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Clinical Trial Results:
Phase Ib/II Study of Cobimetinib Administered as Single Agent and in Combination with Venetoclax, with or without Atezolizumab, in Patients with Relapsed and Refractory Multiple Myeloma.

Summary
EudraCT number	2017-000830-68
Trial protocol	NL DK SE DE CZ ES FR PL
Global end of trial date	18 May 2021

Results information
Results version number	v2(current)
This version publication date	15 Mar 2023
First version publication date	27 May 2022
Other versions	v1
Version creation reason

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

BO39813

ISRCTN number

US NCT number

NCT03312530

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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

18 May 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 May 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

The objective of this trial was to evaluate the efficacy, safety, tolerability, and pharmacokinetics of cobimetinib administered as a single agent, cobimetinib plus venetoclax, and cobimetinib plus venetoclax plus atezolizumab in patients with Relapsed and Refractory Multiple Myeloma (R/R MM).

Protection of trial subjects

All study subjects were required to read and sign and Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Nov 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czechia: 2

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

Norway: 18

Country: Number of subjects enrolled

Poland: 3

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

Sweden: 3

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

This study was conducted at 16 centers in 8 countries.

Screening details

A total of 62 participants were screend, of which 49 participants were enrolled.

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: Cobimetinib + Venetoclax

Arm description

Participants received cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety.

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered PO daily at a dose of 800 mg on Days 1-28.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered PO daily at a dose of 40 mg on Days 1-21.

Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

Arm description

Participants received cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses and atezolizumab (on Day 1 and Day 15) at a fixed dose of 840 mg IV, in 28-day cycles, to identify the dose level with acceptable safety.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered PO daily at a dose of 40 mg on Days 1-21.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered by IV infusion at a dose of 840 mg on Days 1 and 15.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered PO daily at a dose of 800 mg on Days 1-28.

A: Cobimetinib

Arm description

Participants received the standard single-agent cobimetinib dose of 60 milligrams (mg) (3 tablets of 20 mg each) orally (PO) daily on Days 1-21 of each 28-day cycle until disease progression. Upon progression, participants were allowed to receive treatment with cobimetinib and atezolizumab at the recommended Phase II dose of cobimetinib 60 mg PO on Days 1-21 plus atezolizumab intravenous (IV) infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered by IV infusion at a dose of 840 mg on Days 1 and 15.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered PO daily at a dose of 60 mg on Days 1-21.

B: Cobimetinib + Venetoclax

Arm description

Participants received cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase. Treatment continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered PO daily at a dose of 800 mg on Days 1-28.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered PO daily at a dose of 40 mg on Days 1-21.

C: Cobimetinib + Venetoclax + Atezolizumab

Arm description

Participants received cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Cotellic

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered PO daily at a dose of 40 mg on Days 1-21.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered by IV infusion at a dose of 840 mg on Days 1 and 15.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax was administered PO daily at a dose of 800 mg on Days 1-28.

Number of subjects in period 1	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Started	6	6	6	16	15
Completed	0	0	0	0	0
Not completed	6	6	6	16	15
Consent withdrawn by subject	-	1	-	-	-
Death	5	5	4	10	8
Study terminated by sponsor	1	-	2	3	7
Summarized as 'ongoing' due to missing data entry	-	-	-	1	-
Lost to follow-up	-	-	-	1	-
Participant in another sponsor study	-	-	-	1	-

Baseline characteristics

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Reporting group title

Safety Run-In: Cobimetinib + Venetoclax

Reporting group description

Participants received cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety.

Reporting group title

Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

Reporting group description

Reporting group title

A: Cobimetinib

Reporting group description

Reporting group title

B: Cobimetinib + Venetoclax

Reporting group description

Reporting group title

C: Cobimetinib + Venetoclax + Atezolizumab

Reporting group description

Participants received cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first.

