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Phase 1b/2 Study of BKM120 Plus Trastuzumab in Patients With HER2-positive Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01132664
Recruitment Status : Terminated (Due to the rare patient population and challenges to enroll patients.)
First Posted : May 28, 2010
Results First Posted : October 30, 2015
Last Update Posted : August 17, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Metastatic Breast Cancer
HER2+ Breast Cancer
Interventions Drug: BKM120
Drug: Trastuzumab
Drug: Capecitabine
Enrollment 72
Recruitment Details 72 patients (pts) were enrolled: 18 in ph lb, 53 in ph ll, including 8 from ph lb, with 45 new pts in ph ll & 9 in the brain metastasis (BM) cohort. Of the 72 pts, 1 in ph lb & 3 in phase ll, did not receive Burparlisib, only Trastuzumab. Therefore, 68 patients (17 in ph l, 42 in ph ll, 9 in BM cohort) were treated with buparlisib + trastuzumab.
Pre-assignment Details

Primary outcome measure for BM cohort was MTD/RP2D which was not reached/established due to premature termination of the study.

Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR) & Progression Free Survival (PFS)were not calculated for the BM cohort either.

Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg
Hide Arm/Group Description Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug Patients in the phase II expansion + patients from phase Ib dose escalation were included in phase II and received 100 mg of investigational drug - buparsilib Patients in the BM cohort who received 80 mg of buparlisib - investigational drug Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
Period Title: Phase lb
Started 5 12 0 0 0
Completed 0 0 0 0 0
Not Completed 5 12 0 0 0
Reason Not Completed
Adverse Event             0             1             0             0             0
Withdrawal by Subject             1             2             0             0             0
Disease Progression             4             9             0             0             0
Period Title: Phase ll
Started 0 0 50 [1] 0 0
Completed 0 0 0 0 0
Not Completed 0 0 50 0 0
Reason Not Completed
Death             0             0             2             0             0
Adverse Event             0             0             10             0             0
Withdrawal by Subject             0             0             3             0             0
Disease progression             0             0             35             0             0
[1]
Of the 50 patients, 8 were from phase lb & were eligible for inclusion in Phase II
Period Title: BM Cohort
Started 0 0 0 3 6
Completed 0 0 0 0 0
Not Completed 0 0 0 3 6
Reason Not Completed
Disease progression             0             0             0             3             4
Adverse Event             0             0             0             0             1
Withdrawal by Subject             0             0             0             0             1
Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg Total
Hide Arm/Group Description Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug Patients in the phase II only expansion cohort who received 100 mg of buparlisib - investigational drug Patients in the BM cohort who received 80 mg of buparlisib - investigational drug Patients in the BM cohort who received 100 mg of buparlisib - investigational drug Total of all reporting groups
Overall Number of Baseline Participants 5 12 42 3 6 68
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 5 participants 12 participants 42 participants 3 participants 6 participants 68 participants
<65 years 5 11 35 3 6 60
>=65 years 0 1 7 0 0 8
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 12 participants 42 participants 3 participants 6 participants 68 participants
Female
5
 100.0%
12
 100.0%
42
 100.0%
3
 100.0%
6
 100.0%
68
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Female: Child bearing potential  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 5 participants 12 participants 42 participants 3 participants 6 participants 68 participants
Able to bear children 2 3 8 1 1 15
Premenarche 0 0 0 0 0 0
Post-menopausal 3 8 31 2 4 48
Sterile - of child bearing age 0 1 3 0 1 5
1.Primary Outcome
Title Dose Limiting Toxicity (DLT) - Phase l Only
Hide Description Determination of the maximum tolerated dose (MTD) in the dose escalation part of the study was based upon the estimation of the probability of DLT in Cycle 1 in patients of the dose-determining set.
Time Frame cycle 1 - 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
The Dose–determining set (DDS) for the determination of the MTD consisted of all patients from the safety set in the dose escalation phase who had met the minimum safety evaluation requirements and the minimum exposure criterion or had experienced DLT during Cycle 1 and were discontinued. MTD analysis was done only on the phase lb group.
Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg
Hide Arm/Group Description:
Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug
Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug
Patients in the phase II expansion + patients from phase Ib escalation included in phase II
Patients in the BM cohort who received 80 mg of buparlisib - investigational drug
Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
Overall Number of Participants Analyzed 4 11 0 3 5
Measure Type: Number
Unit of Measure: Participants
Primary system orgran class (SOC) PT - grade 1 0 0 0 0
Primary SOC PT - grade 2 0 0 0 0
Primary SOC PT (asthenia) - grade 3 0 1 0 0
Primary SOC PT - grade 4 0 0 0 0
Primary SOC PT - missing 0 0 0 0
Primary SOC PT (somatits/diarrhea) - grade 3 0 0 0 1
2.Primary Outcome
Title Overall Response Rate (ORR) - Phase ll
Hide Description

Objective response rate (ORR) was defined as the rate of patients with best overall response (BOR) equal to complete response (CR) or partial response (PR) according to RECIST 1.0 from the Investigators review.

Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed of the disease status by imaging (i.e. CT/MRI): Complete Response (CR) = Disappearance of all tumor lesions; Partial Response (PR)= >=30% shrinkage of lesions; Overall Response (OR) = patients with CR and PR.

Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib)
Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg
Hide Arm/Group Description:
Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug
Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug
Patients in the phase II expansion + patients from phase Ib escalation included in phase II
Patients in the BM cohort who received 80 mg of buparlisib - investigational drug
Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
Overall Number of Participants Analyzed 0 0 50 0 0
Measure Type: Number
Unit of Measure: Participants
5
3.Secondary Outcome
Title Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll
Hide Description

Disease control rate (DCR) = patients with complete response (CR), partial response (PR) or stable disease (SD) as per RECIST criteria.

Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = disappearance of all tumor lesions; PR = >=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD); PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.

Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description

The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).

CBR analysis was not done for the BM cohort population. DCR analysis was not done for the BM cohort population.

Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg
Hide Arm/Group Description:
Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug
Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug
Patients in the phase II expansion + patients from phase Ib escalation included in phase II
Patients in the BM cohort who received 80 mg of buparlisib - investigational drug
Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
Overall Number of Participants Analyzed 5 12 50 0 0
Measure Type: Number
Unit of Measure: Participants
Phase l 1 7 0
Phase ll 0 0 25
4.Secondary Outcome
Title Clinical Benefit Rate (CBR) - Phase l & ll
Hide Description

CBR = patients with CR, PR or SD ≥ 24 weeks according to RECIST by the investigator.

Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = Disappearance of all tumor lesions; PR= >=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.

Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description

The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).

CBR analysis was not done for the BM cohort population.

Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg
Hide Arm/Group Description:
Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug
Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug
Patients in the phase II expansion + patients from phase Ib escalation included in phase II
Patients in the BM cohort who received 80 mg of buparlisib - investigational drug
Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
Overall Number of Participants Analyzed 5 12 50 0 0
Measure Type: Number
Unit of Measure: Participants
Phase l 0 3 0
Phase ll 0 0 7
5.Secondary Outcome
Title Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll
Hide Description [Not Specified]
Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
FAS consisted of all patients who received at least 1 dose of study drug (buparlisib). PFS analysis was not done for the BM cohort population. MTD/RP2D was not established due to premature termination of the study. In the phase ll portion of the study, PFS was analyzed only in patients with known PIK3 status, thus only 26/50 patients were analyzed.
Arm/Group Title Phase Ib - 50 mg Phase Ib - 100mg Phase II - 100mg BM Cohort - 80mg BM Cohort - 100mg
Hide Arm/Group Description:
Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug
Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug
Patients in the phase II expansion + patients from phase Ib escalation included in phase II
Patients in the BM cohort who received 80 mg of buparlisib - investigational drug
Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
Overall Number of Participants Analyzed 5 12 26 0 0
Median (90% Confidence Interval)
Unit of Measure: Months
Phase l
1.7
(1.3 to 3.6)
3.3
(1.6 to 5.4)
NA [1] 
(NA to NA)
Phase ll: PIK3CA wildtype (n =18)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
1.7
(1.5 to 5.4)
Phase ll: PIK3CA mutated (n =8)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
1.8
(1.3 to 3.4)
[1]
NA = data reported here for phase l only and not for phase ll
[2]
NA = data reported here for phase ll only and not for phase l
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Phase Ib Dose Escalation 50 mg/Day Phase Ib Dose Escalation 100 mg/Day Phase II Dose Expansion 100 mg/Day BM Cohort 80 mg/Day BM Cohort 100 mg/Day
Hide Arm/Group Description Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug. Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug Patients in the phase II expansion + patients from phase Ib dose escalation who received 100 mg/day of buparlisib - investigational drug Patients in the BM cohort who received 80 mg of buparlisib - investigational drug Patients in the BM cohort who received 100 mg of buparlisib - investigational drug
All-Cause Mortality
Phase Ib Dose Escalation 50 mg/Day Phase Ib Dose Escalation 100 mg/Day Phase II Dose Expansion 100 mg/Day BM Cohort 80 mg/Day BM Cohort 100 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Phase Ib Dose Escalation 50 mg/Day Phase Ib Dose Escalation 100 mg/Day Phase II Dose Expansion 100 mg/Day BM Cohort 80 mg/Day BM Cohort 100 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/5 (40.00%)   2/12 (16.67%)   17/50 (34.00%)   2/3 (66.67%)   4/6 (66.67%) 
Blood and lymphatic system disorders           
Anaemia  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Lymphadenopathy  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Gastrointestinal disorders           
Abdominal Pain Upper  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Constipation  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Diarrhoea  1  0/5 (0.00%)  1/12 (8.33%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Nausea  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Vomiting  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
General disorders           
Asthenia  1  0/5 (0.00%)  2/12 (16.67%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
General Physical Health Deterioration  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Oedema Peripheral  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Pain  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Systemic Inflammatory Response Syndrome  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Hepatobiliary disorders           
Cholelithiasis  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hepatic Failure  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Immune system disorders           
Hypersensitivity  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Infections and infestations           
Device Related Infection  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Infection  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Lobar Pneumonia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Lower Respiratory Tract Infection  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Lung Infection  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Sepsis  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Investigations           
Alanine Aminotransferase Increased  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Aspartate Aminotransferase Increased  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Bilirubin Conjugated Increased  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Bilirubin Increased  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Metabolism and nutrition disorders           
Diabetic Ketoacidosis  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hypercreatininaemia  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hypokalaemia  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Musculoskeletal and connective tissue disorders           
Bone Pain  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Muscular Weakness  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Musculoskeletal Stiffness  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Nervous system disorders           
Cerebral Haemorrhage  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Cerebrovascular Accident  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Convulsion  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Epilepsy  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Status Epilepticus  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Psychiatric disorders           
Affective Disorder  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Confusional State  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Delirium  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Depressed Mood  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Depression  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Mood Altered  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Dyspnoea  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Pleural Effusion  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Pneumonitis  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Respiratory Failure  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Skin and subcutaneous tissue disorders           
Photosensitivity Reaction  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Rash Maculo-Papular  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Vascular disorders           
Hypotension  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase Ib Dose Escalation 50 mg/Day Phase Ib Dose Escalation 100 mg/Day Phase II Dose Expansion 100 mg/Day BM Cohort 80 mg/Day BM Cohort 100 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/5 (100.00%)   12/12 (100.00%)   50/50 (100.00%)   3/3 (100.00%)   6/6 (100.00%) 
Blood and lymphatic system disorders           
Anaemia  1  0/5 (0.00%)  1/12 (8.33%)  5/50 (10.00%)  0/3 (0.00%)  0/6 (0.00%) 
Neutropenia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  2/3 (66.67%)  0/6 (0.00%) 
Cardiac disorders           
Palpitations  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Ear and labyrinth disorders           
Tinnitus  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  1/3 (33.33%)  0/6 (0.00%) 
Eye disorders           
Dry Eye  1  0/5 (0.00%)  2/12 (16.67%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Extraocular Muscle Paresis  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Eye Irritation  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Eye Pain  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Ocular Hyperaemia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Photophobia  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Vision Blurred  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  2/3 (66.67%)  1/6 (16.67%) 
Visual Impairment  1  1/5 (20.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  1/6 (16.67%) 
Gastrointestinal disorders           
Abdominal Distension  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Abdominal Pain  1  0/5 (0.00%)  3/12 (25.00%)  7/50 (14.00%)  0/3 (0.00%)  1/6 (16.67%) 
Abdominal Pain Lower  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Abdominal Pain Upper  1  1/5 (20.00%)  2/12 (16.67%)  5/50 (10.00%)  1/3 (33.33%)  1/6 (16.67%) 
Anal Fissure  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Aphthous Stomatitis  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Cheilitis  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Constipation  1  1/5 (20.00%)  1/12 (8.33%)  6/50 (12.00%)  1/3 (33.33%)  2/6 (33.33%) 
Diarrhoea  1  1/5 (20.00%)  5/12 (41.67%)  25/50 (50.00%)  3/3 (100.00%)  5/6 (83.33%) 
Dry Mouth  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  1/3 (33.33%)  0/6 (0.00%) 
Dyspepsia  1  0/5 (0.00%)  1/12 (8.33%)  6/50 (12.00%)  3/3 (100.00%)  0/6 (0.00%) 
Dysphagia  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  1/3 (33.33%)  0/6 (0.00%) 
Flatulence  1  0/5 (0.00%)  1/12 (8.33%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Gastrooesophageal Reflux Disease  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Haematochezia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  1/6 (16.67%) 
Haemorrhoids  1  0/5 (0.00%)  1/12 (8.33%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Haemorrhoids Thrombosed  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Lip Ulceration  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Mouth Ulceration  1  0/5 (0.00%)  1/12 (8.33%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Nausea  1  2/5 (40.00%)  2/12 (16.67%)  24/50 (48.00%)  2/3 (66.67%)  4/6 (66.67%) 
Pigmentation Lip  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Stomatitis  1  0/5 (0.00%)  4/12 (33.33%)  12/50 (24.00%)  1/3 (33.33%)  2/6 (33.33%) 
Tongue Discolouration  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Tooth Disorder  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Toothache  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Vomiting  1  2/5 (40.00%)  2/12 (16.67%)  13/50 (26.00%)  1/3 (33.33%)  4/6 (66.67%) 
General disorders           
Asthenia  1  1/5 (20.00%)  6/12 (50.00%)  13/50 (26.00%)  0/3 (0.00%)  1/6 (16.67%) 
Chest Pain  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Face Oedema  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Fatigue  1  0/5 (0.00%)  0/12 (0.00%)  16/50 (32.00%)  3/3 (100.00%)  4/6 (66.67%) 
Gait Disturbance  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Injection Site Reaction  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Mucosal Dryness  1  0/5 (0.00%)  2/12 (16.67%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Mucosal Inflammation  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Non-Cardiac Chest Pain  1  0/5 (0.00%)  0/12 (0.00%)  7/50 (14.00%)  1/3 (33.33%)  0/6 (0.00%) 
Oedema Peripheral  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Pain  1  0/5 (0.00%)  1/12 (8.33%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Pyrexia  1  1/5 (20.00%)  0/12 (0.00%)  5/50 (10.00%)  1/3 (33.33%)  1/6 (16.67%) 
Hepatobiliary disorders           
Hyperbilirubinaemia  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Immune system disorders           
Hypersensitivity  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Infections and infestations           
Cellulitis  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Conjunctivitis  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Cystitis  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  1/6 (16.67%) 
Device Related Sepsis  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Ear Infection  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Eczema Infected  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Furuncle  1  0/5 (0.00%)  1/12 (8.33%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Herpes Zoster  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Influenza  1  1/5 (20.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Nasopharyngitis  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Oral Herpes  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Paronychia  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Pharyngitis  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Sinusitis  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Urinary Tract Infection  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  1/3 (33.33%)  0/6 (0.00%) 
Injury, poisoning and procedural complications           
Contusion  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Fall  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Rib Fracture  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Spinal Fracture  1  1/5 (20.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Tooth Fracture  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Vaginal Laceration  1  0/5 (0.00%)  1/12 (8.33%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Wound Complication  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Investigations           
Alanine Aminotransferase Decreased  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Alanine Aminotransferase Increased  1  1/5 (20.00%)  4/12 (33.33%)  18/50 (36.00%)  0/3 (0.00%)  1/6 (16.67%) 
Amylase Increased  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Aspartate Aminotransferase Increased  1  1/5 (20.00%)  4/12 (33.33%)  17/50 (34.00%)  0/3 (0.00%)  1/6 (16.67%) 
Blood Alkaline Phosphatase Increased  1  0/5 (0.00%)  2/12 (16.67%)  7/50 (14.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Bilirubin Increased  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Calcium Decreased  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Cholesterol Increased  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Creatine Phosphokinase Increased  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Blood Creatinine Increased  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Glucose Decreased  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Glucose Increased  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Thyroid Stimulating Hormone Increased  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Blood Uric Acid Increased  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
C-Reactive Protein Increased  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Eastern Cooperative Oncology Group Performance Status Worsened  1  0/5 (0.00%)  1/12 (8.33%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Ejection Fraction Decreased  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Gamma-Glutamyltransferase Increased  1  1/5 (20.00%)  3/12 (25.00%)  7/50 (14.00%)  0/3 (0.00%)  0/6 (0.00%) 
Glycosylated Haemoglobin Increased  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Haemoglobin Decreased  1  1/5 (20.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Insulin C-Peptide Increased  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Lipase Increased  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  1/6 (16.67%) 
Liver Function Test Abnormal  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  1/6 (16.67%) 
Low Density Lipoprotein Increased  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Lymphocyte Count Decreased  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Protein Urine Present  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Weight Decreased  1  1/5 (20.00%)  1/12 (8.33%)  7/50 (14.00%)  1/3 (33.33%)  1/6 (16.67%) 
White Blood Cell Count Decreased  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Metabolism and nutrition disorders           
Decreased Appetite  1  1/5 (20.00%)  1/12 (8.33%)  18/50 (36.00%)  2/3 (66.67%)  4/6 (66.67%) 
Hypercholesterolaemia  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hyperglycaemia  1  2/5 (40.00%)  5/12 (41.67%)  15/50 (30.00%)  1/3 (33.33%)  1/6 (16.67%) 
Hyperphagia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Hypoalbuminaemia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Hypocalcaemia  1  0/5 (0.00%)  1/12 (8.33%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hypoglycaemia  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hypokalaemia  1  0/5 (0.00%)  1/12 (8.33%)  3/50 (6.00%)  1/3 (33.33%)  1/6 (16.67%) 
Hyponatraemia  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hypophosphataemia  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Increased Appetite  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  0/5 (0.00%)  1/12 (8.33%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Back Pain  1  0/5 (0.00%)  2/12 (16.67%)  6/50 (12.00%)  0/3 (0.00%)  2/6 (33.33%) 
Bone Pain  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  1/6 (16.67%) 
Muscle Spasms  1  0/5 (0.00%)  1/12 (8.33%)  4/50 (8.00%)  2/3 (66.67%)  2/6 (33.33%) 
Muscular Weakness  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Musculoskeletal Chest Pain  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Musculoskeletal Pain  1  1/5 (20.00%)  2/12 (16.67%)  2/50 (4.00%)  1/3 (33.33%)  0/6 (0.00%) 
Myalgia  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Pain In Extremity  1  0/5 (0.00%)  1/12 (8.33%)  5/50 (10.00%)  0/3 (0.00%)  1/6 (16.67%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Tumour Pain  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Nervous system disorders           
Balance Disorder  1  0/5 (0.00%)  1/12 (8.33%)  5/50 (10.00%)  1/3 (33.33%)  0/6 (0.00%) 
Cluster Headache  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Dizziness  1  0/5 (0.00%)  1/12 (8.33%)  6/50 (12.00%)  1/3 (33.33%)  1/6 (16.67%) 
Dysgeusia  1  1/5 (20.00%)  1/12 (8.33%)  7/50 (14.00%)  1/3 (33.33%)  1/6 (16.67%) 
Headache  1  1/5 (20.00%)  1/12 (8.33%)  11/50 (22.00%)  1/3 (33.33%)  2/6 (33.33%) 
Memory Impairment  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  1/3 (33.33%)  0/6 (0.00%) 
Neuropathy Peripheral  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Paraesthesia  1  1/5 (20.00%)  1/12 (8.33%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Peripheral Sensory Neuropathy  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  1/6 (16.67%) 
Somnolence  1  1/5 (20.00%)  0/12 (0.00%)  2/50 (4.00%)  0/3 (0.00%)  0/6 (0.00%) 
Syncope  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  1/6 (16.67%) 
Tremor  1  1/5 (20.00%)  0/12 (0.00%)  3/50 (6.00%)  1/3 (33.33%)  1/6 (16.67%) 
Psychiatric disorders           
Affective Disorder  1  0/5 (0.00%)  3/12 (25.00%)  5/50 (10.00%)  0/3 (0.00%)  0/6 (0.00%) 
Anxiety  1  0/5 (0.00%)  1/12 (8.33%)  11/50 (22.00%)  1/3 (33.33%)  2/6 (33.33%) 
Binge Eating  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Delirium  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Depressed Mood  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Depression  1  2/5 (40.00%)  1/12 (8.33%)  8/50 (16.00%)  0/3 (0.00%)  1/6 (16.67%) 
Initial Insomnia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Insomnia  1  0/5 (0.00%)  2/12 (16.67%)  6/50 (12.00%)  1/3 (33.33%)  0/6 (0.00%) 
Irritability  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  1/6 (16.67%) 
Mood Altered  1  3/5 (60.00%)  4/12 (33.33%)  7/50 (14.00%)  0/3 (0.00%)  1/6 (16.67%) 
Nervousness  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Restlessness  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Suicidal Ideation  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Renal and urinary disorders           
Chromaturia  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Dysuria  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  1/6 (16.67%) 
Haematuria  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Micturition Urgency  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Reproductive system and breast disorders           
Breast Pain  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  1/6 (16.67%) 
Vulvovaginal Discomfort  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Respiratory, thoracic and mediastinal disorders           
Cough  1  0/5 (0.00%)  4/12 (33.33%)  15/50 (30.00%)  2/3 (66.67%)  1/6 (16.67%) 
Dyspnoea  1  0/5 (0.00%)  1/12 (8.33%)  6/50 (12.00%)  1/3 (33.33%)  0/6 (0.00%) 
Epistaxis  1  1/5 (20.00%)  0/12 (0.00%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Hiccups  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Interstitial Lung Disease  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Oropharyngeal Pain  1  0/5 (0.00%)  1/12 (8.33%)  4/50 (8.00%)  1/3 (33.33%)  2/6 (33.33%) 
Pleural Effusion  1  0/5 (0.00%)  0/12 (0.00%)  1/50 (2.00%)  1/3 (33.33%)  0/6 (0.00%) 
Pleuritic Pain  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Productive Cough  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Respiratory Disorder  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Skin and subcutaneous tissue disorders           
Blister  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Dermatitis Acneiform  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Dry Skin  1  0/5 (0.00%)  3/12 (25.00%)  6/50 (12.00%)  1/3 (33.33%)  0/6 (0.00%) 
Eczema  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Erythema  1  0/5 (0.00%)  1/12 (8.33%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Nail Disorder  1  0/5 (0.00%)  1/12 (8.33%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Night Sweats  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Palmar-Plantar Erythrodysaesthesia Syndrome  1  0/5 (0.00%)  0/12 (0.00%)  2/50 (4.00%)  1/3 (33.33%)  3/6 (50.00%) 
Photosensitivity Reaction  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  1/6 (16.67%) 
Pruritus  1  2/5 (40.00%)  3/12 (25.00%)  7/50 (14.00%)  3/3 (100.00%)  0/6 (0.00%) 
Rash  1  1/5 (20.00%)  6/12 (50.00%)  16/50 (32.00%)  2/3 (66.67%)  1/6 (16.67%) 
Rash Generalised  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Rash Maculo-Papular  1  0/5 (0.00%)  0/12 (0.00%)  3/50 (6.00%)  0/3 (0.00%)  0/6 (0.00%) 
Rash Pruritic  1  0/5 (0.00%)  0/12 (0.00%)  4/50 (8.00%)  0/3 (0.00%)  0/6 (0.00%) 
Skin Discolouration  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Skin Exfoliation  1  0/5 (0.00%)  1/12 (8.33%)  1/50 (2.00%)  0/3 (0.00%)  0/6 (0.00%) 
Skin Lesion  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  1/6 (16.67%) 
Swelling Face  1  1/5 (20.00%)  0/12 (0.00%)  0/50 (0.00%)  0/3 (0.00%)  0/6 (0.00%) 
Vascular disorders           
Hypertension  1  0/5 (0.00%)  3/12 (25.00%)  6/50 (12.00%)  0/3 (0.00%)  0/6 (0.00%) 
Orthostatic Hypotension  1  0/5 (0.00%)  0/12 (0.00%)  0/50 (0.00%)  1/3 (33.33%)  0/6 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01132664     History of Changes
Other Study ID Numbers: CBKM120X2107
2009-015417-46 ( EudraCT Number )
First Submitted: May 7, 2010
First Posted: May 28, 2010
Results First Submitted: August 4, 2015
Results First Posted: October 30, 2015
Last Update Posted: August 17, 2016