kilogram (mg/kg) intravenously (IV) weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab (Atezo) IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Daratumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received daratumumab 16 mg/kg intravenously weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received atezolizumab (Atezo) IV at a dose of 12 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Randomized Phase: Atezolizumab

Arm description

Subjects received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Arm type

Active comparator

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received atezolizumab IV at a dose of 1200 mg on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Randomized Phase: Daratumumab + Atezolizumab

Arm description

Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Daratumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria.

Number of subjects in period 1	Safety Run-in Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Started	7	46	46
Treated	7	44	44
Crossover from Atezo to Dara + Atezo	0 ^[1]	8 ^[2]	0 ^[3]
Completed	2	32	24
Not completed	5	14	22
Death	5	12	20
Unspecified	-	2	2

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: No subjects crossed over from Atezo arm to Dara + Atezo arm.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Only 8 subjects crossed over from Atezo arm to Dara + Atezo arm.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: No subjects crossed over from Atezo arm to Dara + Atezo arm.

Baseline characteristics

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Reporting group title

Safety Run-in Phase: Daratumumab + Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Daratumumab + Atezolizumab

Reporting group description

Reporting group values	Safety Run-in Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab	Total
Number of subjects	7	46	46	99
Title for AgeCategorical
Units: subjects
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	3	29	21	53
From 65 to 84 years	4	17	25	46
85 years and over	0	0	0	0
Title for AgeContinuous
Units: years
arithmetic mean (standard deviation)	61 ( 9.73 )	61.7 ( 10.05 )	63.2 ( 10.76 )	-
Title for Gender
Units: subjects
Female	3	18	8	29
Male	4	28	38	70
Race/Ethnicity
Units: Subjects
Other	0	11	6	17
White Non-Hispanic	7	35	40	82
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	0	0	0
White	7	35	41	83
More than one race	0	0	0	0
Unknown or Not Reported	0	11	5	16
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	0	1
Not Hispanic or Latino	7	36	40	83
Unknown or Not Reported	0	9	6	15
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status was used to evaluate the effect of the disease status on the activities of daily living. ECOG performance status was determined by ECOG 5-point scale: 0=Fully active, 1=Ambulatory, carry out work of sedentary nature, 2=Ambulatory, capable of all self-care, 3=Capable of limited self-care, confined to bed or chair more than 50% of waking hours, 4=Completely disabled, no self-care, totally confined to bed or chair, 5=Dead.
Units: Subjects
ECOG Score 0	3	19	12	34
ECOG Score 1	4	27	33	64
ECOG Score 2	0	0	1	1
Time from initial diagnosis
Time from initial diagnosis is defined as the time from the initial diagnosis of non-small cell lung cancer (NSCLC) to the first dosing date or randomization date (if first dosing date is missing).
Units: Months
arithmetic mean (standard deviation)	10.3 ( 9.29 )	18.8 ( 20.89 )	17.6 ( 14.17 )	-

End points

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Reporting group title

Safety Run-in Phase: Daratumumab + Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Daratumumab + Atezolizumab

Reporting group description

Subject analysis set title

Safety Run-in: Atezolizumab + Daratumumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received daratumumab 16 milligram per kilogram (mg/kg) Intravenously (IV) weekly for first 3 cycles and every 3 weeks for all cycles thereafter along with atezolizumab IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter.

Subject analysis set title

Randomized Phase: Atezolizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Randomized Phase: Daratumumab + Atezolizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Randomized Phase: Atezo Crossed Over to Dara + Atezo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects who crossed over from Atezolizumab arm (Randomized Phase) to Daratumumab + Atezolizumab arm (Randomized Phase) received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol defined treatment discontinuation criteria.