Reporting group values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab	Total
Number of subjects	6	6	6	16	15	49
Age Categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	2	2	1	7	10	22
From 65-84 years	4	4	5	9	5	27
85 years and over	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	65.8 ( 7.6 )	66.5 ( 6.1 )	68.0 ( 5.9 )	64.1 ( 6.0 )	61.5 ( 10.5 )	-
Gender Categorical
Units: Subjects
Female	4	3	2	6	3	18
Male	2	3	4	10	12	31
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	0	0	0	1	1	2
Not Hispanic or Latino	6	6	6	14	11	43
Not Stated	0	0	0	1	2	3
Unknown	0	0	0	0	1	1
Race/Ethnicity, Customized
Units: Subjects
White	6	6	6	16	15	49

End points

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Reporting group title

Safety Run-In: Cobimetinib + Venetoclax

Reporting group description

Participants received cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety.

Reporting group title

Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

Reporting group description

Reporting group title

A: Cobimetinib

Reporting group description

Reporting group title

B: Cobimetinib + Venetoclax

Reporting group description

Reporting group title

C: Cobimetinib + Venetoclax + Atezolizumab

Reporting group description

Participants received cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first.

Primary: Percentage of Participants With Adverse Events (AEs)

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End point title

Percentage of Participants With Adverse Events (AEs) ^[1]

End point description

An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An AE was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. New or pre-existing conditions which worsened during the study were also considered AEs. The safety evaluable population included all participants who received any amount of study drug.

End point type

Primary

End point timeframe

Randomization up to end of study (up to approximately 3 years, 7 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: No statistical analyses provided as no formal hypothesis testing was planned for this study.

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	6	6	6	16	15
Units: Percentage of Participants
number (not applicable)	100.0	100.0	100.0	100.0	100.0

No statistical analyses for this end point

Primary: Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria

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End point title

Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria ^[2]

End point description

ORR was defined as a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) and was analyzed in the safety evaluable population and in the biomarker-selected sub-populations of t(11;14) and RAS mutations. The safety evaluable population included all participants who received any amount of study drug. 9999 to 9999999 = no participants were included in the t(11;14) biomarker-selected population within this arm.

End point type

Primary

End point timeframe

From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 3 years, 7 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: No statistical analyses provided as no formal hypothesis testing was planned for this study.

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	6	6	6	16	15
Units: Percentage of Participants
number (confidence interval 95%)
Safety Population (n=6,6,6,16,15)	16.7 (0.00 to 54.82)	33.3 (0.00 to 79.39)	0 (0.00 to 8.33)	31.3 (5.41 to 57.09)	26.7 (0.95 to 52.38)
t(11;14) Population (n=0,1,1,2,5)	99999 (9999 to 9999999)	100 (50.00 to 100.00)	0 (0.00 to 50.00)	100 (75.00 to 100.00)	80.0 (34.94 to 100.00)
RAS Mutation Population (n=2,1,2,7,8)	0 (0.00 to 25.00)	100 (50.00 to 100.00)	0 (0.00 to 25.00)	14.3 (0.00 to 47.35)	37.5 (0.00 to 77.30)

No statistical analyses for this end point

Secondary: Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria

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End point title

Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria

End point description

Clinical benefit rate (CBR) was defined as a minimal response (MR) or better (PR,VGPR, CR, sCR). The safety evaluable population included all participants who received any amount of study drug.

End point type

Secondary

End point timeframe

From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months)

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	6	6	6	16	15
Units: Percentage of Participants
number (confidence interval 95%)	33.3 (0.00 to 79.39)	33.3 (0.00 to 79.39)	0 (0.00 to 8.33)	43.8 (16.32 to 71.18)	33.3 (6.14 to 60.52)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria

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End point title

Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria

End point description

PFS was defined as the time from randomization (for randomized participants) or first treatment date (for non-ranomized participants) to the first occurrence of disease progression or relapse as determined by the investigator using the IMWG criteria or death from any cause during the study, whichever occurred first. The safety evaluable population included all participants who received any amount of study drug.

End point type

Secondary

End point timeframe

From enrollment or first treatment date to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 3 years, 7 months)

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	6	6	6	16	15
Units: Months
median (confidence interval 95%)	1.7 (0.9 to 3.7)	3.4 (2.1 to 4.6)	2.8 (1.9 to 4.7)	4.9 (1.9 to 10.3)	3.8 (1.4 to 4.7)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria

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End point title

Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria ^[3]

End point description

DOR was applicable to participants who achieved at least a PR, and was measured from the first observation of PR or better to the time of disease progression. The safety evaluable population included all participants who received any amount of study drug. 9999999 = not estimable, could not be calculated due to too few events. 9.999999 to 9999999 = the 95% CI could not be calculated from the data of one participant.

