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Clinical Trial Results:
A Randomized, Multicenter, Open-Label Phase Ib/II Study of RO5083945 in Combination With Cisplatin and Gemcitabine/Pemetrexed Versus Cisplatin and Gemcitabine/Pemetrexed in Patients With Advanced or Recurrent Non-Small Cell Lung Cancer Who Have not Received Prior Chemotherapy

Summary
EudraCT number	2010-018945-72
Trial protocol	DE GB BE
Global end of trial date	01 Aug 2013

Results information
Results version number	v1(current)
This version publication date	02 Mar 2016
First version publication date	02 Mar 2016
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

BP22349

ISRCTN number

US NCT number

NCT01185847

WHO universal trial number (UTN)

Sponsor organisation name

F. HoffmannLa Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. HoffmannLa Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. HoffmannLa Roche AG, +41 61 6878333, 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

01 Aug 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Aug 2013

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the safety and efficacy of RO5083945 in combination with standard chemotherapy in participants with advanced or recurrent NSCLC who have not received prior chemotherapy. In Part 1, participants received RO5083945 intravenously and standard chemotherapy (cisplatin plus either gemcitabine or pemetrexed) for up to 6 cycles of 3 weeks and then RO5083945 until disease progression, unacceptable toxicity, or withdrawal of consent. In Part 1, maximum tolerated dose (MTD) and recommended dose were established for Phase II. In Part 2, participants were randomized to receive either RO5083945 in combination with standard chemotherapy or chemotherapy alone for up to 6 cycles in non-squamous group only. In the absence of disease progression, participants receiving RO5083945 could continue treatment with RO5083945 as monotherapy.

Protection of trial subjects

The investigator ensured that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Conference on Harmonisation Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the participant. For European Union/European Economic Area (EU/EEA) countries, the investigator ensured compliance with the EU Clinical Trial Directive (2001/20/ethics committee). In other countries where “Guideline for Good Clinical Practice” existed Roche and the investigators strictly ensured adherence to the stated provisions.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Nov 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Spain: 48

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Italy: 12

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

Participants were classified into 2 histology groups, with squamous or non-squamous NSCLC and sequentially enrolled into 2 consecutive cohorts (Cohort 1: chemotherapy plus [+] 1000 milligram [mg] RO5083945 followed by RO5083945 monotherapy; Cohort 2: chemotherapy + 1400 mg RO5083945 followed by RO5083945 monotherapy).

Period 1 title

Overall trial (overall period) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy

Arm description

Chemotherapy (75 milligrams per square meter [mg/m^2] cisplatin + 1250 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously, every three weeks (q3w) for a maximum of 6 cycles (18 weeks) followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

RO5083945

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1000 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1250 mg/m^2 gemcitabine intravenously q3w for a maximum of 6 cycles (18 weeks).

Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy

Arm description

Chemotherapy (75 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine ) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

RO5083945

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1000 mg RO5083945 intravenously q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1000 mg/m^2 gemcitabine intravenously q3w for a maximum of 6 cycles (18 weeks).

Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945

Arm description

Chemotherapy (60 mg/m^2 cisplatin + 1000 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

RO5083945

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1000 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 60 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1000 mg/m^2 gemcitabine intravenously q3w for a maximum of 6 cycles (18 weeks).

Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy

Arm description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1000 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

RO5083945

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1000 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy

Arm description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

RO5083945

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1400 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy

Arm description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) and 1400 mg RO5083945 administered intravenously q3w for a maximum of 6 cycles (18 weeks), followed by 1400 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

RO5083945

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1400 mg RO5083945 intravenously, q3w until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy

Arm description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

Arm type

Active comparator

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 75 mg/m^2 cisplatin intravenously q3w for a maximum of 6 cycles (18 weeks).

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Participants received 500 mg/m^2 pemetrexed intravenously q3w for a maximum of 6 cycles (18 weeks).