Primary: Percentage of Subjects with Overall Response Rate (ORR)

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End point title

Percentage of Subjects with Overall Response Rate (ORR)

End point description

ORR was defined as the percentage of subjects with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Criteria for CR: Disappearance of all target lesions; all lymph nodes must be of non-pathological in size (less than [<]10 millimeter [mm] short axis; normalization of tumor marker level. Criteria for PR: greater than or equal to (>=)30 percent (%) decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Overall Response (OR) = CR + PR. The endpoint was planned to be reported for subjects based on their initial assignment to Randomized Phase: Atezolizumab’. Intent-to-treat (ITT) analysis set included all subjects who had entered the Randomized phase of the study.

End point type

Primary

End point timeframe

Up to 1.5 years

End point values	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	46	46
Units: Percentage of Subjects
number (confidence interval 95%)	13.0 (4.9 to 26.3)	4.3 (0.5 to 14.8)

Statistical Analysis 1

Comparison groups

Randomized Phase: Atezolizumab v Randomized Phase: Daratumumab + Atezolizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Odds ratio (OR)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

1.92

Secondary: Number of Subjects with Adverse Events

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End point title

Number of Subjects with Adverse Events

End point description

An adverse event (AE) is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Crossover subjects were counted twice (in ‘Randomized Phase: Atezo arm’ and in ‘Randomized Phase: Atezo Crossed Over to Dara + Atezo’) for safety analysis. For cross-over subjects, AEs after initiation of cross-over treatment were summarized separately in the crossover arm, however, AEs occurred before crossover treatment were included in ‘Randomized Phase: Atezolizumab arm’. Safety analysis set included all subjects who had received at least 1 administration of any study medication.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Safety Run-in: Atezolizumab + Daratumumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezo Crossed Over to Dara + Atezo
Number of subjects analysed	7	44	44	8
Units: Subjects	7	42	44	8

No statistical analyses for this end point

Secondary: Duration of Response (DoR)

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End point title

Duration of Response (DoR)

End point description

DOR: Duration from date of initial documentation of disease response to date of first documented evidence of recurrence/PD/death, whichever occurred first. PD:Sum of diameters increased by >=20%, >=5 mm from nadir. Subjects with measurable disease: Unequivocal progression(non-target disease, overall level of substantial worsening that merits discontinuation of therapy). Subjects without measurable disease: Unequivocal progression (non-target disease, increase in tumor burden comparable to increase required for PD of measurable disease). Endpoint was planned to be reported for subjects based on their initial assignment to 'Randomized Phase:Atezolizumab’. ITT set: subjects who had entered Randomized phase of study. N(number of subjects analyzed): number of subjects who were evaluable for this endpoint. 99999: lower/upper limit of 95% CI were not estimable due: lesser number of subjects with events.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	6	2
Units: Months
median (confidence interval 95%)	5.8 (2.2 to 5.8)	2.9 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Clinical Benefit Rate

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End point title

Clinical Benefit Rate

End point description

Clinical benefit rate was defined as percentage of subjects who achieved disease control (CR, PR, or SD). RECIST 1.1 Criteria for CR: Disappearance of all target lesions; all lymph nodes of non-pathological in size (<10 millimeter [mm] short axis); normalization of tumor marker level. Criteria for PR: >=30 % decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Criteria for SD: <30% decrease in sum of diameters of all target lesions compared with baseline and <20% increase compared with nadir, in absence of new lesions or unequivocal progression of nontarget lesions. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. ITT analysis set included all subjects who had entered the Randomized phase of the study.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	46	46
Units: Percentage of Subjects
number (confidence interval 95%)	43.5 (28.9 to 58.9)	52.2 (36.9 to 67.1)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS)

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End point title

Progression-Free Survival (PFS)