End point type

Secondary

End point timeframe

Time from the first observation of partial response (PR) to the time of disease progression (up to approximately 3 years, 7 months).

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In Arm A, there were no participants who achieved a response and hence why that arm is not presented.

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	1	2	5	4
Units: Months
median (confidence interval 95%)	11.5 (9.999999 to 9999999)	4.9 (2.3 to 9999999)	15.2 (1.9 to 9999999)	999999 (1.9 to 99999999)

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 was defined as the time from randomization until death from any cause. The safety evaluable population included all participants who received any amount of study drug. 9999999 = not estimable, could not be calculated due to too few events.

End point type

Secondary

End point timeframe

From randomization until death from any cause (up to approximately 3 years, 7 months).

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	6	6	6	16	15
Units: Months
median (confidence interval 95%)	11.4 (6.3 to 13.9)	14.3 (14.1 to 9999999)	12.9 (3.2 to 9999999)	13.5 (8.0 to 26.9)	22.0 (15.5 to 9999999)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib

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End point title

Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib

End point description

AUC0-24hr area under the plasma concentration-time curve from time 0 to 24 hrs. The PK population included participants from Arms A, B, and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	4	4	0 ^[4]	11	9
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	2390 ( 53.4 )	3190 ( 55.3 )	( )	2540 ( 78.1 )	2900 ( 54.6 )

Notes
[4] - No PK parameters were calculated due to limited sampling times.

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Cobimetinib

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End point title

Maximum Observed Plasma Concentration (Cmax) of Cobimetinib

End point description

Cmax is the maximum observed plasma concentration at steady state. The PK population included participants from Arms A, B, and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	4	5	0 ^[5]	13	12
Units: ng/mL
geometric mean (geometric coefficient of variation)	157 ( 63.5 )	192 ( 61.7 )	( )	148 ( 72.6 )	166 ( 61.0 )

Notes
[5] - No PK parameters were calculated due to limited sampling times

No statistical analyses for this end point

Secondary: Time to Reach Cmax (Tmax) of Cobimetinib

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End point title

Time to Reach Cmax (Tmax) of Cobimetinib

End point description

Tmax is the time to reach Cmax. The PK population included participants from Arms A, B, and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	4	5	0 ^[6]	13	12
Units: hr
median (full range (min-max))	4.00 (2.10 to 4.02)	4.00 (2.05 to 5.73)	( to )	4.00 (2.00 to 6.08)	4.00 (2.23 to 6.37)

Notes
[6] - No PK parameters were calculated due to limited sampling times.

No statistical analyses for this end point

Secondary: AUClast of Venetoclax

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End point title

AUClast of Venetoclax ^[7]

End point description

AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15). The PK population included participants from Arms B and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This analysis was only performed on the arms with Venetoclax and hence why not all arms are presented.

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	4	5	13	11
Units: hr*ug/mL
geometric mean (geometric coefficient of variation)	4.96 ( 67.2 )	5.13 ( 57.0 )	6.52 ( 63.7 )	6.52 ( 51.3 )

No statistical analyses for this end point

Secondary: Cmax of Venetoclax

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End point title

Cmax of Venetoclax ^[8]

End point description

Cmax is the maximum observed plasma concentration at steady state. The PK population included participants from Arms B and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This analysis was only performed on the arms with Venetoclax and hence why not all arms are presented.

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	4	5	13	11
Units: ug/mL
geometric mean (geometric coefficient of variation)	1.25 ( 81.0 )	1.16 ( 48.7 )	1.32 ( 55.3 )	1.35 ( 18.2 )

No statistical analyses for this end point

Secondary: Tmax of Venetoclax

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End point title

Tmax of Venetoclax ^[9]

End point description

Tmax is the time to reach Cmax. The PK population included participants from Arms B and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This analysis was only performed on the arms with Venetoclax and hence why not all arms are presented.