Number of subjects in period 1	Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945	Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Started	8	1	8	3	11	41	21
Completed	0	0	0	0	0	0	13
Not completed	8	1	8	3	11	41	8
Adverse event, serious fatal	-	1	-	-	-	1	2
Consent withdrawn by subject	-	-	1	-	-	4	1
Non-compliance of subject	-	-	-	-	-	2	-
Intercurrent illness	-	-	-	-	-	9	-
Adverse event, non-fatal	4	-	2	-	1	-	-
Unspecified	-	-	-	-	-	2	-
Progressive disease	4	-	4	3	10	23	5
Not received treatment	-	-	1	-	-	-	-

Baseline characteristics

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Reporting group title

Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy

Reporting group description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

Reporting group values	Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945	Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy	Total
Number of subjects	8	1	8	3	11	41	21
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	63.5 ± 7.87	61 ± 0	63.5 ± 6.59	55 ± 6.08	56.9 ± 10.6	56.3 ± 10.25	58.7 ± 11.4	-
Gender categorical
Units: Subjects
Female	1	0	0	0	4	15	3	23
Male	7	1	8	3	7	26	18	70

End points

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Reporting group title

Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy

Reporting group description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

Primary: Progression-Free Survival (PFS) Assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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End point title

Progression-Free Survival (PFS) Assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 ^[1]

End point description

PFS was defined as the time between randomization and date of first documented disease progression (unequivocal appearance of new malignant lesions denotes) or death, whichever occurred first. Intent-toTreat (ITT) Population defined as all randomized participants. Participants were assigned to the treatment group to which they were randomized.

End point type

Primary

End point timeframe

Baseline and every 6 weeks thereafter until disease progression up to 33 months

Notes
[1] - 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: The data was reported only for the non-squamous NSCLC Phase 2 Arm A (RO5083945 + chemotherapy) and Arm B (chemotherapy).

End point values	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	41	21
Units: months
median (confidence interval 95%)	5.4 (4.1 to 6.5)	6 (3.7 to 8.4)

PFS

Comparison groups

Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy v Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7981

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.92

Primary: Percentage of Participants with Disease Progression or Death Assessed as per RECIST Version 1.1

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End point title

Percentage of Participants with Disease Progression or Death Assessed as per RECIST Version 1.1 ^[2] ^[3]

End point description

End point type

Primary

End point timeframe

Baseline and every 6 weeks thereafter until disease progression up to 33 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 analysis was planned for this endpoint.
[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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.

End point values	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	41	21
Units: percentage of participants
number (not applicable)	92.7	90.5

No statistical analyses for this end point

Primary: Number of Participants With Positive Human Anti-human Antibodies (HAHA) Values

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End point title

Number of Participants With Positive Human Anti-human Antibodies (HAHA) Values ^[4]

End point description

Levels of HAHA in serum were detected at baseline. Safety Population.

End point type

Primary

End point timeframe

Predose on Day 1 of each cycle and on follow-up

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945	Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	8	1	7 ^[5]	3	11	41	21
Units: participants
number (not applicable)	0	0	1	0	1	6	1

Notes
[5] - Participants who received treatment were included in the analysis.

No statistical analyses for this end point

Primary: Pharmacokinetic (PK) Parameters of RO5083945, Cisplatin, Gemcitabine, and Pemetrexed

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End point title

Pharmacokinetic (PK) Parameters of RO5083945, Cisplatin, Gemcitabine, and Pemetrexed ^[6]

End point description

PK parameters were not analyzed due to no further plans for clinical development of RO5083945.

End point type

Primary

End point timeframe

Multiple sampling Cycles 16 (18 weeks)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945	Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]	0 ^[12]	0 ^[13]
Units: micrograms per milliliter (mcg/L)
arithmetic mean (standard deviation)	±	±	±	±	±	±	±

Notes
[7] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
[8] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
[9] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
[10] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
[11] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
[12] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.
[13] - PK parameters were not analyzed due to no further plans for clinical development of RO5083945.

No statistical analyses for this end point

Secondary: Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR)

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End point title

Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR) ^[14]

End point description

Best overall response was defined as CR or PR as assessed by investigator using RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) having reduction in short axis to < 10 millimeter (mm); PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Best Overall Response was not evaluated due to no further plans for clinical development of RO5083945.

End point type

Secondary

End point timeframe

Baseline and every 6 weeks thereafter up to 33 months

Notes
[14] - 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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.