End point description

PFS was defined as the duration from the date of randomization until the first documented disease progression (PD) or death, whichever occurred first. PD: Sum of diameters increased by >=20% and >=5 millimeter (mm) from nadir (including baseline if it was smallest sum). Subjects with measurable disease: for "unequivocal progression" based on non-target disease, overall level of substantial worsening that merits discontinuation of therapy (if target disease was stable disease [SD]/PR). Subjects without measurable disease: for "unequivocal progression" of non-target disease, increase in overall tumor burden comparable to increase required for PD of measurable disease. Appearance of 1/ more new lesions or unequivocal progression of non-target lesion was also considered as PD. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. ITT analysis set included all subjects who had entered the Randomized phase of the study.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	46	46
Units: Months
median (confidence interval 95%)	1.48 (1.38 to 2.76)	1.68 (1.41 to 2.79)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall Survival was defined as the duration from the date of randomization to the date of subject’s death due to any cause. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. ITT analysis set included all subjects who had entered the Randomized phase of the study. Here 99999, signifies that the upper limit of 95% Confidence Interval (CI) was not estimable due to lesser number of events.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	46	46
Units: Months
median (confidence interval 95%)	99999 (7.43 to 99999)	7.13 (3.52 to 99999)

No statistical analyses for this end point

Secondary: Daratumumab Serum Concentration

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End point title

Daratumumab Serum Concentration

End point description

Daratumumab serum concentrations were reported. Each cycle was of 21-days. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. Pharmacokinetic (PK)-evaluable analysis set included all subjects who had received at least 1 dose of daratumumab or atezolizumab and had at least 1 postinfusion sample collected. Here ‘n’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint at a given time point. Here 99999, signifies that Standard Deviation could not be calculated for a single subject.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (C1D1):predose and postdose; C2D1 and C3D1:predose; C3D15: predose and postdose; C4D1: predose and postdose; C8D1: predose and postdose; C12D1: predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years)

End point values	Safety Run-in: Atezolizumab + Daratumumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	7	43
Units: Microgram per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 Predose (n=7, 43)	0.00 ( 0.000 )	0.00 ( 0.000 )
Cycle 1 Day 1 Postdose (n=6, 38)	417.13 ( 141.626 )	296.12 ( 85.660 )
Cycle 2 Day 1 Predose (n=4, 35)	393.95 ( 139.480 )	278.42 ( 89.340 )
Cycle 3 Day 1 Predose (n=3, 26)	740.17 ( 99.515 )	487.65 ( 124.935 )
Cycle 3 Day 15 Predose (n=4, 24)	843.22 ( 156.792 )	552.79 ( 180.549 )
Cycle 3 Day 15 Postdose (n=4, 23)	1088.73 ( 282.349 )	827.72 ( 266.085 )
Cycle 4 Day 1 Predose (n=3, 22)	899.90 ( 123.305 )	574.81 ( 181.193 )
Cycle 4 Day 1 Postdose (n=3, 21)	1416.40 ( 353.415 )	856.30 ( 244.698 )
Cycle 8 Day 1 Predose (n=1, 8)	254.87 ( 99999 )	288.84 ( 177.187 )
Cycle 8 Day 1 Postdose (n=1, 8)	824.64 ( 99999 )	617.21 ( 239.962 )
Cycle 12 Day 1 Predose (n=0, 2)	99999 ( 99999 )	260.21 ( 17.163 )
End of Treatment (n=3, 13)	405.14 ( 242.189 )	187.75 ( 110.531 )
Post Last Dose (n=2, 5)	41.84 ( 23.082 )	112.63 ( 115.727 )

No statistical analyses for this end point

Secondary: Atezolizumab Serum Concentration

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End point title

Atezolizumab Serum Concentration

End point description

Atezolizumab serum concentrations were reported. Each cycle was of 21-days. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. PK-evaluable analysis set: all subjects who received at least 1 dose of daratumumab/atezolizumab and had at least 1 postinfusion sample collected. Here N (number of subjects analyzed): subjects evaluable for this endpoint, and n (number of subjects analyzed): subjects evaluable for this endpoint at given timepoint. Here 99999, signifies that the standard deviation could not be calculated for a single subject.