End point values	Safety Run-In: Cobimetinib + Venetoclax	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	4	5	13	11
Units: hr
median (full range (min-max))	5.73 (3.92 to 5.77)	5.65 (3.75 to 5.78)	6.00 (3.95 to 8.50)	5.92 (0 to 8.17)

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab

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End point title

Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab ^[10]

End point description

The immunogenicity analysis population for atezolizumab consisted of all participants from Arm C with any ADA assessment.

End point type

Secondary

End point timeframe

Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 3 years, 7 months)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This analysis was only performed on the arms with Atezolizumab and hence why not all arms are presented.

End point values	Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab	C: Cobimetinib + Venetoclax + Atezolizumab
Number of subjects analysed	6	14
Units: Percentage of Participants
number (not applicable)	50.0	28.6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Randomization up to end of study (up to approximately 3 years, 7 months)

Adverse event reporting additional description

AEs were recorded for the safety-evaluable population, which included all participants who received any amount of study drug and analyzed according to the treatment arm they received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Safety Run-In: Cobimetinib+Venetoclax

Reporting group description

Participants received cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety.

Reporting group title

Safety Run-In: Cobimetinib+Venetoclax+Atezolizumab

Reporting group description

Reporting group title

A: Cobimetinib

Reporting group description

Reporting group title

B: Cobimetinib + Venetoclax

Reporting group description

Reporting group title

C: Cobimetinib + Venetoclax + Atezolizumab

Reporting group description

Participants received cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first.