End point values	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	0 ^[15]	0 ^[16]
Units: percentage of participants
number (not applicable)

Notes
[15] - Best Overall Response was not evaluated due to no further plans for clinical development of RO508394
[16] - Best Overall Response was not evaluated due to no further plans for clinical development of RO508394

No statistical analyses for this end point

Secondary: Duration of Response

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End point title

Duration of Response ^[17]

End point description

Duration of response was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first). Duration of response was not evaluated due to no further plans for clinical development of RO5083945.

End point type

Secondary

End point timeframe

Baseline and every 6 weeks thereafter up to 33 months

Notes
[17] - 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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.

End point values	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	0 ^[18]	0 ^[19]
Units: months
median (confidence interval 95%)	( to )	( to )

Notes
[18] - Duration of response was not evaluated due to no further plans for clinical development of RO5083945
[19] - Duration of response was not evaluated due to no further plans for clinical development of RO5083945

No statistical analyses for this end point

Secondary: Percentage of Participants With Stable Disease for at Least 6 Weeks, CR or PR

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End point title

Percentage of Participants With Stable Disease for at Least 6 Weeks, CR or PR ^[20]

End point description

Stable Disease was defined as the condition which neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease was not evaluated due to no further plans for clinical development of RO5083945.

End point type

Secondary

End point timeframe

Baseline and every 6 weeks thereafter up to 33 months

Notes
[20] - 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: No statistical analysis was planned for this endpoint.

End point values	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	0 ^[21]	0 ^[22]
Units: percentage of participants
number (not applicable)

Notes
[21] - Stable Disease was not evaluated due to no further plans for clinical development of RO5083945.
[22] - Stable Disease was not evaluated due to no further plans for clinical development of RO5083945.

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[23]

End point description

OS was defined as the time between randomization and date of death. Participants without an event will be censored at the last date known to be alive. OS was not evaluated due to no further plans for clinical development of RO5083945.

End point type

Secondary

End point timeframe

Baseline and every 6 weeks thereafter up to 33 months

Notes
[23] - 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: The study was conducted in two phases. The endpoint was assessed in Phase 2 only, therefore the data for the Phase 1 arm group are not presented.

End point values	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Number of subjects analysed	0 ^[24]	0 ^[25]
Units: percentage of participants
number (not applicable)

Notes
[24] - OS was not evaluated due to no further plans for clinical development of RO5083945.
[25] - OS was not evaluated due to no further plans for clinical development of RO5083945.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From baseline up to 28 days after the last dose of study medication

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy

Reporting group description

Chemotherapy (75 mg/m^2 cisplatin + 1250 mg/m^2 gemcitabine) and 1000 mg RO5083945 administered intravenously, every three weeks (q3w) for a maximum of 6 cycles (18 weeks) followed by 1000 mg RO5083945 monotherapy until disease progression, unacceptable toxicity, or withdrawal of consent.

Reporting group title

Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy

Reporting group description

Reporting group title

Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy

Reporting group description

Chemotherapy (75 mg/m^2 cisplatin + 500 mg/m^2 pemetrexed) administered intravenously q3w for a maximum of 6 cycles (18 weeks).

Serious adverse events	Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945	Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 8 (75.00%)	1 / 1 (100.00%)	1 / 8 (12.50%)	2 / 3 (66.67%)	1 / 11 (9.09%)	16 / 41 (39.02%)	3 / 21 (14.29%)
number of deaths (all causes)	5	1	5	2	9	28	16
number of deaths resulting from adverse events
Vascular disorders
Superior vena cava syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	2 / 41 (4.88%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	2 / 8 (25.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	1 / 1	0 / 0	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	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal inflammation
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis toxic
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	0 / 8 (0.00%)	1 / 1 (100.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia necrotising
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cachexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0