End point type

Secondary

End point timeframe

C1D1:predose and postdose; C1D2:predose and postdose; C2D1, C3D1:predose; C3D15:predose and postdose; C4D1:predose and postdose; C8D1:predose and postdose; C12D1:predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years)

End point values	Safety Run-in: Atezolizumab + Daratumumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	7	39	39
Units: Microgram per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 Predose (n=0,37,13)	99999 ( 99999 )	0.00 ( 0.000 )	0.00 ( 0.000 )
Cycle 1 Day 1 Postdose (n=0,37,3)	99999 ( 99999 )	396.51 ( 103.196 )	440.00 ( 93.145 )
Cycle 1 Day 2 Predose (n=7,0,24)	0.00 ( 0.000 )	99999 ( 99999 )	0.00 ( 0.000 )
Cycle 1 Day 2 Postdose (n=7,0,34)	362.14 ( 43.434 )	99999 ( 99999 )	343.82 ( 135.476 )
Cycle 2 Day 1 Predose (n=5,30,20)	91.16 ( 15.305 )	78.85 ( 30.575 )	81.90 ( 20.021 )
Cycle 3 Day 1 Predose (n=2,21,17)	176.50 ( 33.234 )	117.61 ( 33.227 )	123.51 ( 31.882 )
Cycle 4 Day 1 Predose (n=2,18,12)	166.50 ( 37.477 )	145.64 ( 37.323 )	157.79 ( 37.819 )
Cycle 4 Day 1 Postdose (n=4,17,18)	612.25 ( 81.578 )	539.24 ( 116.291 )	482.33 ( 139.879 )
Cycle 8 Day 1 Predose (n-0,6,0)	99999 ( 99999 )	158.23 ( 77.778 )	99999 ( 99999 )
Cycle 8 Day 1 Postdose (n-0,8,4)	99999 ( 99999 )	527.50 ( 213.492 )	515.25 ( 214.177 )
Cycle 12 Day 1 Predose (n=0,1,1)	99999 ( 99999 )	183.00 ( 99999 )	248.00 ( 99999 )
End of Treatment (n=3,11,12)	136.43 ( 73.002 )	129.55 ( 79.720 )	141.62 ( 71.756 )
Post Last Dose (n=1,2,2)	33.10 ( 99999 )	13.17 ( 8.386 )	115.10 ( 146.937 )

No statistical analyses for this end point

Secondary: Number of Subjects with Anti-Daratumumab Antibodies

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End point title

Number of Subjects with Anti-Daratumumab Antibodies

End point description

Number of subjects with antibodies to daratumumab (tested using a validated immunoassay method) were reported. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. The immunogenicity-evaluable analysis set included all subjects who received at least 1 dose of atezolizumab or daratumumab and had appropriate samples for detection of antibodies to atezolizumab or daratumumab. Here 'N' (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	7	37
Units: Subjects
number (not applicable)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Anti-Atezolizumab Antibodies

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End point title

Number of Subjects with Anti-Atezolizumab Antibodies

End point description

Number of subjects with antibodies to atezolizumab (tested using a validated immunoassay method) were reported. The endpoint was planned to be reported for subjects based on their initial assignment to ‘Randomized Phase: Atezolizumab’. The immunogenicity-evaluable analysis set included all subjects who received at least 1 dose of atezolizumab or daratumumab and had appropriate samples for detection of antibodies to atezolizumab or daratumumab.

End point type

Secondary

End point timeframe

Up to 1.5 years

End point values	Safety Run-in: Atezolizumab + Daratumumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab
Number of subjects analysed	7	39	38
Units: Subjects	0	6	5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 1.5 years

Adverse event reporting additional description

Safety analysis set=subjects who received at least 1 administration of any study drug. Crossover subjects were counted twice (in ‘Randomized Phase:Atezo arm’ and ‘Randomized Phase: Atezo Crossed Over to Dara+Atezo’). AEs summarized separately in crossover arm and occurred before crossover treatment were included in ‘Randomized Phase: Atezolizumab’.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Safety Run-in Phase: Daratumumab + Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Daratumumab + Atezolizumab