Serious adverse events	Safety Run-In: Cobimetinib+Venetoclax	Safety Run-In: Cobimetinib+Venetoclax+Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	3 / 6 (50.00%)	12 / 16 (75.00%)	11 / 15 (73.33%)
number of deaths (all causes)	5	5	4	11	8
number of deaths resulting from adverse events	0	0	0	0	1
Investigations
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIROVIRUS TEST POSITIVE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
SYNCOPE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMORRHAGIC STROKE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
SPINAL CORD COMPRESSION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
PYREXIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	4 / 5	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	4 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
VOMITING
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTESTINAL ULCER
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
RESPIRATORY FAILURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
NECK PAIN
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
INTERVERTEBRAL DISCITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PROSTATE INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	4 / 16 (25.00%)	2 / 15 (13.33%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	2 / 5	2 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOCOCCAL BACTERAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LISTERIA SEPSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	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
INFECTION
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMOPHILUS SEPSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORAL HERPES
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA PNEUMOCOCCAL
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
HYPOKALAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	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
HYPONATRAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Safety Run-In: Cobimetinib+Venetoclax	Safety Run-In: Cobimetinib+Venetoclax+Atezolizumab	A: Cobimetinib	B: Cobimetinib + Venetoclax	C: Cobimetinib + Venetoclax + Atezolizumab
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	5 / 6 (83.33%)	15 / 16 (93.75%)	15 / 15 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
TUMOUR PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Vascular disorders
ESSENTIAL HYPERTENSION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
HAEMATOMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1
PERIPHERAL VENOUS DISEASE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
HYPERTENSION
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	0	1	1	1	1
General disorders and administration site conditions
OEDEMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
FEELING COLD
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
PYREXIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	3 / 15 (20.00%)
occurrences all number	1	0	0	3	4
PAIN
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0
FACE OEDEMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
FATIGUE
subjects affected / exposed	4 / 6 (66.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 16 (18.75%)	3 / 15 (20.00%)
occurrences all number	5	1	0	5	3
CHEST PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
OEDEMA PERIPHERAL
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 16 (12.50%)	2 / 15 (13.33%)
occurrences all number	2	1	1	4	2
ASTHENIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	2 / 15 (13.33%)
occurrences all number	1	0	0	4	2
Immune system disorders
HYPERSENSITIVITY
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Reproductive system and breast disorders
BALANOPOSTHITIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
PRODUCTIVE COUGH
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
DYSPNOEA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	0	0	1	1	1
EPISTAXIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	1	1	2
SINUS PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
COUGH
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
Psychiatric disorders
INSOMNIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
Investigations
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 16 (18.75%)	2 / 15 (13.33%)
occurrences all number	0	1	0	5	3
BLOOD LACTATE DEHYDROGENASE INCREASED
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
BLOOD CREATININE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 16 (6.25%)	3 / 15 (20.00%)
occurrences all number	0	1	0	1	3
EJECTION FRACTION DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	0	1	2
BLOOD CREATINE PHOSPHOKINASE INCREASED
subjects affected / exposed	3 / 6 (50.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	4 / 16 (25.00%)	2 / 15 (13.33%)
occurrences all number	3	3	1	4	6
BLOOD BILIRUBIN INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	4
INFLUENZA A VIRUS TEST POSITIVE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
VITAMIN B12 DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
BLOOD POTASSIUM DECREASED
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0
BLOOD URIC ACID INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
LIPASE INCREASED
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	3 / 15 (20.00%)
occurrences all number	1	0	0	7	5
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	0	0	0	2	1
TROPONIN INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HAEMOGLOBIN DECREASED
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
BLOOD CREATINE INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
PLATELET COUNT DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences all number	0	0	0	2	2
TROPONIN T INCREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)
occurrences all number	0	0	0	0	3
WEIGHT DECREASED
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	0	1	2
LYMPHOCYTE COUNT DECREASED
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
BLOOD CALCIUM INCREASED
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
AMYLASE INCREASED
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	2	0	0	1	4
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	1	1	0	1	0
Injury, poisoning and procedural complications
EYE CONTUSION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
FALL
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0
Cardiac disorders
ATRIOVENTRICULAR BLOCK
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
CARDIAC FAILURE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
Nervous system disorders
DYSGEUSIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	1
NEURALGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
SYNCOPE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)
occurrences all number	0	0	0	0	3
PARAESTHESIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
SCIATICA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
HYPERSOMNIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
DYSAESTHESIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
HYPERAESTHESIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
POST HERPETIC NEURALGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HEADACHE
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)
occurrences all number	3	0	0	0	2
HYPOAESTHESIA
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0
NEUROPATHY PERIPHERAL
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
AUTONOMIC NEUROPATHY
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
Blood and lymphatic system disorders
LYMPHOPENIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 15 (26.67%)
occurrences all number	0	0	0	1	4
NEUTROPENIA
subjects affected / exposed	3 / 6 (50.00%)	4 / 6 (66.67%)	0 / 6 (0.00%)	2 / 16 (12.50%)	7 / 15 (46.67%)
occurrences all number	4	10	0	2	17
LEUKOPENIA
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)
occurrences all number	4	0	0	0	9
PANCYTOPENIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