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

Non-serious adverse events	Squamous NSCLC Phase 1b Cohort 1a: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1b: RO5083945 + Chemotherapy	Squamous NSCLC Phase 1b Cohort 1c: Chemotherapy +RO5083945	Non-Squamous NSCLC Phase 1b Cohort 1: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 1b Cohort 2: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm A: RO5083945 + Chemotherapy	Non-Squamous NSCLC Phase 2 Arm B: Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 8 (87.50%)	1 / 1 (100.00%)	5 / 8 (62.50%)	3 / 3 (100.00%)	11 / 11 (100.00%)	41 / 41 (100.00%)	19 / 21 (90.48%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0	0	2	0
Hypotension
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 8 (37.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	2 / 3 (66.67%)	4 / 11 (36.36%)	13 / 41 (31.71%)	12 / 21 (57.14%)
occurrences all number	4	0	1	2	12	27	26
Fatigue
subjects affected / exposed	3 / 8 (37.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 11 (9.09%)	13 / 41 (31.71%)	4 / 21 (19.05%)
occurrences all number	3	0	0	1	1	18	4
Pyrexia
subjects affected / exposed	3 / 8 (37.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	1 / 11 (9.09%)	3 / 41 (7.32%)	6 / 21 (28.57%)
occurrences all number	3	0	0	2	1	4	9
Oedema peripheral
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	2 / 8 (25.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	5 / 41 (12.20%)	0 / 21 (0.00%)
occurrences all number	0	0	4	1	0	6	0
Chest pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	3 / 3 (100.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	0 / 21 (0.00%)
occurrences all number	1	0	0	3	0	2	0
Gait disturbance
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Xerosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 11 (18.18%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	3	3	0
Mucosal inflammation
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	4 / 11 (36.36%)	5 / 41 (12.20%)	3 / 21 (14.29%)
occurrences all number	1	0	0	2	4	5	4
Cough
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	4 / 41 (9.76%)	3 / 21 (14.29%)
occurrences all number	1	0	0	0	1	4	5
Productive cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 11 (18.18%)	2 / 41 (4.88%)	1 / 21 (4.76%)
occurrences all number	0	0	1	1	2	5	1
Epistaxis
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	4 / 41 (9.76%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	0	4	1
Dyspnoea Exertional
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Nasal dryness
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Dysphonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 11 (18.18%)	1 / 41 (2.44%)	2 / 21 (9.52%)
occurrences all number	0	0	0	0	2	1	2
Pulmonary embolism
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	1 / 21 (4.76%)
occurrences all number	0	0	0	0	1	1	1
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 11 (18.18%)	2 / 41 (4.88%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	2	2	0
Anxiety
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	2 / 21 (9.52%)
occurrences all number	0	0	1	0	0	1	2
Confusional state
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	2	0
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	1 / 11 (9.09%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences all number	0	0	1	1	1	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences all number	0	0	1	0	1	0	1
Blood bilirubin increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Blood sodium decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Platelet count decreased
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Urine output decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	2	1	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Weight decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	5 / 41 (12.20%)	2 / 21 (9.52%)
occurrences all number	0	0	0	0	0	5	2
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	3 / 8 (37.50%)	1 / 1 (100.00%)	1 / 8 (12.50%)	2 / 3 (66.67%)	7 / 11 (63.64%)	19 / 41 (46.34%)	0 / 21 (0.00%)
occurrences all number	3	1	3	2	8	21	0
Fall
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	0	1	1
Atrial flutter
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Nervous system disorders