Reporting group description

Reporting group title

Randomized Phase: Atezo Crossed Over to Dara + Atezo

Reporting group description

Serious adverse events	Safety Run-in Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezo Crossed Over to Dara + Atezo
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 7 (57.14%)	15 / 44 (34.09%)	21 / 44 (47.73%)	3 / 8 (37.50%)
number of deaths (all causes)	2	9	11	3
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Femur Fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial Fibrillation
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Failure
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cardio-Respiratory Arrest
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Myocardial Infarction
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pericardial Effusion
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular Accident
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Transient Ischaemic Attack
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal Cord Paralysis
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General Physical Health Deterioration
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Non-Cardiac Chest Pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden Death
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal Haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchial Fistula
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial Obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	6 / 44 (13.64%)	2 / 8 (25.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 7	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	1 / 2
Haemoptysis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
Painful Respiration
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Respiratory Failure
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back Pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in Extremity
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	3 / 44 (6.82%)	3 / 44 (6.82%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	1 / 5	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
Respiratory Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	3 / 44 (6.82%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superinfection
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Safety Run-in Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezolizumab	Randomized Phase: Daratumumab + Atezolizumab	Randomized Phase: Atezo Crossed Over to Dara + Atezo
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	41 / 44 (93.18%)	41 / 44 (93.18%)	8 / 8 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Vascular disorders
Flushing
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	1	0	2	0
Hypertension
subjects affected / exposed	4 / 7 (57.14%)	0 / 44 (0.00%)	4 / 44 (9.09%)	0 / 8 (0.00%)
occurrences all number	7	0	5	0
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Venous Thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 7 (42.86%)	15 / 44 (34.09%)	14 / 44 (31.82%)	2 / 8 (25.00%)
occurrences all number	4	21	23	2
Chest Discomfort
subjects affected / exposed	2 / 7 (28.57%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	2	0	2	0
Chest Pain
subjects affected / exposed	0 / 7 (0.00%)	3 / 44 (6.82%)	3 / 44 (6.82%)	2 / 8 (25.00%)
occurrences all number	0	3	3	2
Chills
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	3 / 44 (6.82%)	1 / 8 (12.50%)
occurrences all number	1	0	3	1
Fatigue
subjects affected / exposed	3 / 7 (42.86%)	7 / 44 (15.91%)	9 / 44 (20.45%)	2 / 8 (25.00%)
occurrences all number	3	11	11	4
General Physical Health Deterioration
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Hypothermia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Localised Oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Malaise
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0
Mucosal Inflammation
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	1 / 8 (12.50%)
occurrences all number	0	1	2	1
Oedema Peripheral
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	2	2	0
Pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	2	0	1
Pyrexia
subjects affected / exposed	2 / 7 (28.57%)	5 / 44 (11.36%)	4 / 44 (9.09%)	2 / 8 (25.00%)
occurrences all number	3	5	5	2
Secretion Discharge
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Temperature Intolerance
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Immune system disorders
Drug Hypersensitivity
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0
Hypersensitivity
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	4 / 44 (9.09%)	0 / 8 (0.00%)
occurrences all number	0	0	4	0
Reproductive system and breast disorders
Gynaecomastia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1
Bronchospasm
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	3 / 44 (6.82%)	0 / 8 (0.00%)
occurrences all number	0	0	4	0
Cough
subjects affected / exposed	1 / 7 (14.29%)	10 / 44 (22.73%)	16 / 44 (36.36%)	3 / 8 (37.50%)
occurrences all number	1	13	19	4
Dry Throat