THROMBOCYTOPENIA
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	3 / 16 (18.75%)	5 / 15 (33.33%)
occurrences all number	1	2	0	3	5
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
ANAEMIA
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)	9 / 16 (56.25%)	9 / 15 (60.00%)
occurrences all number	2	2	1	11	14
HAEMORRHAGIC DIATHESIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
TINNITUS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
Eye disorders
DETACHMENT OF RETINAL PIGMENT EPITHELIUM
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
EYE HAEMORRHAGE
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
RETINAL HAEMORRHAGE
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	1	0	0
OPTIC NERVE CUPPING
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
DRY EYE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
VISUAL IMPAIRMENT
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	0	1	2
SWELLING OF EYELID
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
PHOTOPHOBIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
SUBRETINAL FLUID
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0
BLEPHAROCHALASIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
BLEPHARITIS
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)
occurrences all number	1	1	0	0	3
CHALAZION
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
DYSPHAGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
MELAENA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
CONSTIPATION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	0	0	3	2	1
VOMITING
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	6 / 16 (37.50%)	3 / 15 (20.00%)
occurrences all number	2	0	0	10	8
GASTROINTESTINAL PAIN
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
ORAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
DRY MOUTH
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)
occurrences all number	1	0	0	0	2
FAECES DISCOLOURED
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
HAEMATEMESIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
STOMATITIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
FLATULENCE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	0	1	2
ABDOMINAL PAIN UPPER
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	1	0	0	1	0
ANORECTAL DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HAEMORRHOIDS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
DIARRHOEA
subjects affected / exposed	5 / 6 (83.33%)	6 / 6 (100.00%)	2 / 6 (33.33%)	13 / 16 (81.25%)	13 / 15 (86.67%)
occurrences all number	10	9	2	17	21
NAUSEA
subjects affected / exposed	6 / 6 (100.00%)	4 / 6 (66.67%)	1 / 6 (16.67%)	5 / 16 (31.25%)	10 / 15 (66.67%)
occurrences all number	7	4	1	7	11
ABDOMINAL PAIN
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)
occurrences all number	0	1	0	0	2
DYSPEPSIA
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	1	0	0	1	0
ORAL DISCOMFORT
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
PROCTITIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Skin and subcutaneous tissue disorders
HYPERHIDROSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
RASH
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 16 (6.25%)	5 / 15 (33.33%)
occurrences all number	2	2	4	1	6
SKIN ULCER
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0
DERMATITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
PRURITUS
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	3	0	3	0	1
RASH MACULO-PAPULAR
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	1
ERYTHEMA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
ECCHYMOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
DRY SKIN
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 16 (6.25%)	5 / 15 (33.33%)
occurrences all number	0	1	0	1	5
SEBORRHOEA
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
DERMATITIS ACNEIFORM
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	0	1	3
ALOPECIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Renal and urinary disorders
URINARY TRACT PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
URINARY INCONTINENCE
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
POLLAKIURIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
RENAL FAILURE
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
RENAL COLIC
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Endocrine disorders
HYPERTHYROIDISM
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HYPERPARATHYROIDISM
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HYPOTHYROIDISM
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	1
Musculoskeletal and connective tissue disorders
BONE PAIN
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1
MUSCULAR WEAKNESS
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
BACK PAIN
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences all number	1	1	2	4	1
OSTEOARTHRITIS
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0
MUSCLE SPASMS
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	0 / 15 (0.00%)
occurrences all number	1	0	0	5	0
ARTHRALGIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1
PAIN IN EXTREMITY
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1
Infections and infestations
BRONCHIOLITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
BRONCHITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
INFLUENZA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
EAR INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
RESPIRATORY SYNCYTIAL VIRUS INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
IMPETIGO
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	4	0
INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
OTITIS EXTERNA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
URINARY TRACT INFECTION
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences all number	1	0	1	2	1
ORAL HERPES
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	1	0	0	0
SINUSITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
RASH PUSTULAR
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	1	0	1
HERPES SIMPLEX
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
HERPES ZOSTER
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
PNEUMONIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences all number	0	0	0	2	1
CONJUNCTIVITIS
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	3	0	0	0
SKIN INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences all number	1	0	2	2	2
NASOPHARYNGITIS
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)
occurrences all number	1	3	0	0	5
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
ORAL CANDIDIASIS
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)
occurrences all number	0	1	0	1	4
PNEUMONIA PNEUMOCOCCAL
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
CELLULITIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
WOUND INFECTION
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
CANDIDA INFECTION
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
SALMONELLOSIS
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
Metabolism and nutrition disorders
HYPONATRAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
HYPERTRIGLYCERIDAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
HYPERPHOSPHATAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0
HYPOKALAEMIA
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	2
HYPOMAGNESAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)
occurrences all number	0	0	0	5	2
HYPERKALAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HYPOPHOSPHATAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)
occurrences all number	0	0	0	0	6
DECREASED APPETITE
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	1	0	0	1
HYPOCALCAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)
occurrences all number	0	0	0	1	2
FOLATE DEFICIENCY
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
HYPERURICAEMIA
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

10 Aug 2017

The following updates were made: 1) Safety data for cobimetinib plus venetoclax was updated; 2) Information was added regarding the Cobimetinib plus Venetoclax plus Atezolizumab Safety Run-In Cohort design; 3) Clarifications were made to the Definition of Evaluable Patients in the Safety Run-In Cohorts and the Determination of Sample Size; 4) Pregnancy testing was updated; 5) Instructions for recordings of participant vital signs and left ventricular dysfunction were updated.

02 Mar 2018

The following updates were made: 1) Clinical data for atezolizumab was updated; 2) Updated the potential risk associated with atezolizumab; 3) Guidelines for atezolizumab-related dose modification and treatment interruption or discontinuation were updated; 4) Guidelines for managing patients who experience atezolizumab-associated AEs was updated; 5) Appendix 8 was added to the protocol.

20 Sep 2018

The following updates were made: 1) The number of participants randomized to each treatment arm was modified; 2) Inclusion criteria was updated; 3) Prohibited therapies were updated; 4) The timing of the optional bone marrow biopsy was changed; 5) Instructions on participant withdrawl were modified; 6) Lists of risks for atezolizumab were revised; 7) The maximum time for interrupting atezolizumab treatment was changed; 8) AESIs were revised; 9) Clarification of reporting of events that occur after study drug initiation.

27 Mar 2019

The following updates were made: 1) Enrollment of new participants was put on hold and a decision to continue study treatment for participants already enrolled would be made on a case-by-case basis; 2) The protocol was updated with topline data from an ongoing study; 3) Language was added to clarify recommendations on the administration of certain vaccinations; 4) The list of permitted therapies was updated; 5) Guidelines for managing hematological toxicities was modified; 6) A section was added to the protocol to address the management of infective complications.

24 Jan 2020

The following updates were made: 1) Background information on atezolizumab was updated; 2) "Immune-related" was changed to "immune-mediated" when describing events associated with atezolizumab; 3) Clinical data for cobimetinib plus venetoclax was updated; 4) Language clarified that after withdrawal of consent for participation in the Research Biosample Repository (RBR), remaining samples would be destroyed or no longer linked to the participant; 5) Identified risks associated with cobimetinib were updated; 6) Cobimetinib safety risk data was updated; 7) Serious infection, an important risk for venetoclax was closely monitored across all indications; 8) The list of atezolizumab risks was updated; 9) Systemic immune activation was replaced by hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the list of potential risks for atezolizumab. The management guidelines for systemic immune activation were replaced with management guidelines for hemophagocytic lymphohistiocytosis and macrophage activation syndrome; 10) AESIs were updated; 11) Language was revised as some site might not allow follow-up on partner pregnancies; 11) Language was updated that therapeutic or elective abortions were not considered AEs; 12) The atezolizumab AE management guidelines were revised.

18 Feb 2021

The following updates were made: 1) The list of approved indications for atezolizumab was updated; 2) Clarification for the use of investigational medicinal product accountability; 3) Immunosuppressive medications were removed from the prohibited therapy and added to the cautionary therapy for atezolizumab-treated participants; 4) Updates to the identified risks associated with cobimetinib; 5) The list of identified risks for atezolizumab was revised; 6) Guidelines for the management of atezolizumab-associated AEs and IRRs were revised; 7) The list of atezolizumab-associated AESIs was revised; 8) Language was added regarding female participants informing the investigator if they became pregnant; 9) Appendix 7 of the protocol was revised; 10) AE management guidelines for IRRs and CRS' were updated; 11) The management guidelines for HLH and MAS have been modified.

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.

In March 2019, this study was placed on voluntary enrollment hold. In May 2019, after an informal efficacy review, the Sponsor decided not to remove the hold and discontinued further development of the combination.

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Clinical trials

Clinical Trial Results: Phase Ib/II Study of Cobimetinib Administered as Single Agent and in Combination with Venetoclax, with or without Atezolizumab, in Patients with Relapsed and Refractory Multiple Myeloma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Adverse Events (AEs)

Primary: Percentage of Participants With Adverse Events (AEs)

Primary: Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria

Primary: Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria

Secondary: Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria

Secondary: Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria

Secondary: Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria

Secondary: Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria

Secondary: Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria

Secondary: Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib

Secondary: Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib

Secondary: Maximum Observed Plasma Concentration (Cmax) of Cobimetinib

Secondary: Maximum Observed Plasma Concentration (Cmax) of Cobimetinib

Secondary: Time to Reach Cmax (Tmax) of Cobimetinib

Secondary: Time to Reach Cmax (Tmax) of Cobimetinib

Secondary: AUClast of Venetoclax

Secondary: AUClast of Venetoclax

Secondary: Cmax of Venetoclax

Secondary: Cmax of Venetoclax

Secondary: Tmax of Venetoclax

Secondary: Tmax of Venetoclax

Secondary: Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab

Secondary: Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Phase Ib/II Study of Cobimetinib Administered as Single Agent and in Combination with Venetoclax, with or without Atezolizumab, in Patients with Relapsed and Refractory Multiple Myeloma.