Dysgeusia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	2 / 11 (18.18%)	1 / 41 (2.44%)	1 / 21 (4.76%)
occurrences all number	1	0	0	1	2	1	1
Headache
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	2 / 21 (9.52%)
occurrences all number	1	0	1	0	1	1	2
Dizziness
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	2 / 41 (4.88%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	1	2	1
Sciatica
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Syncope
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	4 / 41 (9.76%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	7	0
Hypoaesthesia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Lethargy
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Trigeminal neuralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	5 / 8 (62.50%)	0 / 1 (0.00%)	2 / 8 (25.00%)	1 / 3 (33.33%)	4 / 11 (36.36%)	18 / 41 (43.90%)	10 / 21 (47.62%)
occurrences all number	6	0	3	1	8	30	22
Anaemia
subjects affected / exposed	2 / 8 (25.00%)	0 / 1 (0.00%)	2 / 8 (25.00%)	3 / 3 (100.00%)	5 / 11 (45.45%)	12 / 41 (29.27%)	10 / 21 (47.62%)
occurrences all number	4	0	2	4	5	13	10
Thrombocytopenia
subjects affected / exposed	3 / 8 (37.50%)	1 / 1 (100.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	6 / 41 (14.63%)	3 / 21 (14.29%)
occurrences all number	7	1	5	0	0	10	4
Leukopenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	0	3	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Deafness
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Hearing impaired
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Ototoxicity
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	2 / 11 (18.18%)	2 / 41 (4.88%)	4 / 21 (19.05%)
occurrences all number	0	0	0	2	2	2	4
Tinnitus
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	3 / 41 (7.32%)	2 / 21 (9.52%)
occurrences all number	0	0	0	0	0	3	2
Eye disorders
Conjunctivitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	3 / 11 (27.27%)	4 / 41 (9.76%)	0 / 21 (0.00%)
occurrences all number	1	0	0	1	6	7	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	0	2	1
Nausea
subjects affected / exposed	4 / 8 (50.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	2 / 3 (66.67%)	4 / 11 (36.36%)	22 / 41 (53.66%)	11 / 21 (52.38%)
occurrences all number	5	0	2	4	8	44	29
Diarrhoea
subjects affected / exposed	4 / 8 (50.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	4 / 11 (36.36%)	16 / 41 (39.02%)	6 / 21 (28.57%)
occurrences all number	6	0	1	1	6	22	9
Vomiting
subjects affected / exposed	3 / 8 (37.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	2 / 3 (66.67%)	3 / 11 (27.27%)	17 / 41 (41.46%)	5 / 21 (23.81%)
occurrences all number	4	0	1	4	5	29	6
Stomatitis
subjects affected / exposed	3 / 8 (37.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	5 / 11 (45.45%)	18 / 41 (43.90%)	2 / 21 (9.52%)
occurrences all number	4	0	0	3	7	28	2
Constipation
subjects affected / exposed	2 / 8 (25.00%)	0 / 1 (0.00%)	3 / 8 (37.50%)	1 / 3 (33.33%)	4 / 11 (36.36%)	8 / 41 (19.51%)	7 / 21 (33.33%)
occurrences all number	2	0	5	1	4	10	10
Dyspepsia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	3 / 41 (7.32%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	0	3	2
Cheilitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	5	0	1	0
Dry mouth
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	1 / 41 (2.44%)	1 / 21 (4.76%)
occurrences all number	0	0	0	1	0	1	1
Mouth ulceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	4	0
Gastrointestinal motility disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Haemorrhoids
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Oral mucosal erythema
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Proctitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Flatulence
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Odynophagia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	6 / 8 (75.00%)	0 / 1 (0.00%)	2 / 8 (25.00%)	3 / 3 (100.00%)	11 / 11 (100.00%)	28 / 41 (68.29%)	4 / 21 (19.05%)
occurrences all number	11	0	2	6	23	40	4
Dry skin
subjects affected / exposed	2 / 8 (25.00%)	0 / 1 (0.00%)	2 / 8 (25.00%)	1 / 3 (33.33%)	1 / 11 (9.09%)	9 / 41 (21.95%)	1 / 21 (4.76%)
occurrences all number	2	0	2	1	1	9	1
Alopecia
subjects affected / exposed	2 / 8 (25.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	6 / 41 (14.63%)	1 / 21 (4.76%)
occurrences all number	2	0	0	0	0	7	2
Pruritus
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	0 / 11 (0.00%)	5 / 41 (12.20%)	1 / 21 (4.76%)
occurrences all number	1	0	1	1	0	7	2
Erythema
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 11 (9.09%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	1	3	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	1	0	1	0	0	1	0
Exfoliative rash
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Telangiectasia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypertrichosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Hair colour changes
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Skin fissures
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	5 / 11 (45.45%)	7 / 41 (17.07%)	0 / 21 (0.00%)
occurrences all number	0	0	0	2	12	15	0
Dermatitis acneiform
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	8 / 41 (19.51%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	0	8	0
Renal and urinary disorders
Nocturia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dysuria
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Oliguria
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 11 (18.18%)	6 / 41 (14.63%)	1 / 21 (4.76%)
occurrences all number	0	0	1	0	2	7	2
Pain in extremity
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 41 (4.88%)	1 / 21 (4.76%)
occurrences all number	1	0	0	0	0	2	1
Bone pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Tendon pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	0	1	0	4	0
Muscle spasms
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	6	0
Musculoskeletal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	2	1	0
Myalgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Infections and infestations
Paronychia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	6 / 11 (54.55%)	8 / 41 (19.51%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	12	15	0
Nasopharyngitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	1 / 41 (2.44%)	3 / 21 (14.29%)
occurrences all number	1	0	0	1	0	1	3
Oral fungal infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 41 (0.00%)	2 / 21 (9.52%)
occurrences all number	1	0	0	2	0	0	2
Candida infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Pharyngitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Tooth abscess
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 11 (9.09%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences all number	0	0	0	1	1	0	1
Oral candidiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences all number	0	0	0	0	1	0	1
Device related infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Furuncle
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Urethritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Metabolism and nutrition disorders
Hypomagnesaemia
subjects affected / exposed	4 / 8 (50.00%)	0 / 1 (0.00%)	3 / 8 (37.50%)	2 / 3 (66.67%)	8 / 11 (72.73%)	25 / 41 (60.98%)	4 / 21 (19.05%)
occurrences all number	4	0	4	2	8	39	4
Decreased appetite
subjects affected / exposed	3 / 8 (37.50%)	0 / 1 (0.00%)	2 / 8 (25.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	18 / 41 (43.90%)	7 / 21 (33.33%)
occurrences all number	4	0	3	1	0	25	9
Hypocalcaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	2 / 8 (25.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	4 / 41 (9.76%)	1 / 21 (4.76%)
occurrences all number	1	0	2	1	0	4	1
Hypokalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 11 (9.09%)	3 / 41 (7.32%)	0 / 21 (0.00%)
occurrences all number	0	0	3	0	1	3	0
Hypophosphataemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 41 (2.44%)	1 / 21 (4.76%)
occurrences all number	1	0	1	0	1	1	1
Hyperglycaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	1 / 21 (4.76%)
occurrences all number	1	0	1	0	0	0	1
Dehydration
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Hypoalbuminaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 41 (2.44%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Electrolyte imbalance
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Fluid imbalance
subjects affected / exposed	1 / 8 (12.50%)	0 / 1 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 41 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

27 May 2010

This amendment was done for including the following information: - To allow the two formulations of RO5083945 (RO508-3945/F02 and RO5083945/F03) to be used in this study. Formulation RO508-3945/F02 was used in earlier clinical trials. Formulation RO5083945/F03 contained RO508-3945 derived from a modified drug substance processes, i.e. different manufacturing site, different fermentation scale using the same cell line and a slightly modified purification process. - To include the preparation guidelines for both formulations. - To clarify the wording for blood collection timepoints has been updated to clarify this for participants not receiving RO5083945 (i.e. Phase II, Arm B participants). - Clarified the extension of blood pharmacodynamic (PD) parameters to permit residual sample material to be investigated to provide a more in-depth analysis of peripheral blood immunophenotype.

25 Oct 2010

This amendment was done for including the following information: - To update with new data from the BO21495 and BP22350 studies. - To clarify timepoints for participants in Arm B i.e. those not receiving RO5083945. - To correct the typographical errors. - To clarify the treatment of epidermal growth factor receptor (EGFR)-related skin toxicity. - To limit analysis up to ITT and Safety populations which were deemed sufficient to gather preliminary evidence of superior activity and safety of RO5083945.

31 Jan 2011

This amendment was done to include the following information: - To update the clinical section for the first 2 participants with squamous cell NSCLC treated in the Phase Ib part of study BP22349 both experienced Grade 3 infusion-related reaction (IRR) event and added premedication required to reduce the incidence of IRRs events. - To update additional measures required for Phase 2 start to ensure the safety of squamous NSCLC participants. - To collect additional blood sample to confirm the biology of the IRRs in terms of cytokine release (levels and types). - Clarified that the recommended dose may be differ between histology groups. - To collect the blood samples at a later cycle if if the drug administration schedule is altered due to toxicity or other reasons. - To advice additional safety measures with early high dose oral supplementation for participants who developed hypomagnesemia. - To include PK blood samples collection for Phase II participants at Cycle 4 Day 15 and Cycle 6 Day 1. - To update the guidelines for prophylactic measures for EGFR-inhibition-associated rash based on clinical experience with RO5083945.

26 Aug 2011

This amendment was done to include the following information: - To correct inconsistency for tumour response criteria. - To add 2 additional PK samples for Phase Ib and 1 additional sample for Phase II to enable a better characterization of the PK profile of RO5083945 on Cycle 4, and to enable a better comparison of exposure parameters between Cycle 4 and Cycle 1. - Clarified to avoid the collection of cytological samples for tumour biopsies. - To include the need of prophylaxis treatment for EGFR-related skin toxicity. - To include the information for interruption of infusion if participants developed IRRs. - To extend time window for allowing more flexibility to perform the Safety Follow-Up Visit. - To revise the hypomagnesaemia management guidelines. - To clarify PK/PD sampling in Phase II as some PK/PD samplings were not applicable for participants in Arm B. - To include the information regarding gemcitabine dose reduction. To implement a safety run-in stage within Phase II to closely monitor the hematological profile and to mitigate the risk of potential unexpected toxicities. - To provide clarification on storage conditions of RO5083945. - To allow more flexibility for scheduling visits during treatment.

28 Jun 2012

This amendment was done to reduce the dose of cisplatin from 75 mg/m^2 to 60 mg/m^2 as the first participant from the squamous histology group enrolled in the first cohort of RO5083945 1000 mg on Day 1 and Day 8 and then every two weeks, cisplatin 75 mg/m^2 q3w and the reduced dose of gemcitabine 1000 mg/m^2 Day 1 and Day 8 q3w died of sepsis (related to cisplatin as per investigator) in the presence of pancytopenia on Day 15 of Cycle 1.

22 Nov 2012

This amendment was done to include the initial results received from Phase II Study BP22349 in non-squamous NSCLC group. Based on these results the overall benefit risk ratio for the BP22349 Phase II in non-squamous was negative.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
21 Dec 2010	In response to Grade 3 IRR events observed in the first 2 participants with squamous NSCLC treated in the Phase Ib part of study BP22349, recruitment of participants with squamous cell histology into study BP22349 was put on hold on 21 December 2010 in order to review the data and plan subsequent actions. A 2-step approach with intensified premedication was taken for squamous cancer NSCLC participants in the Phase Ib part of study BP22349 for the first infusion of RO5083945. In addition the same 2-step safety approach was taken if Grade 3 IRRs are seen in non-squamous participants in Phase Ib.	08 Mar 2011

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 Randomized, Multicenter, Open-Label Phase Ib/II Study of RO5083945 in Combination With Cisplatin and Gemcitabine/Pemetrexed Versus Cisplatin and Gemcitabine/Pemetrexed in Patients With Advanced or Recurrent Non-Small Cell Lung Cancer Who Have not Received Prior Chemotherapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) Assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Primary: Progression-Free Survival (PFS) Assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Primary: Percentage of Participants with Disease Progression or Death Assessed as per RECIST Version 1.1

Primary: Percentage of Participants with Disease Progression or Death Assessed as per RECIST Version 1.1

Primary: Number of Participants With Positive Human Anti-human Antibodies (HAHA) Values

Primary: Number of Participants With Positive Human Anti-human Antibodies (HAHA) Values

Primary: Pharmacokinetic (PK) Parameters of RO5083945, Cisplatin, Gemcitabine, and Pemetrexed

Primary: Pharmacokinetic (PK) Parameters of RO5083945, Cisplatin, Gemcitabine, and Pemetrexed

Secondary: Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR)

Secondary: Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR)

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Percentage of Participants With Stable Disease for at Least 6 Weeks, CR or PR

Secondary: Percentage of Participants With Stable Disease for at Least 6 Weeks, CR or PR

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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