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0
Dysphonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Dyspnoea
subjects affected / exposed	5 / 7 (71.43%)	9 / 44 (20.45%)	13 / 44 (29.55%)	0 / 8 (0.00%)
occurrences all number	5	10	18	0
Dyspnoea Exertional
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	1
Haemoptysis
subjects affected / exposed	0 / 7 (0.00%)	5 / 44 (11.36%)	5 / 44 (11.36%)	0 / 8 (0.00%)
occurrences all number	0	6	5	0
Laryngeal Oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Nasal Congestion
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	1 / 8 (12.50%)
occurrences all number	0	0	1	2
Oropharyngeal Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1
Pleural Effusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Pleurisy
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Pleuritic Pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Pneumothorax
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Productive Cough
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	1	2	0
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Sneezing
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Throat Irritation
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	4 / 44 (9.09%)	0 / 8 (0.00%)
occurrences all number	0	0	5	0
Throat Tightness
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Upper-Airway Cough Syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Depression
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	1 / 44 (2.27%)	1 / 8 (12.50%)
occurrences all number	1	0	1	1
Insomnia
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0
Nervousness
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Sleep Disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	2	1	0
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	2	3	0
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	3	0
Blood Lactate Dehydrogenase Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Eastern Cooperative Oncology Group Performance Status Worsened
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Lipase Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	1	4	0
Oxygen Saturation Decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Weight Decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	3 / 44 (6.82%)	0 / 8 (0.00%)
occurrences all number	0	1	3	0
Weight Increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Buttock Injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Fall
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Pericardial Effusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Sinus Bradycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Sinus Tachycardia
subjects affected / exposed	2 / 7 (28.57%)	0 / 44 (0.00%)	2 / 44 (4.55%)	1 / 8 (12.50%)
occurrences all number	2	0	2	1
Tachycardia
subjects affected / exposed	1 / 7 (14.29%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	1	1	1	0
Ventricular Extrasystoles
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Aphonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Dizziness
subjects affected / exposed	2 / 7 (28.57%)	1 / 44 (2.27%)	2 / 44 (4.55%)	1 / 8 (12.50%)
occurrences all number	2	1	2	1
Dysgeusia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Headache
subjects affected / exposed	3 / 7 (42.86%)	2 / 44 (4.55%)	0 / 44 (0.00%)	2 / 8 (25.00%)
occurrences all number	3	2	0	2
Hypokinesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	3 / 44 (6.82%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	4	2	0
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Sciatica
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0
Seizure
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Somnolence
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Tremor
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 7 (14.29%)	6 / 44 (13.64%)	7 / 44 (15.91%)	1 / 8 (12.50%)
occurrences all number	1	10	11	1
Deficiency Anaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Leukopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1
Lymphopenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	1	3	0
Thrombocytopenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	2	2	0
Eye disorders
Diplopia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Dry Eye
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0
Eye Irritation
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Vision Blurred
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Visual Acuity Reduced
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Abdominal Pain
subjects affected / exposed	2 / 7 (28.57%)	0 / 44 (0.00%)	6 / 44 (13.64%)	0 / 8 (0.00%)
occurrences all number	2	0	6	0
Abdominal Pain Upper
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Colitis
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0
Constipation
subjects affected / exposed	2 / 7 (28.57%)	5 / 44 (11.36%)	4 / 44 (9.09%)	1 / 8 (12.50%)
occurrences all number	2	6	7	3
Diarrhoea
subjects affected / exposed	1 / 7 (14.29%)	4 / 44 (9.09%)	4 / 44 (9.09%)	0 / 8 (0.00%)
occurrences all number	2	5	4	0
Dry Mouth
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	3 / 44 (6.82%)	0 / 8 (0.00%)
occurrences all number	0	1	3	0
Flatulence
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Nausea
subjects affected / exposed	3 / 7 (42.86%)	8 / 44 (18.18%)	7 / 44 (15.91%)	2 / 8 (25.00%)
occurrences all number	4	9	9	2
Odynophagia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Stomatitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	1	0	2	0
Toothache
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Vomiting
subjects affected / exposed	1 / 7 (14.29%)	3 / 44 (6.82%)	6 / 44 (13.64%)	1 / 8 (12.50%)
occurrences all number	1	3	7	1
Skin and subcutaneous tissue disorders
Dermatitis Acneiform
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Dry Skin
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0
Eczema
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	3	0
Hair Disorder
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Hyperhidrosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Night Sweats
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Pruritus
subjects affected / exposed	0 / 7 (0.00%)	4 / 44 (9.09%)	0 / 44 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	5	0	2
Rash
subjects affected / exposed	2 / 7 (28.57%)	2 / 44 (4.55%)	3 / 44 (6.82%)	1 / 8 (12.50%)
occurrences all number	2	2	4	1
Rash Maculo-Papular
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Rash Papular
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Rash Pruritic
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Skin Lesion
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Urticaria
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 44 (0.00%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0
Bladder Spasm
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0
Pollakiuria
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Renal Colic
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Renal Failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Renal Vein Thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Urinary Retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 7 (0.00%)	3 / 44 (6.82%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	3	0	0
Hypothyroidism
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	1 / 8 (12.50%)
occurrences all number	0	1	1	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 7 (14.29%)	8 / 44 (18.18%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	2	11	1	0
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Back Pain
subjects affected / exposed	0 / 7 (0.00%)	3 / 44 (6.82%)	3 / 44 (6.82%)	0 / 8 (0.00%)
occurrences all number	0	5	3	0
Groin Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Muscle Contracture
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Muscle Spasms
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0
Muscular Weakness
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 7 (14.29%)	2 / 44 (4.55%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	1	2	1	0
Musculoskeletal Discomfort
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal Pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 44 (4.55%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0
Myalgia
subjects affected / exposed	1 / 7 (14.29%)	5 / 44 (11.36%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	1	11	1	0
Neck Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Pain in Extremity
subjects affected / exposed	1 / 7 (14.29%)	4 / 44 (9.09%)	4 / 44 (9.09%)	0 / 8 (0.00%)
occurrences all number	1	5	5	0
Spinal Pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Furuncle
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Influenza
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	0	4	0
Oral Herpes
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Respiratory Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	5 / 44 (11.36%)	1 / 8 (12.50%)
occurrences all number	0	0	15	1
Rhinitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0
Tooth Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0
Urinary Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	1	2	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	2 / 7 (28.57%)	7 / 44 (15.91%)	11 / 44 (25.00%)	1 / 8 (12.50%)
occurrences all number	2	10	16	1
Dehydration
subjects affected / exposed	2 / 7 (28.57%)	0 / 44 (0.00%)	1 / 44 (2.27%)	0 / 8 (0.00%)
occurrences all number	2	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	3 / 44 (6.82%)	0 / 8 (0.00%)
occurrences all number	0	0	3	0
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	0 / 44 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0
Hypocalcaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 44 (2.27%)	2 / 44 (4.55%)	0 / 8 (0.00%)
occurrences all number	0	1	2	0
Hypokalaemia
subjects affected / exposed	1 / 7 (14.29%)	1 / 44 (2.27%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	1	0	1
Hyponatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 44 (0.00%)	0 / 44 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

