Download PDF

Clinical Trial Results:
A Phase II study of the BRAF inhibitor dabrafenib as a single agent and in combination with the MEK inhibitor trametinib in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer

Summary
EudraCT number	2011-001161-41
Trial protocol	GB NO DE ES NL IT
Global end of trial date

Results information
Results version number	v2
This version publication date	18 Aug 2017
First version publication date	21 Oct 2016
Other versions	v1 , v3 , v4
Version creation reason

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

113928

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

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

Interim

Date of interim/final analysis

09 Feb 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Dec 2016

Global end of trial reached?

Main objective of the trial

To assess the overall response rate (ORR) in subjects with stage IV BRAF V600E mutant non-small cell lung cancer administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C)

Protection of trial subjects

Participants in this study received supportive care according to standard medical practice.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Jun 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 3

Country: Number of subjects enrolled

Korea, Republic of: 15

Country: Number of subjects enrolled

Taiwan: 3

Country: Number of subjects enrolled

France: 59

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Netherlands: 26

Country: Number of subjects enrolled

Norway: 2

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United States: 44

Worldwide total number of subjects

177

EEA total number of subjects

112

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

Top of page

Recruitment details

Eligible participants (par.) were enrolled in Cohort (Coh) A (monotherapy [Dabrafenib{DAB}]). Par. in Coh-A who had disease progression and adequately tolerating DAB were given option to crossover to Coh-B who received combination therapy (DAB+Trametinib). In Coh-C, par. without prior anti-cancer treatment received combination therapy.

Screening details

Par. with metastatic non-small cell lung cancer (NSCLC) were screened and allocated to Coh-A (DAB twice daily [BID] i.e. monotherapy), Coh-B (Combination Second-Line Plus) and Coh-C (Combination First-Line) according to their eligibility. The results presented are based on the Interim Analysis.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Monotherapy All Treated

Arm description

Participants with or without prior systemic anti-cancer therapy received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.

Arm type

Experimental

Investigational medicinal product name

Dabrafenib (GSK2118436)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

It will be provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Dabrafenib will be administered as a single agent in all cohorts

Combination Second-Line Plus

Arm description

Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received dabrafenib 150 mg BID and trametinib 2 mg once daily (OD). It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue.

Arm type

Experimental

Investigational medicinal product name

Dabrafenib (GSK2118436)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

It will be provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Dabrafenib will be administered as a single agent in all cohorts

Investigational medicinal product name

Trametinib (GSK1120212)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

It will be provided as 0.5 mg and 2 mg tablets. Trametinib will be administered in combination with dabrafenib in Cohorts B and C

Combination First-Line

Arm description

Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given dabrafenib 150 mg BID and trametinib 2 mg OD. It was continued until disease progression or death or unacceptable AEs or at investigator discretion to discontinue.

Arm type

Experimental

Investigational medicinal product name

Dabrafenib (GSK2118436)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

It will be provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Dabrafenib will be administered as a single agent in all cohorts

Investigational medicinal product name

Trametinib (GSK1120212)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

It will be provided as 0.5 mg and 2 mg tablets. Trametinib will be administered in combination with dabrafenib in Cohorts B and C

Number of subjects in period 1	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Started	84	57	36
Completed	0	0	0
Not completed	84	57	36
Adverse event, serious fatal	60	33	10
Consent withdrawn by subject	6	-	1
Physician decision	1	1	-
Ongoing	15	22	24
Lost to follow-up	2	1	1

Baseline characteristics

Top of page

Reporting group title

Monotherapy All Treated

Reporting group description

Reporting group title

Combination Second-Line Plus

Reporting group description

Reporting group title

Combination First-Line

Reporting group description

Reporting group values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line	Total
Number of subjects	84	57	36
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	64.8 ± 10.51	65.1 ± 10.14	67.8 ± 11	-
Gender categorical
Units: Subjects
Female	44	28	22	94
Male	40	29	14	83
Race/Ethnicity, Customized
Units: Subjects
Asian - East Asian Heritage	14	3	3	20
Asian - Central/South Asian Heritage	2	0	0	2
Asian - Japanese Heritage	2	1	0	3
African American/African Heritage	2	2	1	5
Native Hawaiian Or Other Pacific Islander	0	0	1	1
White - Arabic/North African Heritage	2	2	0	4
White - White/Caucasian/European Heritage	62	47	30	139
Other-African American/African Heritage	0	1	0	1
Other-missing	0	1	1	2

End points

Top of page

Reporting group title

Monotherapy All Treated

Reporting group description

Reporting group title

Combination Second-Line Plus

Reporting group description

Reporting group title

Combination First-Line

Reporting group description

Subject analysis set title

monotherapy second-line plus

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.

Primary: Percentage of participants with overall response rate (ORR) at the date of analysis

Top of page

End point title

Percentage of participants with overall response rate (ORR) at the date of analysis ^[1] ^[2]

End point description

ORR is defined as the percentage of par. with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per Response Evaluation Criteria In Solid Tumors evaluates the response on the basis of target and non-target lesions, and best over all response. The response rate was analyzed every 6 weeks (wks) after initiation of study treatment until Week 36 and then every 12 wks until discharge or crossover. Percentage of par. analyzed as number of par. having overall response on the date of analysis from Baseline multiply by 100. The Second Line Plus All Treated Population used for cohort A and B consisted of all par. in the All Treated Population who had received at least one line of prior anti-cancer therapy for advanced/metastatic disease. The First-Line All Treated Population used for cohort C consisted of all par. in the All Treated Population who had not received any prior anti-cancer therapy for advanced/metastatic disease.

End point type

Primary

End point timeframe

At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge

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 analysis is available
[2] - 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 endpoint is only reporting on a subset of the arms that are contained in the baseline period.

End point values	Combination Second-Line Plus	Combination First-Line	monotherapy second-line plus
Number of subjects analysed	57 ^[3]	36 ^[4]	78 ^[5]
Units: Percentage of Participants
number (confidence interval 95%)
Percentage of Participants	66.7 (52.9 to 78.6)	61.1 (43.5 to 76.9)	33.3 (23.1 to 44.9)

Notes
[3] - Second-Line All Treated Population for Coh-A and Coh-B, First-Line All Treated Population for Coh-C
[4] - Second-Line All Treated Population for Coh-A and Coh-B, First-Line All Treated Population for Coh-C
[5] - Second-Line All Treated Population for Coh-A and Coh-B, First-Line All Treated Population for Coh-C

No statistical analyses for this end point

Secondary: Duration of response (DoR) at the date of analysis

Top of page

End point title

Duration of response (DoR) at the date of analysis ^[6]

End point description

DoR is defined for the subset of participants with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause. The response was analyzed every 6 weeks after initiation of study treatment until Week 36 and then every 12 wks. Disease progression will be based on radiological assessments [magnetic resonance imaging (MRI) or computed tomography (CT)]. Confidence Intervals (CIs) estimated using the Brookmeyer Crowley method. Upper limit of confidence interval was not reached as data were not yet mature. A value of 99999 indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in that population (27 percent).

End point type

Secondary

End point timeframe

At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge

Notes
[6] - 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 endpoint is only reporting on a subset of the arms that are contained in the baseline period.

End point values	Combination Second-Line Plus	Combination First-Line	monotherapy second-line plus
Number of subjects analysed	57 ^[7]	36 ^[8]	78 ^[9]
Units: Months
median (confidence interval 95%)
Months	9.8 (6.9 to 16)	99999 (8.3 to 99999)	9.6 (5.4 to 15.2)

Notes
[7] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
[8] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
[9] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C

No statistical analyses for this end point

Secondary: Progression free survival (PFS) at the date of analysis

Top of page

End point title

Progression free survival (PFS) at the date of analysis ^[10]

End point description

PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. The target and non-target lesions were identified at time of screening and the same lesions were re-assessed by a contrast-enhanced brain magnetic resonance imaging (MRI) or Computed tomography (CT) every 6 wks after initiation of study treatment until Week 36 and then every 12 wks. CI estimated using the Brookmeyer Crowley method. A value of 99999 indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in the population (36 percent).

End point type

Secondary

End point timeframe

At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge

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 endpoint is only reporting on a subset of the arms that are contained in the baseline period.

End point values	Combination Second-Line Plus	Combination First-Line	monotherapy second-line plus
Number of subjects analysed	57 ^[11]	36 ^[12]	78 ^[13]
Units: Months
median (confidence interval 95%)
Months	10.2 (6.9 to 16.7)	99999 (7 to 99999)	5.5 (3.4 to 7.3)

Notes
[11] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
[12] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
[13] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C

No statistical analyses for this end point

Secondary: Overall survival (OS) at the date of analysis

Top of page

End point title

Overall survival (OS) at the date of analysis ^[14]

End point description

OS defined as the time from first dose until death due to any cause. CI estimated using the Brookmeyer Crowley method. A value of 99999 indicates where no data is available or not able to determine the value. The upper bound of the 95 percent CI for the median was not reached due to insufficient event rates for Arm 2 (58 percent) and Arm 3 (28 percent).

End point type

Secondary

End point timeframe

At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge

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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.

End point values	Combination Second-Line Plus	Combination First-Line	monotherapy second-line plus
Number of subjects analysed	57 ^[15]	36 ^[16]	78 ^[17]
Units: Months
median (confidence interval 95%)
Months	18.2 (14.3 to 99999)	24.6 (11.7 to 99999)	12.7 (7.3 to 16.3)

Notes
[15] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
[16] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
[17] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C

No statistical analyses for this end point

Secondary: Number of participants with abnormal vital signs values

Top of page

End point title

Number of participants with abnormal vital signs values

End point description

Number of participants with abnormal values of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and temperature were evaluated. Participants with worst case post-Baseline vital sign values were presented at the given timepoints. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). All treated population was used for monotherapy cohort which comprised of all participants in the monotherapy cohort who receive at least one dose of study treatment.

End point type

Secondary

End point timeframe

Up to Week 12 and then every 3 weeks until discharge

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	84 ^[18]	57 ^[19]	36 ^[20]
Units: Participants
Heart rate; decrease to <60; n= 83, 56, 35	9	10	8
Heart rate; increase to >100; n= 83, 56, 35	22	17	8
SBP; grade 0 to 0; n= 83,56, 35	13	1	2
SBP; grade 0 to 1; n= 83, 56, 35	11	9	7
SBP; grade 0 to 2; n= 83, 56, 35	3	4	4
SBP; grade 0 to 3; n= 83, 56, 35	2	0	2
SBP; grade 1 to 0; n= 83, 56, 35	5	0	1
SBP; grade 1 to 1; n= 83, 56, 35	13	10	1
SBP; grade 1 to 2; n= 83, 56, 35	13	13	5
SBP; grade 1 to 3; n= 83, 56, 35	4	6	5
SBP; grade 2 to 0; n= 83, 56, 35	2	0	0
SBP; grade 2 to 1; n= 83, 56, 35	1	1	0
SBP; grade 2 to 2; n= 83, 56, 35	6	4	2
SBP; grade 2 to 3; n= 83, 56, 35	6	5	3
SBP; grade 3 to 0; n= 83, 56, 35	1	0	0
SBP; grade 3 to 1; n= 83, 56, 35	0	0	0
SBP; grade 3 to 2; n= 83, 56, 35	0	1	0
SBP; grade 3 to 3; n= 83, 56, 35	3	2	3
DBP; grade 0 to 0; n= 83, 56, 35	28	4	19
DBP; grade 0 to 1; n= 83, 56, 35	15	12	9
DBP; grade 0 to 2; n= 83, 56, 35	4	6	3
DBP; grade 0 to 3; n= 83, 56, 35	3	5	1
DBP; grade 1 to 0; n= 83, 56, 35	3	0	0
DBP; grade 1 to 1; n= 83, 56, 35	11	6	1
DBP; grade 1 to 2; n= 83, 56, 35	5	12	1
DBP; grade 1 to 3; n= 83, 56, 35	3	5	1
DBP; grade 2 to 0; n= 83, 56, 35	3	0	0
DBP; grade 2 to 1; n= 83, 56, 35	1	0	0
DBP; grade 2 to 2; n= 83, 56, 35	4	2	0
DBP; grade 2 to 3; n= 83, 56, 35	1	3	0
DBP; grade 3 to 0; n= 83, 56, 35	0	0	0
DBP; grade 3 to 1; n= 83, 56, 35	0	0	0
DBP; grade 3 to 2; n= 83, 56, 35	1	1	0
DBP; grade 3 to 3; n= 83, 56, 35	1	0	0
Temperature; decrease to <=35; n= 82, 56, 35	2	4	3
Temperature; increase to >=38; n= 82, 56, 35	20	15	14

Notes
[18] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[19] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[20] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC

No statistical analyses for this end point

Secondary: Number of participants with abnormal electrocardiogram (ECG) values

Top of page

End point title

Number of participants with abnormal electrocardiogram (ECG) values

End point description

Single measurements of 12-lead ECGs were obtained at given time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) interval. ECG values at worst case post-Baseline were categorized as 'clinically significant change from Baseline' and 'not a clinically significant change'.

End point type

Secondary

End point timeframe

Week 3, Week 6, Week 15 and then every 9 weeks until discharge

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	80 ^[21]	56 ^[22]	35 ^[23]
Units: Participants
Clinically significant	3	1	1
Not clinically significant	77	55	34

Notes
[21] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[22] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[23] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC

No statistical analyses for this end point

Secondary: Number of participants with abnormal echocardiogram findings

Top of page

End point title

Number of participants with abnormal echocardiogram findings

End point description

Echocardiography scans were obtained at given time points using an echocardiogram and the findings for left ventricular ejection fraction (LVEF) were obtained. LVEF values at worst case post-Baseline were recorded as any increase and any decrease values.

End point type

Secondary

End point timeframe

Week 6, Week 15 and then every 9 weeks until discharge

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	77 ^[24]	50 ^[25]	32 ^[26]
Units: Participants
Any increase	14	5	5
Any decrease	51	39	20
No change	12	6	7

Notes
[24] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[25] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[26] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC

No statistical analyses for this end point

Secondary: Number of participants with abnormal clinical chemistry values

Top of page

End point title

Number of participants with abnormal clinical chemistry values

End point description

Blood samples were collected from participants for evaluation of clinical chemistry parameters by worst case post-Baseline increase. The clinical chemistry parameters included creatinine, phosphate and high and low calcium, glucose, magnesium, potassium and sodium. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 12 and then every 3 weeks until discharge

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	84 ^[27]	57 ^[28]	36 ^[29]
Units: Participants
Calcium high;n=80,55, 35	9	7	0
Calcium, low;n=80,55,35	10	8	7
Creatinine;n=80,55,35	8	11	6
Glucose high;n=80, 55,35	54	40	24
Glucose low;n=80, 55,35	9	9	4
Magnesium high; n=80, 55,35	1	1	4
Magnesium low; n= 80, 55,35	9	9	1
Phosphate; n= 81,55,35	19	16	15
Potassium high; n= 80,55,35	2	4	1
Potassium low; n= 80,55,35	13	7	5
Sodium high; n= 80, 55,35	4	1	0
Sodium low; n= 80, 55,35	18	36	17

Notes
[27] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[28] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[29] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC

No statistical analyses for this end point

Secondary: Number of participants with abnormal hematology values

Top of page

End point title

Number of participants with abnormal hematology values

End point description

Blood samples were collected from participants for evaluation of hematology parameters by worst case post-Baseline increase. The hematology parameters included leukocytes, neutrophils, platelets and high and low hemoglobin and lymphocytes. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 12 and then every 3 weeks until discharge

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	84 ^[30]	57 ^[31]	36 ^[32]
Units: Participants
Hemoglobin high; n= 81,56,35	1	0	0
Hemoglobin low; n= 81, 56,35	28	31	18
Leukocytes; n= 82, 56,35	17	27	16
Lymphocytes high; n= 82, 56,35	3	2	0
Lymphocytes low; n= 82, 56,35	21	18	16
Neutrophils; n= 82, 56,35	10	25	13
Platelets; n= 81,56,35	5	11	4

Notes
[30] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[31] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[32] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC

No statistical analyses for this end point

Secondary: Number of participants with AEs and serious AEs (SAEs)

Top of page

End point title

Number of participants with AEs and serious AEs (SAEs)

End point description

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function.

End point type

Secondary

End point timeframe

Up to Week 12 and then every 3 weeks up to follow up

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	84 ^[33]	57 ^[34]	36 ^[35]
Units: Participants
Any AE	83	56	36
Any SAE	37	35	21

Notes
[33] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[34] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
[35] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC

No statistical analyses for this end point

Secondary: Apparent clearance (CL/F) of Dabrafenib and trametinib

Top of page

End point title

Apparent clearance (CL/F) of Dabrafenib and trametinib

End point description

Blood samples from participants were collected for pharmacokinetic analysis including CL/F following oral dosing of dabrafenib and trametinib.

End point type

Secondary

End point timeframe

Week 3, Week 6, Week 12 and Week 18

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	0 ^[36]	0 ^[37]	0 ^[38]
Units: Liter/day
arithmetic mean (standard error)
Liter/day	±	±	±

Notes
[36] - No data was analyzed
[37] - No data was analyzed
[38] - No data was analyzed

No statistical analyses for this end point

Secondary: Volume of distribution (V/F) of Dabrafenib and trametinib

Top of page

End point title

Volume of distribution (V/F) of Dabrafenib and trametinib

End point description

Blood samples from participants were collected for pharmacokinetic analysis including V/F following oral dosing of dabrafenib and trametinib.

End point type

Secondary

End point timeframe

Week 3, Week 6, Week 12 and Week 18

End point values	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Number of subjects analysed	0 ^[39]	0 ^[40]	0 ^[41]
Units: Liter
arithmetic mean (standard error)
Liter	±	±	±

Notes
[39] - No data was analyzed
[40] - No data was analyzed
[41] - No data was analyzed

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events and serious adverse events will be collected from time the first study dose is administered until 30 days following discontinuation of study treatment.

Adverse event reporting additional description

Adverse events will be graded according to the common terminology criteria for adverse events (CTCAE), version 4. For participants in the Crossover Population, any treatment-emergent AEs related to the initiation of combination treatment will be summarized for Crossover Population only.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Monotherapy All Treated

Reporting group description

Reporting group title

Combination Second-Line Plus

Reporting group description

Reporting group title

Combination First-Line

Reporting group description

Serious adverse events	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Total subjects affected by serious adverse events
subjects affected / exposed	37 / 84 (44.05%)	35 / 57 (61.40%)	21 / 36 (58.33%)
number of deaths (all causes)	1	7	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoma benign
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	4 / 84 (4.76%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	3 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Keratoacanthoma
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lip squamous cell carcinoma
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	8 / 84 (9.52%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	8 / 8	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences causally related to treatment / all	0 / 0	1 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	5 / 84 (5.95%)	9 / 57 (15.79%)	4 / 36 (11.11%)
occurrences causally related to treatment / all	3 / 6	8 / 13	4 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Respiratory distress
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 84 (1.19%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	4 / 36 (11.11%)
occurrences causally related to treatment / all	1 / 1	1 / 1	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	3 / 36 (8.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	2 / 84 (2.38%)	4 / 57 (7.02%)	3 / 36 (8.33%)
occurrences causally related to treatment / all	2 / 2	4 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Incisional hernia
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiopulmonary failure
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 84 (0.00%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic thrombosis
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Detachment of retinal pigment epithelium
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal dystrophy
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uveitis
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterovesical fistula
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal pain
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 84 (1.19%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic duct stenosis
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Vomiting
subjects affected / exposed	1 / 84 (1.19%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal artery thrombosis
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial infection
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Furuncle
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Legionella infection
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pneumonia
subjects affected / exposed	2 / 84 (2.38%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 84 (2.38%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 84 (1.19%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 84 (1.19%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Monotherapy All Treated	Combination Second-Line Plus	Combination First-Line
Total subjects affected by non serious adverse events
subjects affected / exposed	82 / 84 (97.62%)	54 / 57 (94.74%)	36 / 36 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon
subjects affected / exposed	5 / 84 (5.95%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences all number	5	0	0
Basal cell carcinoma
subjects affected / exposed	2 / 84 (2.38%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences all number	2	2	2
Keratoacanthoma
subjects affected / exposed	6 / 84 (7.14%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences all number	6	0	0
Melanocytic naevus
subjects affected / exposed	9 / 84 (10.71%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences all number	12	3	0
Papilloma
subjects affected / exposed	6 / 84 (7.14%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences all number	6	0	0
Seborrhoeic keratosis
subjects affected / exposed	9 / 84 (10.71%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences all number	11	1	1
Skin papilloma
subjects affected / exposed	23 / 84 (27.38%)	2 / 57 (3.51%)	0 / 36 (0.00%)
occurrences all number	40	2	0
Vascular disorders
Hypertension
subjects affected / exposed	4 / 84 (4.76%)	5 / 57 (8.77%)	2 / 36 (5.56%)
occurrences all number	4	6	2
Hypotension
subjects affected / exposed	6 / 84 (7.14%)	6 / 57 (10.53%)	5 / 36 (13.89%)
occurrences all number	6	7	5
General disorders and administration site conditions
Asthenia
subjects affected / exposed	25 / 84 (29.76%)	19 / 57 (33.33%)	3 / 36 (8.33%)
occurrences all number	31	23	4
Chest pain
subjects affected / exposed	7 / 84 (8.33%)	9 / 57 (15.79%)	1 / 36 (2.78%)
occurrences all number	8	10	1
Chills
subjects affected / exposed	12 / 84 (14.29%)	13 / 57 (22.81%)	9 / 36 (25.00%)
occurrences all number	16	18	14
Fatigue
subjects affected / exposed	23 / 84 (27.38%)	9 / 57 (15.79%)	11 / 36 (30.56%)
occurrences all number	24	14	11
Hyperthermia
subjects affected / exposed	0 / 84 (0.00%)	3 / 57 (5.26%)	1 / 36 (2.78%)
occurrences all number	0	3	1
Influenza like illness
subjects affected / exposed	2 / 84 (2.38%)	4 / 57 (7.02%)	3 / 36 (8.33%)
occurrences all number	2	6	6
Malaise
subjects affected / exposed	5 / 84 (5.95%)	3 / 57 (5.26%)	3 / 36 (8.33%)
occurrences all number	5	4	4
Mucosal inflammation
subjects affected / exposed	5 / 84 (5.95%)	4 / 57 (7.02%)	2 / 36 (5.56%)
occurrences all number	6	5	2
Oedema peripheral
subjects affected / exposed	3 / 84 (3.57%)	20 / 57 (35.09%)	12 / 36 (33.33%)
occurrences all number	7	27	14
Pain
subjects affected / exposed	1 / 84 (1.19%)	1 / 57 (1.75%)	3 / 36 (8.33%)
occurrences all number	1	1	3
Pyrexia
subjects affected / exposed	30 / 84 (35.71%)	24 / 57 (42.11%)	22 / 36 (61.11%)
occurrences all number	47	83	62
Xerosis
subjects affected / exposed	7 / 84 (8.33%)	4 / 57 (7.02%)	0 / 36 (0.00%)
occurrences all number	7	4	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	26 / 84 (30.95%)	14 / 57 (24.56%)	6 / 36 (16.67%)
occurrences all number	35	14	6
Dysphonia
subjects affected / exposed	8 / 84 (9.52%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences all number	8	2	2
Dyspnoea
subjects affected / exposed	16 / 84 (19.05%)	12 / 57 (21.05%)	5 / 36 (13.89%)
occurrences all number	18	16	6
Epistaxis
subjects affected / exposed	1 / 84 (1.19%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	1	4	2
Haemoptysis
subjects affected / exposed	7 / 84 (8.33%)	3 / 57 (5.26%)	1 / 36 (2.78%)
occurrences all number	8	3	1
Nasal congestion
subjects affected / exposed	3 / 84 (3.57%)	0 / 57 (0.00%)	2 / 36 (5.56%)
occurrences all number	3	0	2
Oropharyngeal pain
subjects affected / exposed	2 / 84 (2.38%)	3 / 57 (5.26%)	1 / 36 (2.78%)
occurrences all number	2	3	1
Productive cough
subjects affected / exposed	6 / 84 (7.14%)	7 / 57 (12.28%)	0 / 36 (0.00%)
occurrences all number	6	11	0
Psychiatric disorders
Confusional state
subjects affected / exposed	2 / 84 (2.38%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	2	6	1
Depression
subjects affected / exposed	3 / 84 (3.57%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences all number	3	3	0
Insomnia
subjects affected / exposed	6 / 84 (7.14%)	4 / 57 (7.02%)	3 / 36 (8.33%)
occurrences all number	6	4	3
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 84 (3.57%)	4 / 57 (7.02%)	2 / 36 (5.56%)
occurrences all number	3	5	2
Aspartate aminotransferase increased
subjects affected / exposed	3 / 84 (3.57%)	5 / 57 (8.77%)	2 / 36 (5.56%)
occurrences all number	3	6	2
Blood alkaline phosphatase increased
subjects affected / exposed	5 / 84 (5.95%)	9 / 57 (15.79%)	1 / 36 (2.78%)
occurrences all number	5	10	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 84 (0.00%)	5 / 57 (8.77%)	1 / 36 (2.78%)
occurrences all number	0	6	1
Blood creatinine increased
subjects affected / exposed	3 / 84 (3.57%)	5 / 57 (8.77%)	1 / 36 (2.78%)
occurrences all number	4	6	2
Lipase increased
subjects affected / exposed	2 / 84 (2.38%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences all number	2	4	0
Weight decreased
subjects affected / exposed	15 / 84 (17.86%)	8 / 57 (14.04%)	4 / 36 (11.11%)
occurrences all number	16	9	4
Weight increased
subjects affected / exposed	0 / 84 (0.00%)	8 / 57 (14.04%)	1 / 36 (2.78%)
occurrences all number	0	9	1
Injury, poisoning and procedural complications
Wound
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	2 / 36 (5.56%)
occurrences all number	0	1	2
Cardiac disorders
Tachycardia
subjects affected / exposed	2 / 84 (2.38%)	1 / 57 (1.75%)	2 / 36 (5.56%)
occurrences all number	4	1	2
Nervous system disorders
Dizziness
subjects affected / exposed	7 / 84 (8.33%)	7 / 57 (12.28%)	5 / 36 (13.89%)
occurrences all number	7	8	5
Dysgeusia
subjects affected / exposed	4 / 84 (4.76%)	6 / 57 (10.53%)	1 / 36 (2.78%)
occurrences all number	4	8	1
Headache
subjects affected / exposed	16 / 84 (19.05%)	8 / 57 (14.04%)	7 / 36 (19.44%)
occurrences all number	18	14	10
Sciatica
subjects affected / exposed	0 / 84 (0.00%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences all number	0	3	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 84 (11.90%)	8 / 57 (14.04%)	4 / 36 (11.11%)
occurrences all number	11	11	6
Leukopenia
subjects affected / exposed	4 / 84 (4.76%)	5 / 57 (8.77%)	1 / 36 (2.78%)
occurrences all number	4	7	1
Lymphopenia
subjects affected / exposed	6 / 84 (7.14%)	2 / 57 (3.51%)	1 / 36 (2.78%)
occurrences all number	7	2	3
Neutropenia
subjects affected / exposed	2 / 84 (2.38%)	11 / 57 (19.30%)	1 / 36 (2.78%)
occurrences all number	2	23	3
Thrombocytopenia
subjects affected / exposed	5 / 84 (5.95%)	5 / 57 (8.77%)	0 / 36 (0.00%)
occurrences all number	5	6	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 84 (0.00%)	5 / 57 (8.77%)	1 / 36 (2.78%)
occurrences all number	0	9	1
Eye disorders
Dry eye
subjects affected / exposed	4 / 84 (4.76%)	6 / 57 (10.53%)	1 / 36 (2.78%)
occurrences all number	5	7	1
Eye pain
subjects affected / exposed	1 / 84 (1.19%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences all number	1	2	2
Periorbital oedema
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	2
Photopsia
subjects affected / exposed	0 / 84 (0.00%)	1 / 57 (1.75%)	2 / 36 (5.56%)
occurrences all number	0	1	2
Vision blurred
subjects affected / exposed	5 / 84 (5.95%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences all number	5	3	0
Visual acuity reduced
subjects affected / exposed	3 / 84 (3.57%)	6 / 57 (10.53%)	1 / 36 (2.78%)
occurrences all number	3	7	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	8 / 84 (9.52%)	4 / 57 (7.02%)	3 / 36 (8.33%)
occurrences all number	10	4	3
Abdominal pain upper
subjects affected / exposed	3 / 84 (3.57%)	8 / 57 (14.04%)	0 / 36 (0.00%)
occurrences all number	3	12	0
Constipation
subjects affected / exposed	9 / 84 (10.71%)	10 / 57 (17.54%)	5 / 36 (13.89%)
occurrences all number	9	13	5
Diarrhoea
subjects affected / exposed	17 / 84 (20.24%)	17 / 57 (29.82%)	13 / 36 (36.11%)
occurrences all number	27	32	19
Dry mouth
subjects affected / exposed	1 / 84 (1.19%)	3 / 57 (5.26%)	3 / 36 (8.33%)
occurrences all number	1	4	3
Dyspepsia
subjects affected / exposed	2 / 84 (2.38%)	5 / 57 (8.77%)	2 / 36 (5.56%)
occurrences all number	2	5	2
Dysphagia
subjects affected / exposed	2 / 84 (2.38%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences all number	2	3	0
Nausea
subjects affected / exposed	24 / 84 (28.57%)	22 / 57 (38.60%)	19 / 36 (52.78%)
occurrences all number	32	38	29
Vomiting
subjects affected / exposed	18 / 84 (21.43%)	22 / 57 (38.60%)	9 / 36 (25.00%)
occurrences all number	27	59	18
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	10 / 84 (11.90%)	1 / 57 (1.75%)	3 / 36 (8.33%)
occurrences all number	17	1	3
Alopecia
subjects affected / exposed	18 / 84 (21.43%)	6 / 57 (10.53%)	2 / 36 (5.56%)
occurrences all number	18	6	2
Dermal cyst
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	2
Dry skin
subjects affected / exposed	20 / 84 (23.81%)	19 / 57 (33.33%)	11 / 36 (30.56%)
occurrences all number	22	22	11
Eczema
subjects affected / exposed	3 / 84 (3.57%)	3 / 57 (5.26%)	1 / 36 (2.78%)
occurrences all number	3	5	1
Erythema
subjects affected / exposed	1 / 84 (1.19%)	5 / 57 (8.77%)	4 / 36 (11.11%)
occurrences all number	1	6	5
Hair texture abnormal
subjects affected / exposed	7 / 84 (8.33%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences all number	7	3	0
Hyperhidrosis
subjects affected / exposed	3 / 84 (3.57%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	3	4	1
Hyperkeratosis
subjects affected / exposed	25 / 84 (29.76%)	6 / 57 (10.53%)	0 / 36 (0.00%)
occurrences all number	54	6	0
Madarosis
subjects affected / exposed	5 / 84 (5.95%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences all number	5	1	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	19 / 84 (22.62%)	2 / 57 (3.51%)	1 / 36 (2.78%)
occurrences all number	22	3	1
Papule
subjects affected / exposed	8 / 84 (9.52%)	1 / 57 (1.75%)	1 / 36 (2.78%)
occurrences all number	8	1	1
Pruritus
subjects affected / exposed	12 / 84 (14.29%)	9 / 57 (15.79%)	4 / 36 (11.11%)
occurrences all number	12	11	5
Pruritus generalised
subjects affected / exposed	1 / 84 (1.19%)	3 / 57 (5.26%)	1 / 36 (2.78%)
occurrences all number	1	5	1
Rash
subjects affected / exposed	15 / 84 (17.86%)	13 / 57 (22.81%)	7 / 36 (19.44%)
occurrences all number	15	19	7
Rash generalised
subjects affected / exposed	2 / 84 (2.38%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	2	4	1
Rash macular
subjects affected / exposed	0 / 84 (0.00%)	0 / 57 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	3
Rash maculo-papular
subjects affected / exposed	5 / 84 (5.95%)	0 / 57 (0.00%)	0 / 36 (0.00%)
occurrences all number	5	0	0
Rash papular
subjects affected / exposed	6 / 84 (7.14%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences all number	6	2	3
Skin lesion
subjects affected / exposed	5 / 84 (5.95%)	2 / 57 (3.51%)	2 / 36 (5.56%)
occurrences all number	8	2	3
Urticaria
subjects affected / exposed	2 / 84 (2.38%)	3 / 57 (5.26%)	1 / 36 (2.78%)
occurrences all number	5	3	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	17 / 84 (20.24%)	12 / 57 (21.05%)	3 / 36 (8.33%)
occurrences all number	26	15	3
Back pain
subjects affected / exposed	10 / 84 (11.90%)	4 / 57 (7.02%)	5 / 36 (13.89%)
occurrences all number	11	6	5
Muscle spasms
subjects affected / exposed	2 / 84 (2.38%)	6 / 57 (10.53%)	3 / 36 (8.33%)
occurrences all number	2	8	3
Muscular weakness
subjects affected / exposed	6 / 84 (7.14%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences all number	7	1	0
Musculoskeletal chest pain
subjects affected / exposed	4 / 84 (4.76%)	3 / 57 (5.26%)	3 / 36 (8.33%)
occurrences all number	5	3	3
Musculoskeletal pain
subjects affected / exposed	5 / 84 (5.95%)	4 / 57 (7.02%)	3 / 36 (8.33%)
occurrences all number	7	5	3
Myalgia
subjects affected / exposed	12 / 84 (14.29%)	7 / 57 (12.28%)	4 / 36 (11.11%)
occurrences all number	15	10	5
Pain in extremity
subjects affected / exposed	15 / 84 (17.86%)	2 / 57 (3.51%)	3 / 36 (8.33%)
occurrences all number	17	2	3
Infections and infestations
Bronchitis
subjects affected / exposed	6 / 84 (7.14%)	6 / 57 (10.53%)	0 / 36 (0.00%)
occurrences all number	9	10	0
Conjunctivitis
subjects affected / exposed	2 / 84 (2.38%)	3 / 57 (5.26%)	0 / 36 (0.00%)
occurrences all number	2	4	0
Folliculitis
subjects affected / exposed	3 / 84 (3.57%)	4 / 57 (7.02%)	0 / 36 (0.00%)
occurrences all number	3	4	0
Gastroenteritis
subjects affected / exposed	2 / 84 (2.38%)	0 / 57 (0.00%)	2 / 36 (5.56%)
occurrences all number	3	0	2
Nasopharyngitis
subjects affected / exposed	9 / 84 (10.71%)	7 / 57 (12.28%)	2 / 36 (5.56%)
occurrences all number	10	9	2
Pneumonia
subjects affected / exposed	0 / 84 (0.00%)	2 / 57 (3.51%)	3 / 36 (8.33%)
occurrences all number	0	2	3
Rhinitis
subjects affected / exposed	5 / 84 (5.95%)	5 / 57 (8.77%)	0 / 36 (0.00%)
occurrences all number	6	8	0
Upper respiratory tract infection
subjects affected / exposed	7 / 84 (8.33%)	1 / 57 (1.75%)	0 / 36 (0.00%)
occurrences all number	7	1	0
Urinary tract infection
subjects affected / exposed	5 / 84 (5.95%)	4 / 57 (7.02%)	4 / 36 (11.11%)
occurrences all number	6	5	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	24 / 84 (28.57%)	15 / 57 (26.32%)	9 / 36 (25.00%)
occurrences all number	31	20	10
Dehydration
subjects affected / exposed	4 / 84 (4.76%)	3 / 57 (5.26%)	2 / 36 (5.56%)
occurrences all number	4	3	2
Hyperglycaemia
subjects affected / exposed	7 / 84 (8.33%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	8	5	1
Hypoalbuminaemia
subjects affected / exposed	3 / 84 (3.57%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	5	4	1
Hypokalaemia
subjects affected / exposed	5 / 84 (5.95%)	4 / 57 (7.02%)	3 / 36 (8.33%)
occurrences all number	7	4	3
Hypomagnesaemia
subjects affected / exposed	3 / 84 (3.57%)	1 / 57 (1.75%)	2 / 36 (5.56%)
occurrences all number	4	1	5
Hyponatraemia
subjects affected / exposed	3 / 84 (3.57%)	9 / 57 (15.79%)	4 / 36 (11.11%)
occurrences all number	4	11	6
Hypophosphataemia
subjects affected / exposed	6 / 84 (7.14%)	4 / 57 (7.02%)	1 / 36 (2.78%)
occurrences all number	12	4	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

31 May 2011

Updated the inclusion / exclusion criteria, updated the QTc withdrawal criteria and the Dose Modification section, added an Independent Data Monitoring Committee. In addition, language specific to French sites was added. Throughout the protocol, minor administrative and typographical changes were made.

13 Oct 2011

Increased the frequency of cardiac monitoring from every 12 weeks to every 9 weeks. Other clarifications to the PGx sections in the main text and in Appendix 1, description of physical exam and list of laboratory tests were made. Guidelines for management of renal insufficiency were added. A Baseline sample for cytokine profiling was added (in the event a subject develops fever, the baseline cytokine values are available).

30 Apr 2012

Is a country specific amendment that changed the QTc stopping criteria to 500 msec for UK subjects and clarified the definition of abstinence.

15 Jun 2012

Changed Inclusion to clarify that the failed chemotherapy regimen must have been a platinum-based chemotherapy; changed Exclusion Criteria #9 regarding the length of time a subject must be disease free from 5 years to 3 years; allowed for continued treatment with GSK2118436 beyond disease progression; updated the Dose Modification Guidelines for Fever and the Renal Insufficiency Guidelines for consistency with the current asset-specific language; added the UK to Appendix 3 (country-specific QTc stopping criteria of 500 msec); clarified restrictions on certain foods known to affect drug metabolism; clarified when an MRI or CT is required at baseline and on-study; removed the requirement for males who choose abstinence as their contraceptive method to begin abstinence 14 days BEFORE administration of GSK2118436; clarified the definition of abstinence; fixed T&E footnotes, lessened the frequency of efficacy assessments beginning at Week 36 and onwards, and removed the ANC measurement on Day 8; clarified SAE language for consistency with current asset language.

20 Aug 2012

Updated the Background section (Section 1.1) to include the currently available safety and efficacy data for GSK2118436; changed Inclusion Criterion (#7) to clarify for the reader that additional details on mutation testing and central confirmation of mutation testing are provided in Section 7.1.1; changes to Section 7.1.1 included clarification onBRAF mutation testing and intent that all subject have tissue available for central confirmation (when testing at inclusion is performed at a local laboratory) (also affected T&E footnote); removed the requirement for men to use contraception (Inclusion Criterion #9 and Section 7.4.2); changed the limit for use of anti-cancer treatment prior to dosing with GSK2118436 from 28 days to 14 days (Exclusion Criteria #2 and #3); added defined safety and efficacy criteria that need to be met in order to allow treatment with GSK2118436 beyond disease progression (Section 4.2.1); updated Section 5.7, Guidelines for Dose Modification and Events of Special Interest, in line with current asset language; clarified QTc Stopping Criteria to delineate QTcF v QTcB and QTc uncorrected stopping values; and clarified protocol-specific SAE language for consistency with current asset language (removed LVEF stopping criteria as a protocol specific SAE).

24 Jan 2013

Is a country specific amendment for France and the UK that specifies QTc stopping criteria in Appendix 3. Footnotes to the Time and Events Table were also renumbered.

16 Apr 2013

Added the study expansion cohort (n=20) increasing total sample size to 60 subjects, updated the eligibility criteria to remove the requirement of disease progression on a platinum-based chemotherapy prior to study enrollment to allow inclusion of first line metastatic patients in the expansion cohort and allow subjects with HCV clearance, updated QTc stopping criteria, removed herbal remedies as a prohibitive medication (St Johns Wort still prohibited), updated the prohibitive and cautionary medication list, increased the frequency of dermatologic assessments to every 9 weeks, changed blood sample for cfDNA at disease progression from optional to required, replaced “GSK2118436” with “dabrafenib” throughout the document and additional administrative level clarifications and edits. Section 1.2.1 deleted, please refer to the Dabrafenib Investigator’s Brochure for all background/clinical trial information on dabrafenib.

25 Sep 2013

Added the dabrafenib/trametinib combination therapy cohort (n=40) increasing the total sample size to 100 subjects, ophthalmic examination added at screening, Week 6 and as clinically necessary thereafter for combination treatment only, combination cohort specific inclusion/exclusion criteria added, combination cohort specific dose modification and toxicity management guidelines added, option to crossover from monotherapy to combination treatment at time of radiologic disease progression added, ECHO and ECG schedule clarified as baseline, Week 6 and every 9 weeks thereafter

14 Oct 2014

Updated secondary medical monitor. Added Cohort C to enroll 25 first line subjects. Additional language added to study rationale in Section 1.2.1. Revised required laboratory value for PT/INR and PTT in Section 4.1.2. Removed HIV from ExclusionCriterion #7 and revised Exclusion Criterion #15 in Section 4.1.3. Additional language added to Section 4.2.1 and Section 4.2.3 to clarify requirements for continuing study treatment post-PD and for crossover requirements. Updated dose modification and toxicity management language throughout Section 5.9. Updated general dose modification guidelines in Section 5.9.2. Updated dose modification guidelines and stopping criteria for LVEF in Section 5.10.1. Updated liver chemistry stopping and follow-up criteria in Section 5.10.3. Guidelines for holding study drug following radiation treatment added to Section 6.1. Specified that body fluid sample (e.g., pleural effusion) is not acceptable for BRAF mutation testing sample in Section 7.1.1. Added confirmation of measurable disease by independent review at baseline prior to enrolment in Section 7.1.2. Updated language regarding ophthalmic examination requirements in Section 7.3.2.3. Added language in Section 7.3.2.9.2 allowing investigator to decide if basal cell carcinoma should be reported as SAE or not. Specified in Section 7.4.1 that females should wait at least 4 months after last dose of the combination therapy before nursing. Specified in Section 7.7 that body fluid sample (e.g., pleural effusion) is not preferred for PD biomarker sample. Added Section 9.1.3 to describe hypothesis and study design for Cohort C. Updated Section 9.2 regarding Cohort C. Updated Investigator Brochures citations to current versions. Appendix 4 added regarding additional monitoring requirements for subjects in France only.

Were there any global interruptions to the trial? No

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

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase II study of the BRAF inhibitor dabrafenib as a single agent and in combination with the MEK inhibitor trametinib in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of participants with overall response rate (ORR) at the date of analysis

Primary: Percentage of participants with overall response rate (ORR) at the date of analysis

Secondary: Duration of response (DoR) at the date of analysis

Secondary: Duration of response (DoR) at the date of analysis

Secondary: Progression free survival (PFS) at the date of analysis

Secondary: Progression free survival (PFS) at the date of analysis

Secondary: Overall survival (OS) at the date of analysis

Secondary: Overall survival (OS) at the date of analysis

Secondary: Number of participants with abnormal vital signs values

Secondary: Number of participants with abnormal vital signs values

Secondary: Number of participants with abnormal electrocardiogram (ECG) values

Secondary: Number of participants with abnormal electrocardiogram (ECG) values

Secondary: Number of participants with abnormal echocardiogram findings

Secondary: Number of participants with abnormal echocardiogram findings

Secondary: Number of participants with abnormal clinical chemistry values

Secondary: Number of participants with abnormal clinical chemistry values

Secondary: Number of participants with abnormal hematology values

Secondary: Number of participants with abnormal hematology values

Secondary: Number of participants with AEs and serious AEs (SAEs)

Secondary: Number of participants with AEs and serious AEs (SAEs)

Secondary: Apparent clearance (CL/F) of Dabrafenib and trametinib

Secondary: Apparent clearance (CL/F) of Dabrafenib and trametinib

Secondary: Volume of distribution (V/F) of Dabrafenib and trametinib

Secondary: Volume of distribution (V/F) of Dabrafenib and trametinib

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase II study of the BRAF inhibitor dabrafenib as a single agent and in combination with the MEK inhibitor trametinib in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer