Trial Outcomes & Findings for AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive NSCLC Patients (NCT NCT00890825)

Last Updated: 2018-06-20

Results Overview

OS was calculated as the interval from the date of randomisation to the date of patient death (any cause). Patients who had not died at the time of the final analysis, or who withdrew consent, were censored at the last date the patient was known to be alive.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

88 participants

Primary outcome timeframe

At least 12 months since start of treatment.

Results posted on

2018-06-20

Participant Flow

Selection of patients was in 2nd line patients with KRAS mutation positive locally advanced or metastatic NSCLC (Stage IIIB - IV).First patient enrolled: 20 April 2009.Last patient last visit: 30 June 2010.Data Cut Off (DCO): 01 May 2011

Participant milestones

Participant milestones
Measure	AZD6244 + Docetaxel AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel Placebo + Docetaxel 75 mg/m\^2
Overall Study STARTED	44	43
Overall Study COMPLETED	30	29
Overall Study NOT COMPLETED	14	14

Reasons for withdrawal

Reasons for withdrawal
Measure	AZD6244 + Docetaxel AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel Placebo + Docetaxel 75 mg/m\^2
Overall Study Withdrawal by Subject	1	0
Overall Study Alive at data cut off (DCO)	13	14

Baseline Characteristics

AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive NSCLC Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AZD6244 + Docetaxel n=44 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=43 Participants Placebo + Docetaxel 75 mg/m\^2	Total n=87 Participants Total of all reporting groups
Age, Continuous	58.2 Years STANDARD_DEVIATION 9.22 • n=99 Participants	58.6 Years STANDARD_DEVIATION 8.38 • n=107 Participants	58.4 Years STANDARD_DEVIATION 8.77 • n=206 Participants
Age, Customized Age group : <=55 years	15 Participants n=99 Participants	15 Participants n=107 Participants	30 Participants n=206 Participants
Age, Customized Age group : >55 years	29 Participants n=99 Participants	28 Participants n=107 Participants	57 Participants n=206 Participants
Sex: Female, Male Female	23 Participants n=99 Participants	23 Participants n=107 Participants	46 Participants n=206 Participants
Sex: Female, Male Male	21 Participants n=99 Participants	20 Participants n=107 Participants	41 Participants n=206 Participants
Race/Ethnicity, Customized White	41 Participants n=99 Participants	40 Participants n=107 Participants	81 Participants n=206 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants
Race/Ethnicity, Customized Other	2 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants
Race/Ethnicity, Customized Hispanic or Latino	7 Participants n=99 Participants	10 Participants n=107 Participants	17 Participants n=206 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	37 Participants n=99 Participants	33 Participants n=107 Participants	70 Participants n=206 Participants

PRIMARY outcome

Timeframe: At least 12 months since start of treatment.

Population: MITT

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Overall Survival Died	29 Participants	27 Participants
Overall Survival Alive at DCO	13 Participants	13 Participants
Overall Survival Withdrawn	1 Participants	0 Participants

SECONDARY outcome

Timeframe: At least 12 months after start of treatment

Population: MITT

PFS was defined as the interval between the date of randomisation and the earlier date of objective disease progression per RECIST criteria or death due to any cause in the absence of progression. Patients who did not progress or die at the time of analysis were censored at the time of their latest evaluable objective tumour assessment. This also included patients who withdrew consent.

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Progression Free Survival Progression	35 Participants	36 Participants
Progression Free Survival Prog. after >2 missed or non-eval. assessments	1 Participants	2 Participants
Progression Free Survival No progression	7 Participants	2 Participants

SECONDARY outcome

Timeframe: At least 12 months after start of treatment

Population: MITT

ORR is defined as the ratio of proportions, patients with at least one visit response of CR or PR in AZD6244 + Docetaxel vs Placebo + Docetaxel.

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Objective Response Rate Response	16 Participants	0 Participants
Objective Response Rate No response	27 Participants	40 Participants

SECONDARY outcome

Timeframe: At least 12 months after start of treatment

Population: MITT

Duration of response is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Duration of Response	193.4 Days Standard Error 0.207	NA Days Standard Error NA No instance of complete or partial response was recorded for this arm.

SECONDARY outcome

Timeframe: 6 weeks after first dose of treatment

Population: MITT

Percentage change from baseline in tumour size at 6 week. Values calculated as tumour sizes at 6 weeks minus value at baseline.

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Change From Baseline in Tumour Size at 6 Week.	-16.98 Percentage change from baseline Interval -27.1 to -6.85	0.05 Percentage change from baseline Interval -9.84 to 9.93

SECONDARY outcome

Timeframe: 12 weeks

Population: MITT

Percentage change from baseline in tumour size at Week 12. Values calculated as tumour sizes at 12 weeks minus value at baseline.

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Change From Baseline in Tumour Size at Week 12	-19.38 Percent change from baseline Interval -34.7 to -4.09	6.62 Percent change from baseline Interval -8.31 to 21.54

SECONDARY outcome

Timeframe: 6 months after first dose of treatment

Population: MITT

Percentage of patients alive and progression-free at 6 months

Outcome measures

Outcome measures
Measure	AZD6244 + Docetaxel n=43 Participants AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=40 Participants Placebo + Docetaxel 75 mg/m\^2
Alive and Progression-Free at 6 Months	37.1 percentage	15.8 percentage

Adverse Events

AZD6244 + Docetaxel

Serious events: 26 serious events

Other events: 43 other events

Deaths: 0 deaths

Placebo + Docetaxel

Serious events: 13 serious events

Other events: 42 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Tracy Cunningham

AstraZeneca

Phone: 1-877-400-4656

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	AZD6244 + Docetaxel n=44 participants at risk AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=42 participants at risk Placebo + Docetaxel 75 mg/m\^2
Blood and lymphatic system disorders Febrile neutropena	13.6% 6/44 • Number of events 6 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Blood and lymphatic system disorders Neutropena	6.8% 3/44 • Number of events 3 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	7.1% 3/42 • Number of events 3 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Respiratory failure	6.8% 3/44 • Number of events 3 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	4.8% 2/42 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	4.5% 2/44 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	4.5% 2/44 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Pneumonia	9.1% 4/44 • Number of events 4 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Lower respiratory tract infection bacterial	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Cystitis	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Empyema	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Influenza	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Neutropenic infection	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Respiratory tract infection viral	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Sepsis	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Infections and infestations Urinary tract infection	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Cardiac disorders Acute coronary syndrome	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Cardiac disorders Atrial flutter	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Cardiac disorders Cardiac arrest	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Cardiac disorders Pericardial effusion	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Cardiac disorders Sinus bradycardia	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Vomiting	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Abdominal pain	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Colitis	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Dyspepsia	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Gastric ulcer haemorrhage	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Retroperitoneal haematoma	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
General disorders Face oedema	4.5% 2/44 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
General disorders Pyrexia	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Investigations Blood creatine phosphokinase increased	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Investigations Creatinine renal clearance decreased	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Investigations Electrocardiogram t wave inversion	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Investigations Neutrophil count decreased	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	4.8% 2/42 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour necrosis	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Skin and subcutaneous tissue disorders Dermatitis acneiform	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Skin and subcutaneous tissue disorders Psoriasis	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Immune system disorders Drug hypersensitivity	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Metabolism and nutrition disorders Decreased appetite	0.00% 0/44 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Nervous system disorders Syncope	2.3% 1/44 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later

Measure	AZD6244 + Docetaxel n=44 participants at risk AZD6244 75 mg bd + Docetaxel 75 mg/m\^2	Placebo + Docetaxel n=42 participants at risk Placebo + Docetaxel 75 mg/m\^2
Gastrointestinal disorders Diarrhoea	72.7% 32/44 • Number of events 32 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	16.7% 7/42 • Number of events 7 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Nausea	43.2% 19/44 • Number of events 19 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	28.6% 12/42 • Number of events 12 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Vomiting	43.2% 19/44 • Number of events 19 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	21.4% 9/42 • Number of events 9 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Stomatitis	36.4% 16/44 • Number of events 16 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	19.0% 8/42 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Constipation	31.8% 14/44 • Number of events 14 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	19.0% 8/42 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Abdominal pain upper	18.2% 8/44 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	9.5% 4/42 • Number of events 4 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Dyspepsia	18.2% 8/44 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	9.5% 4/42 • Number of events 4 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Gastrointestinal disorders Abdominal pain	18.2% 8/44 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
General disorders Fatigue	27.3% 12/44 • Number of events 12 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	33.3% 14/42 • Number of events 14 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
General disorders Asthenia	70.5% 31/44 • Number of events 31 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	66.7% 28/42 • Number of events 28 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
General disorders Oedema peripheral	40.9% 18/44 • Number of events 18 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	16.7% 7/42 • Number of events 7 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
General disorders Pyrexia	27.3% 12/44 • Number of events 12 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	11.9% 5/42 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Cough	22.7% 10/44 • Number of events 10 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	19.0% 8/42 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Dysonoea exertional	18.2% 8/44 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	23.8% 10/42 • Number of events 10 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.4% 5/44 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	23.8% 10/42 • Number of events 10 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Respiratory, thoracic and mediastinal disorders Epistaxis	15.9% 7/44 • Number of events 7 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	4.8% 2/42 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Skin and subcutaneous tissue disorders Alopecia	29.5% 13/44 • Number of events 13 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	21.4% 9/42 • Number of events 9 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Skin and subcutaneous tissue disorders Dermatitis acneiform	38.6% 17/44 • Number of events 17 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	4.8% 2/42 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Skin and subcutaneous tissue disorders Dry skin	22.7% 10/44 • Number of events 10 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	9.5% 4/42 • Number of events 4 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Blood and lymphatic system disorders Neutropenia	38.6% 17/44 • Number of events 17 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	35.7% 15/42 • Number of events 15 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Blood and lymphatic system disorders Anaemia	15.9% 7/44 • Number of events 7 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	11.9% 5/42 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Blood and lymphatic system disorders Febrile neutropenia	15.9% 7/44 • Number of events 7 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	0.00% 0/42 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Metabolism and nutrition disorders Decreased appetite	34.1% 15/44 • Number of events 15 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	26.2% 11/42 • Number of events 11 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Musculoskeletal and connective tissue disorders Myalgia	13.6% 6/44 • Number of events 6 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	16.7% 7/42 • Number of events 7 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	6.8% 3/44 • Number of events 3 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	19.0% 8/42 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Musculoskeletal and connective tissue disorders Arthralgia	4.5% 2/44 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	19.0% 8/42 • Number of events 8 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Musculoskeletal and connective tissue disorders Back pain	4.5% 2/44 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	14.3% 6/42 • Number of events 6 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Nervous system disorders Headache	13.6% 6/44 • Number of events 6 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	11.9% 5/42 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Nervous system disorders Dysgeusia	11.4% 5/44 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	4.8% 2/42 • Number of events 2 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Nervous system disorders Neuropathy peripheral	11.4% 5/44 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Metabolism and nutrition disorders Dehydration	11.4% 5/44 • Number of events 5 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later
Eye disorders Vision blurred	13.6% 6/44 • Number of events 6 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later	2.4% 1/42 • Number of events 1 • Over a minimum period of 12 months since start of treatment, or the date of the final analysis of the data, whichever is the later