01 Sep 2016

The overall reason for the amendment was to update toxicity and adverse event (AE) management in response to Health Authority request, to remove the subject-reported outcomes assessments (PRO), and to add timepoints for biomarker sample collection.

22 Mar 2017

The overall reason for the amendment was to allow subjects in Arm A (atezolizumab monotherapy) to cross over to Arm B (atezolizumab + daratumumab combination therapy) after confirmed disease progression. Combination therapy of daratumumab and atezolizumab may provide clinical benefit in non-small cell lung cancer (NSCLC) subjects who had disease progression on atezolizumab monotherapy. The combination of daratumumab with atezolizumab may lead to an improvement in clinical responses in NSCLC by enhancing the anti-tumor T cell responses facilitated by checkpoint inhibition. Therefore, subjects in Arm A with confirmed disease progression based on RECIST 1.1 may cross over to Arm B, provided all crossover eligibility criteria are met.

24 Aug 2017

The overall reason for the amendment was to allow for the enrollment of subjects in certain programmed-death ligand 1 (PD-L1) sub-groups to collect sufficient data to confirm clinical benefit.

26 Feb 2018

The overall reason for the amendment was to expand the Screening period for the informed consent and for PD-L1 testing, and to specify the PD-L1 score inclusion criterion. During its review of the study data at the initial interim analysis (40 evaluable subjects), the DMC determined that the study had enrolled a sufficient number of subjects with a PD-L1 score of tumor cells (TC0) and recommended continued enrollment only in subjects in the TC1-3 subgroups. In addition, the safety management guidelines for atezolizumab have been updated based on the current Investigator’s Brochure.

19 Apr 2018

The overall reason for the amendment was to added a phase 1b Dara-SC cohort combined with a corticosteroid tapering regimen to the study protocol, to minimize the risk of IRRs and to improve the safety outcomes after daratumumab administration. An optional prescreening phase for archival testing to assess PD-L1 status was specified.

14 Aug 2018

The overall reason for the amendment was to initiated response to the third planned (Data monitoring committee) DMC review of safety data on 23 May 2018 (88 subjects) and added the DMC recommendation to stop further enrollment into the study, with discontinuation of daratumumab+atezolizumab treatment and specified that ongoing subjects could continue on atezolizumab monotherapy until the subject met one or more of the treatment discontinuation criteria.

04 Oct 2018

The overall reason for the amendment was to pursuant to the DMC recommendation to stop enrollment into the study, it was clarified that subjects who were deriving clinical benefit from atezolizumab monotherapy, but did not have access to commercial atezolizumab, could continue treatment according to the local regulatory approvals and standard of care guidelines. Data from efficacy and safety evaluations performed according to the local regulatory approvals and standard of care guidelines were no longer to be collected with the exception of serious adverse events that were to be reported and entered in the Sponsor safety repository.

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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Clinical trials

Clinical Trial Results:
A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects with Overall Response Rate (ORR)

Primary: Percentage of Subjects with Overall Response Rate (ORR)

Secondary: Number of Subjects with Adverse Events

Secondary: Number of Subjects with Adverse Events

Secondary: Duration of Response (DoR)

Secondary: Duration of Response (DoR)

Secondary: Clinical Benefit Rate

Secondary: Clinical Benefit Rate

Secondary: Progression-Free Survival (PFS)

Secondary: Progression-Free Survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Daratumumab Serum Concentration

Secondary: Daratumumab Serum Concentration

Secondary: Atezolizumab Serum Concentration

Secondary: Atezolizumab Serum Concentration

Secondary: Number of Subjects with Anti-Daratumumab Antibodies

Secondary: Number of Subjects with Anti-Daratumumab Antibodies

Secondary: Number of Subjects with Anti-Atezolizumab Antibodies

Secondary: Number of Subjects with Anti-Atezolizumab Antibodies

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects with Overall Response Rate (ORR)

Primary: Percentage of Subjects with Overall Response Rate (ORR)

Secondary: Number of Subjects with Adverse Events

Secondary: Number of Subjects with Adverse Events

Secondary: Duration of Response (DoR)

Secondary: Duration of Response (DoR)

Secondary: Clinical Benefit Rate

Secondary: Clinical Benefit Rate

Secondary: Progression-Free Survival (PFS)

Secondary: Progression-Free Survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Daratumumab Serum Concentration

Secondary: Daratumumab Serum Concentration

Secondary: Atezolizumab Serum Concentration

Secondary: Atezolizumab Serum Concentration

Secondary: Number of Subjects with Anti-Daratumumab Antibodies

Secondary: Number of Subjects with Anti-Daratumumab Antibodies

Secondary: Number of Subjects with Anti-Atezolizumab Antibodies

Secondary: Number of Subjects with Anti-Atezolizumab Antibodies

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer