Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study Evaluating SKI-606 (Bosutinib) In Advanced Malignant Solid Tumors

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: NCT00195260
Recruitment Status : Completed
First Posted : September 19, 2005
Results First Posted : February 11, 2013
Last Update Posted : February 11, 2013
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Neoplasms
Intervention Drug: bosutinib
Enrollment 151
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg Maximum Tolerated Dose (MTD) lead-in Colorectal Cancer Pancreatic Cancer Non-small Cell Lung Cancer (NSCLC)
Hide Arm/Group Description Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Participants with colorectal cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Participants with pancreatic cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Participants with NSCLC received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Period Title: Part 1: Dose Escalation
Started 4 4 6 7 7 7 10 6 0 0 0
Completed 0 0 0 0 0 0 0 0 0 0 0
Not Completed 4 4 6 7 7 7 10 6 0 0 0
Reason Not Completed
Adverse Event             0             1             0             1             1             0             3             0             0             0             0
Withdrawal by Subject             0             0             0             0             2             0             0             1             0             0             0
Death             0             0             0             0             0             0             0             1             0             0             0
Disease Progression             3             2             5             6             4             6             7             4             0             0             0
Symptomatic Deterioration             1             1             1             0             0             1             0             0             0             0             0
Period Title: Part 2: Recommended Phase 2 Dose (RP2D)
Started 0 0 0 0 0 0 0 0 37 38 25
Completed 0 0 0 0 0 0 0 0 4 0 2
Not Completed 0 0 0 0 0 0 0 0 33 38 23
Reason Not Completed
Death             0             0             0             0             0             0             0             0             21             29             15
Withdrawal by Subject             0             0             0             0             0             0             0             0             5             3             2
Lost to Follow-up             0             0             0             0             0             0             0             0             1             2             3
Other             0             0             0             0             0             0             0             0             6             4             3
Arm/Group Title Part 1 RP2D 400 mg Total
Hide Arm/Group Description Participants received bosutinib capsule orally once daily continuously in 21-day cycles in dose escalation schemes of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, MTD-lead in (500 mg) until disease progression, unacceptable toxicity, or consent withdrawal. Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Total of all reporting groups
Overall Number of Baseline Participants 51 100 151
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 51 participants 100 participants 151 participants
57.00  (12.67) 60.30  (11.48) 59.10  (11.95)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 100 participants 151 participants
Female
29
  56.9%
54
  54.0%
83
  55.0%
Male
22
  43.1%
46
  46.0%
68
  45.0%
1.Primary Outcome
Title Number of Participants With Dose-limiting Toxicities (DLT) in Part 1
Hide Description DLT included any grade 3 or 4 clinically-evident non-hematologic toxicity, grade 4 neutropenia of greater than or equal to (>=) 7-day duration or with fever >= 38.5 degrees Celsius (febrile neutropenia); grade 4 thrombocytopenia >= 2-day duration or with bleeding requiring platelet transfusion, any clinically-significant grade >= 2 toxicity that requires >=14 days to resolve (to less than or equal to [=<] grade 1) which occurred in first 21 days of study and considered at least possibly related to bosutinib.
Time Frame Part 1 Baseline up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants enrolled in a dose escalation cohort who had taken at least 1 dose of study medication.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 10 6
Measure Type: Number
Unit of Measure: participants
0 0 1 1 0 1 3 0
2.Primary Outcome
Title Number of Participants With Adverse Events (AEs) by Seriousness
Hide Description Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Participants with multiple occurrences of an AE within a category were counted once within the category.
Time Frame Baseline up to 30 days after last dose
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who had taken at least 1 dose of study medication.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 10 6 100
Measure Type: Number
Unit of Measure: participants
AEs 4 4 6 7 7 7 10 6 100
Serious adverse events (SAEs) 4 3 2 3 5 2 7 3 47
3.Primary Outcome
Title Duration of Most Frequently Observed Adverse Events (AEs)
Hide Description The most frequently observed treatment-emergent AEs were gastrointestinal disorders which included diarrhea, nausea and vomiting. Duration of AE per event is calculated as AE stop date minus AE start date plus 1.
Time Frame Baseline up to 30 days after last dose
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who had taken at least 1 dose of study medication.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD lead-in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 10 6 100
Median (Full Range)
Unit of Measure: days
Diarrhea
1.0
(1 to 1)
NA [1] 
(NA to NA)
12.0
(1 to 27)
2.0
(1 to 15)
3.5
(1 to 7)
7.0
(1 to 33)
1.0
(1 to 23)
1.0
(1 to 30)
3.0
(1 to 75)
Nausea
2.0
(1 to 14)
1.0
(1 to 11)
1.0
(1 to 8)
9.0
(1 to 366)
4.0
(1 to 15)
7.0
(1 to 94)
3.0
(1 to 24)
7.0
(1 to 24)
13.0
(1 to 126)
Vomiting
2.5
(1 to 4)
1.0
(1 to 9)
NA [1] 
(NA to NA)
1.0
(1 to 13)
3.0
(1 to 5)
1.0
(1 to 3)
2.0
(1 to 24)
2.5
(1 to 9)
2.0
(1 to 62)
[1]
Data was not analyzed as no participants reported the event in this particular cohort.
4.Primary Outcome
Title Number of Participants With Best Overall Response (BOR) in Part 1
Hide Description BOR:investigator assessment by modified Response Evaluation Criteria in Solid Tumors (RECIST), recorded from treatment start until disease progression/recurrence. Complete Response:disappearance of all lesions. Partial Response (PR):>=30% decrease in sum of longest diameters (SLDs) of target lesions (TLs) taking as reference baseline SLD. Progressive disease (PD):>=20% increase in SLD of TLs taking as reference smallest SLD since treatment start, or appearance of >=1 new lesion. Stable disease: neither shrinkage for PR nor increase for PD taking as reference smallest SLD since treatment start.
Time Frame Part 1 Baseline, last week (Day 15 to 23) of cycles 2, 4, 6, 8 and thereafter every 3 cycles up to 30 days after last dose
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy evaluable population: participants who received at least 1 cycle (15 doses) of study medication, had no eligibility violations, did not use prohibited anti-cancer treatment, had baseline disease assessment, at least 1 disease assessment post-baseline/had experienced clinical progression/death before first post-baseline disease assessment.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 3 3 6 6 6 6 4 3
Measure Type: Number
Unit of Measure: participants
Complete response 0 0 0 0 0 0 0 0
Partial response 0 0 0 0 0 1 0 0
Stable disease 0 2 2 5 3 2 4 2
Progressive disease 3 1 4 1 2 3 0 1
Indeterminate 0 0 0 0 1 0 0 0
Not done 0 0 0 0 0 0 0 0
5.Primary Outcome
Title Number of Participants With Best Overall Response (BOR) in Part 2
Hide Description BOR: investigator assessment by modified RECIST, recorded from treatment start until disease progression/recurrence. Complete Response: disappearance of all lesions. PR: >=30% decrease in SLDs of TLs taking as reference baseline SLD. PD: >=20% increase in SLD of TLs taking as reference smallest SLD since treatment start, or appearance of >=1 new lesion. Stable disease: neither shrinkage for PR nor increase for PD taking as reference smallest SLD since treatment start.
Time Frame Part 2 Baseline, last week (Day 15 to 23) of cycles 2, 4, 6, 8 and thereafter every 3 cycles up to 30 days after last dose
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy evaluable population: participants who received at least 1 cycle (15 doses) of study medication, had no eligibility violations, did not use prohibited anti-cancer treatment, had baseline disease assessment, at least 1 disease assessment post-baseline/had experienced clinical progression/death before first post-baseline disease assessment.
Arm/Group Title Colorectal Cancer Pancreatic Cancer Non-small Cell Lung Cancer (NSCLC)
Hide Arm/Group Description:
Participants with colorectal cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with pancreatic cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with NSCLC received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 34 22 19
Measure Type: Number
Unit of Measure: participants
Complete response 0 0 0
Partial response 0 0 0
Stable disease 10 3 9
Progressive disease 24 18 9
Indeterminate 0 0 0
Not done 0 1 1
6.Primary Outcome
Title Maximum Tolerated Dose (MTD) in Part 1
Hide Description MTD: highest dose level at which not more than 1 of 6 participants experienced DLT after 21 days of treatment (Cycle 1). DLT included any grade 3 or 4 clinically-evident non-hematologic toxicity, grade 4 neutropenia of >= 7-day duration or with fever >= 38.5 degrees Celsius (febrile neutropenia); grade 4 thrombocytopenia >= 2-day duration or with bleeding requiring platelet transfusion, any clinically-significant grade >= 2 toxicity that requires >=14 days to resolve (to =< grade 1) which occurred in first 21 days of study and considered at least possibly related to bosutinib.
Time Frame Part 1 Day 1 up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants enrolled in a dose escalation cohort who had taken at least 1 dose of study medication.
Arm/Group Title All Participant
Hide Arm/Group Description:
All participants who received bosutinib capsule (50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, MTD-lead in) orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 51
Measure Type: Number
Unit of Measure: mg
500
7.Secondary Outcome
Title Maximum Tolerated Dose (MTD) for Prolonged Use
Hide Description MTD for prolonged use was the highest dose level at which not more than 1 of 6 participants experienced DLT after 21 days of treatment (Cycle 1) and was selected as recommended dose in Phase 2, due to substantial number of Grade 2 gastrointestinal toxicities observed in the MTD lead-in cohort (500 mg).
Time Frame Part 1 Day 1 up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants enrolled in a dose escalation cohort who had taken at least 1 dose of study medication.
Arm/Group Title All Participant
Hide Arm/Group Description:
All participants who received bosutinib capsule (50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, MTD-lead in) orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 51
Measure Type: Number
Unit of Measure: mg
400
8.Secondary Outcome
Title Number of Participants With Change From Baseline in Laboratory Test Results
Hide Description Criteria for potentially clinically significant (PCS) laboratory values: albumin <20, hemoglobin <80 gram/liter(g/L); alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase >5*upper limit of normal(ULN) milliunit/milliliter(mU/mL); bilirubin total, creatinine>3*ULN micromole/L; calcium <1.75 and >3.1,potassium <3 and >6, sodium <130, glucose <2.2,phosphorous <0.6 millimole/L; international normalized ratio >2*ULN, partial thromboplastin time, prothrombin time >2*ULN seconds; platelet count <50*10^9/L. Participants meeting at least 1 PCS criteria are reported.
Time Frame Baseline up to end of treatment (Week 95)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable (at least 1 on-therapy laboratory assessment) for this measure for each group respectively.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 8 6 96
Measure Type: Number
Unit of Measure: participants
Albumin (<20 g/L) 0 0 0 0 0 0 0 0 1
Alkaline phosphatase (>5*ULN) 0 1 0 0 0 1 0 0 5
Bilirubin total (>3*ULN) 0 0 0 0 0 0 1 0 2
Calcium (<1.75 mmol/L) 0 0 0 0 0 0 0 0 1
Calcium (>3.1 mmol/L) 0 0 0 0 0 0 0 0 1
Creatinine (>3*ULN) 0 0 0 0 0 0 0 0 2
Glucose (<2.2 mmol/L) 0 0 0 0 0 0 0 0 2
Phosphorus (<0.6 mmol/L) 0 0 0 1 1 0 0 0 0
Potassium (<3 mmol/L) 0 1 0 0 0 0 1 0 1
Potassium (>6 mmol/L) 0 0 0 0 0 0 0 0 1
Aspartate aminotransferase (> 5*ULN)) 0 0 0 0 0 1 0 0 5
Alanine aminotransferase (> 5*ULN) 0 0 0 0 0 1 0 0 5
Sodium (<130 mmol/L) 0 0 0 1 0 1 0 0 7
International normalized ratio (>2*ULN) 0 1 0 1 2 0 0 1 6
Prothrombin time (>2*ULN) 0 1 0 0 2 0 0 0 7
Partial thromboplastin time (>2*ULN) 0 0 0 2 0 0 1 1 1
Hemoglobin (<80 g/L) 0 0 0 0 0 0 0 0 3
Platelets (<50*10^9/L) 0 1 0 0 0 0 0 1 0
9.Secondary Outcome
Title Number of Participants With Change From Baseline in Electrocardiogram (ECG) and Chest X-ray
Hide Description Number of participants with PCS ECG findings is reported on-therapy (OT) and at final visit (FV). Criteria for PCS ECG findings: heart rate (HR) =<45 beats/minute (bpm) and decrease (Dec) >15/>=120 bpm and decrease of >15 bpm; PR interval (Int) >=220 millisecond (msec), increase (Inc) >=20 msec, QRS Int >=120 msec, corrected QT (QTc) and QTc using fridericia formula(QTcF) Int >500 msec, increase >60 msec; no sinus rhythm; overall ECG abnormal. Participants with at least 1 measurement exceeding the criteria for PCS are reported.
Time Frame Baseline up to end of treatment (Week 95)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable (at least 1 on-therapy assessment) for this measure and 'n' represents participants evaluable under each category for each group respectively.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 10 6 93
Measure Type: Number
Unit of Measure: participants
OT: HR (<=45/Dec >15bpm) (n=4,4,6,7,7,7,10,6,93) 0 0 0 0 0 0 0 0 1
OT: HR (>=120/Inc >15bpm) (n=4,4,6,7,7,7,10,6,93) 1 0 1 0 0 0 0 0 3
OT:PR Int(>=220/Inc>20msec)(n=4,4,6,7,7,7,10,6,93) 0 0 0 0 0 0 0 2 3
OT: QRS Int (>=120 msec) (n=4,4,6,7,7,7,10,6,93) 0 0 1 1 1 0 1 0 8
OT: QTc Int (Inc >60 msec) (n=4,4,6,7,7,7,10,6,93) 0 0 1 0 0 0 0 0 3
OT: QTc Int (>500 msec) (n=4,4,6,7,7,7,10,6,93) 0 0 1 0 0 1 0 0 3
OT: QTcF Int (Inc >60 msec) (n=0,0,0,0,0,0,1,3,89) 0 0 0 0 0 0 0 0 3
OT: QTcF Int (>500 msec) (n=0,0,0,0,0,0,1,3,89) 0 0 0 0 0 0 0 0 1
OT: No sinus rhythm (n=4,4,6,7,7,7,10,6,93) 0 0 0 0 0 0 0 0 29
OT: Overall ECG abnormal (n=4,4,6,7,7,7,10,6,93) 3 4 5 7 6 6 8 6 63
FV: HR (>=120/Inc >15bpm) (n=1,2,2,4,3,4,3,1,42) 0 0 0 0 0 0 0 0 1
FV:PR Int(>=220/Inc >20msec)(n=1,2,3,4,3,4,3,1,42) 0 0 1 0 0 0 0 0 0
FV: QRS Int (>=120 msec) (n=1,2,2,4,3,4,3,1,42) 0 0 0 0 0 0 1 0 4
FV: QTc Int (>500 msec) (n=1,2,3,4,3,4,3,1,42) 0 0 0 0 0 0 0 0 1
FV: No sinus rhythm (n=1,2,2,4,3,4,3,1,42) 0 0 0 0 0 0 0 0 2
FV: Overall ECG abnormal (n=1,2,3,4,3,4,3,1,42) 1 1 1 0 2 3 3 1 18
Chest X-ray (n=0,0,0,0,0,0,0,0,0) NA [1]  NA [1]  NA [1]  NA [1]  NA [1]  NA [1]  NA [1]  NA [1]  NA [1] 
[1]
Data for this pre-specified category was collected but not statistically summarized for analysis as there were no clinically significant changes observed.
10.Secondary Outcome
Title Concomitant Medications Used for Management of Adverse Events (AEs)
Hide Description Number of participants taking any non-study medications which were administered from Day 1 up to end of treatment (Week 95) as a management of an AE was to be reported.
Time Frame Day 1 up to end of treatment (Week 95)
Hide Outcome Measure Data
Hide Analysis Population Description
Data for this pre-specified outcome measure was not statistically summarized for analysis, but collected and reported in individual participant listings as planned.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Change From Baseline in Karnofsky Performance Score
Hide Description Karnofsky performance score is used to quantify participant's general well-being and activities of daily life and participants are classified based on their functional impairment. Karnofsky performance score is 11 level score which ranges between 0 (death) to 100 (complete healthy status). Higher score means higher ability to perform daily tasks.
Time Frame Baseline up to end of treatment (Week 95)
Hide Outcome Measure Data
Hide Analysis Population Description
Data for this pre-specified outcome was collected but not statistically summarized for analysis as there were no clinically significant changes observed.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
12.Secondary Outcome
Title Number of Participants With Change From Baseline in Physical Examination
Hide Description Physical examinations included body weight, height and vital signs and only finding that exceeded the criterion for PCS was weight. Criteria for weight was: an increase or decrease of >=10% from baseline.
Time Frame Baseline up to end of treatment (Week 95)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable (at least 1 on-therapy assessment) for this measure for each group respectively.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 7 6 87
Measure Type: Number
Unit of Measure: participants
Weight (decrease >=10%) 0 0 2 2 0 0 0 0 3
Weight (increase >=10%) 1 1 0 1 0 1 1 0 3
13.Secondary Outcome
Title Number of Participants With Change From Baseline in Opthalmologic Examination
Hide Description Ophthalmologic evaluation included visual acuity, funduscopic examination, and any clinically-significant abnormality.
Time Frame Baseline up to end of treatment (Week 95)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who had taken at least 1 dose of study medication.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in RP2D 400 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 7 7 10 6 100
Measure Type: Number
Unit of Measure: participants
0 0 0 1 0 0 0 0 4
14.Secondary Outcome
Title Overall Survival (OS) in Part 2
Hide Description Time in weeks from the start of study treatment to date of death due to any cause. OS was calculated as (the death date minus the date of first dose of study medication plus 1) divided by 7. Death was determined from death case report forms (CRFs) or from follow-up contact data (where the participant current status was death).
Time Frame Part 2 Baseline until death or 3, 6, 9 and 12 months after treatment discontinuation
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy evaluable population: participants who received at least 1 cycle (15 doses) of study medication, had no eligibility violations, did not use prohibited anti-cancer treatment, had baseline disease assessment, at least 1 disease assessment post-baseline/had experienced clinical progression/death before first post-baseline disease assessment.
Arm/Group Title Colorectal Cancer Pancreatic Cancer Non-small Cell Lung Cancer (NSCLC)
Hide Arm/Group Description:
Participants with colorectal cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with pancreatic cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with NSCLC received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 34 22 19
Median (95% Confidence Interval)
Unit of Measure: weeks
27.7
(23.0 to 34.3)
14.7
(8.1 to 22.9)
34.0
(16.7 to 55.0)
15.Secondary Outcome
Title Progression Free Survival (PFS) in Part 2
Hide Description Time in weeks from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 7. Tumor progression was determined from oncologic assessment data (where data meet the criteria for PD, or from death CRFs).
Time Frame Part 2 Baseline until death or 3, 6, 9 and 12 months after treatment discontinuation
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy evaluable population: participants who received at least 1 cycle (15 doses) of study medication, had no eligibility violations, did not use prohibited anti-cancer treatment, had baseline disease assessment, at least 1 disease assessment post-baseline/had experienced clinical progression/death before first post-baseline disease assessment.
Arm/Group Title Colorectal Cancer Pancreatic Cancer Non-small Cell Lung Cancer (NSCLC)
Hide Arm/Group Description:
Participants with colorectal cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with pancreatic cancer received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Participants with NSCLC received bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 34 22 19
Median (95% Confidence Interval)
Unit of Measure: weeks
6.0
(5.3 to 7.1)
6.0
(5.3 to 6.1)
5.7
(5.3 to 19.3)
16.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax)
Hide Description [Not Specified]
Time Frame 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies those participants evaluable for specific time points.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg (Part 1 + Part 2) Bosutinib 500 mg Bosutinib 600 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal in both Part 1 and Part 2 participants.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 69 13 10
Mean (Standard Deviation)
Unit of Measure: nanogram/milliliter (ng/mL)
Day 1 (n = 4, 4, 6, 7, 54, 13, 10) 4.89  (3.69) 17.0  (9.75) 43.1  (26.9) 63.7  (34.7) 117.0  (69.0) 125.0  (63.2) 206.0  (190.0)
Day 15 (n = 3, 4, 5, 5, 69, 10, 2) 6.92  (3.07) 19.6  (3.31) 95.4  (60.0) 76.6  (37.0) 190.0  (116.0) 273.0  (197.0) 304.0 [1]   (NA)
[1]
Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.
17.Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax)
Hide Description [Not Specified]
Time Frame 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population included all participants who had taken at least one dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies those participants evaluable for specific time points.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg (Part 1 + Part 2) Bosutinib 500 mg Bosutinib 600 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal in both Part 1 and Part 2 participants.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 69 13 10
Median (Full Range)
Unit of Measure: hours
Day 1 (n = 4, 4, 6, 7, 54, 13, 10)
6.01
(4.00 to 8.00)
4.08
(2.00 to 6.00)
6.00
(2.05 to 8.00)
6.00
(3.23 to 6.17)
4.00
(1.00 to 8.68)
4.00
(2.00 to 8.00)
6.00
(1.30 to 8.00)
Day 15 (n = 3, 4, 5, 5, 69, 10, 2)
4.00
(3.00 to 6.00)
3.50
(2.25 to 4.03)
4.00
(3.00 to 6.10)
4.02
(3.00 to 6.00)
4.00
(1.00 to 8.33)
5.00
(1.00 to 8.00)
3.53
(3.00 to 4.05)
18.Secondary Outcome
Title Plasma Decay Half-Life (t1/2)
Hide Description Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies those participants evaluable for specific time points.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg (Part 1 + Part 2) Bosutinib 500 mg Bosutinib 600 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal in both Part 1 and Part 2 participants.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 69 13 10
Mean (Standard Deviation)
Unit of Measure: hours
Day 1 (n = 3, 4, 6, 7, 47, 13, 10) 12.86  (7.36) 18.61  (4.91) 20.80  (6.07) 17.12  (6.01) 18.63  (7.67) 21.87  (7.39) 19.94  (5.47)
Day 15 (n = 3, 4, 5, 4, 53, 9, 2) 25.84  (12.26) 64.65  (67.31) 30.04  (20.13) 19.35  (7.54) 19.89  (16.72) 23.25  (15.00) 16.29 [1]   (NA)
[1]
Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.
19.Secondary Outcome
Title Area Under the Concentration-Time Curve (AUC)
Hide Description AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Steady state concentration was achieved at Day 15.
Time Frame 0 hour (pre-dose) on Day 1, 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 (0 hour [pre-dose] on Day 15) hours post-dose on Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population included all participants who had taken at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies those participants evaluable for specific time points.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg (Part 1 + Part 2) Bosutinib 500 mg Bosutinib 600 mg
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal in both Part 1 and Part 2 participants.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 4 4 6 7 69 13 10
Mean (Standard Deviation)
Unit of Measure: ng*hour/mL
Day 1 (n = 3, 4, 6, 7, 47, 13, 10) 129.0  (131.0) 284.0  (72.8) 920.0  (338.0) 1200.0  (736.0) 2340.0  (1230.0) 2950.0  (1470.0) 4300.0  (3310.0)
Day 15 (n = 3, 4, 5, 4, 58, 9, 2) 114.0  (33.3) 329.0  (58.1) 1670.0  (1130.0) 1170.0  (699.0) 2900.0  (1700.0) 3580.0  (1820.0) 4220.0 [1]   (NA)
[1]
Standard deviation obtained by sampling distribution of 2 participants was not meaningful, hence not reported.
20.Other Pre-specified Outcome
Title Gene Expression at Baseline
Hide Description Gene expression profile was evaluated by measuring transcript levels of messenger RNA (mRNA) in peripheral blood samples. Expression profiling of mRNA: done to measure the expressed genome of mRNA transcripts or done in a gene-specific targeted manner.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
Data was not analyzed as the analysis was cancelled due to lack of samples provided from sites.
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD-lead in
Hide Arm/Group Description:
Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame [Not Specified]
Adverse Event Reporting Description The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
 
Arm/Group Title Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD lead-in RP2D 400 mg
Hide Arm/Group Description Bosutinib 50 milligram (mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 100 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 200 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 300 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 400 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 600 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Bosutinib 500 mg capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. Participants with colorectal cancer, pancreatic cancer, NSCLC received RP2D of bosutinib (400 mg) capsule orally once daily continuously in 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal.
All-Cause Mortality
Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD lead-in RP2D 400 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD lead-in RP2D 400 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/4 (100.00%)   3/4 (75.00%)   2/6 (33.33%)   3/7 (42.86%)   5/7 (71.43%)   2/7 (28.57%)   7/10 (70.00%)   3/6 (50.00%)   47/100 (47.00%) 
Blood and lymphatic system disorders                   
Anaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Coagulopathy * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Leukocytosis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Cardiac disorders                   
Sinus tachycardia * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Atrial fibrillation * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Cardiac arrest * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Cardio-respiratory arrest * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Pericardial effusion * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Gastrointestinal disorders                   
Abdominal pain upper * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Small intestinal obstruction * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Vomiting * 1  1/4 (25.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  1/100 (1.00%) 
Diarrhoea * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  2/10 (20.00%)  0/6 (0.00%)  1/100 (1.00%) 
Abdominal pain * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  0/100 (0.00%) 
Nausea * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  2/100 (2.00%) 
Duodenal ulcer * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Faecaloma * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Gastrointestinal haemorrhage * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Haematemesis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Intestinal ischaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Large intestinal obstruction * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Dysphagia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Ileus * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Peptic ulcer haemorrhage * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Ascites * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Upper gastrointestinal haemorrhage * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Abdominal discomfort * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Oesophageal stenosis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Pancreatitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Varices oesophageal * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
General disorders                   
Pyrexia * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Chest pain * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Chills * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Death * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Hepatobiliary disorders                   
Bile duct obstruction * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Hyperbilirubinaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Cholangitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Hepatic failure * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Infections and infestations                   
Pneumonia * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Bacteraemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Pneumonia staphylococcal * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Sepsis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Systemic candida * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Urinary tract infection * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Urinary tract infection staphylococcal * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Infection * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Abdominal abscess * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Bronchitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Clostridium difficile colitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Klebsiella bacteraemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Parotitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Pneumonia klebsiella * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Injury, poisoning and procedural complications                   
Procedural pain * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Feeding tube complication * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Femur fracture * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Overdose * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Investigations                   
Liver function test abnormal * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Activated partial thromboplastin time prolonged * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Blood creatinine increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
International normalised ratio increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Prothrombin time prolonged * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Alanine aminotransferase increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Aspartate aminotransferase increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Metabolism and nutrition disorders                   
Dehydration * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  3/100 (3.00%) 
Hypoglycaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Decreased appetite * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hypokalaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hyponatraemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Failure to thrive * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Hyperammonaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Musculoskeletal and connective tissue disorders                   
Back pain * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Flank pain * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Neck mass * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                   
Metastases to central nervous system * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  2/7 (28.57%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Metastases to rectum * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Metastasis * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Metastatic malignant melanoma * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Pancreatic carcinoma * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Colorectal cancer * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Malignant neoplasm progression * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Colorectal cancer metastatic * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Nervous system disorders                   
Headache * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hepatic encephalopathy * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Psychiatric disorders                   
Delirium * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Mental status changes * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Renal and urinary disorders                   
Nephrolithiasis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Renal failure * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Renal failure acute * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Renal impairment * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Reproductive system and breast disorders                   
Menorrhagia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Vaginal haemorrhage * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Respiratory, thoracic and mediastinal disorders                   
Dyspnoea * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Pleural effusion * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Acute respiratory distress syndrome * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Pulmonary embolism * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  3/100 (3.00%) 
Respiratory failure * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Pneumonia aspiration * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Skin and subcutaneous tissue disorders                   
Rash maculo-papular * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Rash * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Urticaria * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Surgical and medical procedures                   
Hospitalisation * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Vascular disorders                   
Circulatory collapse * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Haemorrhage * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hypertension * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Deep vein thrombosis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Thrombosis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Thrombophlebitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Bosutinib 50 mg Bosutinib 100 mg Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg MTD lead-in RP2D 400 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/4 (100.00%)   4/4 (100.00%)   6/6 (100.00%)   7/7 (100.00%)   7/7 (100.00%)   7/7 (100.00%)   10/10 (100.00%)   6/6 (100.00%)   99/100 (99.00%) 
Blood and lymphatic system disorders                   
Anaemia * 1  1/4 (25.00%)  1/4 (25.00%)  0/6 (0.00%)  3/7 (42.86%)  3/7 (42.86%)  1/7 (14.29%)  2/10 (20.00%)  1/6 (16.67%)  20/100 (20.00%) 
Lymphopenia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  3/10 (30.00%)  0/6 (0.00%)  3/100 (3.00%) 
Thrombocytopenia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  2/7 (28.57%)  1/7 (14.29%)  3/10 (30.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hypercoagulation * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Lymphadenopathy * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  0/100 (0.00%) 
Leukopenia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Cardiac disorders                   
Tachycardia * 1  1/4 (25.00%)  1/4 (25.00%)  1/6 (16.67%)  0/7 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Atrial fibrillation * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Sinus tachycardia * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Cardiac failure congestive * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  1/100 (1.00%) 
Pericardial effusion * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Bradycardia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Supraventricular tachycardia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Extrasystoles * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Palpitations * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Ear and labyrinth disorders                   
Tinnitus * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Eye disorders                   
Vision blurred * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  3/10 (30.00%)  0/6 (0.00%)  3/100 (3.00%) 
Conjunctivitis * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Lacrimation increased * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Dry eye * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Eye oedema * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Visual acuity reduced * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Diplopia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Orbital oedema * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Visual impairment * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Photophobia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Gastrointestinal disorders                   
Vomiting * 1  2/4 (50.00%)  2/4 (50.00%)  0/6 (0.00%)  2/7 (28.57%)  4/7 (57.14%)  3/7 (42.86%)  9/10 (90.00%)  3/6 (50.00%)  51/100 (51.00%) 
Nausea * 1  3/4 (75.00%)  3/4 (75.00%)  3/6 (50.00%)  4/7 (57.14%)  5/7 (71.43%)  6/7 (85.71%)  8/10 (80.00%)  4/6 (66.67%)  65/100 (65.00%) 
Diarrhoea * 1  1/4 (25.00%)  0/4 (0.00%)  4/6 (66.67%)  4/7 (57.14%)  5/7 (71.43%)  5/7 (71.43%)  7/10 (70.00%)  4/6 (66.67%)  48/100 (48.00%) 
Abdominal distension * 1  2/4 (50.00%)  0/4 (0.00%)  2/6 (33.33%)  0/7 (0.00%)  1/7 (14.29%)  3/7 (42.86%)  3/10 (30.00%)  1/6 (16.67%)  12/100 (12.00%) 
Abdominal pain * 1  2/4 (50.00%)  0/4 (0.00%)  1/6 (16.67%)  2/7 (28.57%)  3/7 (42.86%)  1/7 (14.29%)  5/10 (50.00%)  1/6 (16.67%)  27/100 (27.00%) 
Constipation * 1  1/4 (25.00%)  2/4 (50.00%)  2/6 (33.33%)  2/7 (28.57%)  3/7 (42.86%)  2/7 (28.57%)  2/10 (20.00%)  3/6 (50.00%)  15/100 (15.00%) 
Eructation * 1  0/4 (0.00%)  0/4 (0.00%)  3/6 (50.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Flatulence * 1  2/4 (50.00%)  0/4 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  1/7 (14.29%)  3/7 (42.86%)  2/10 (20.00%)  1/6 (16.67%)  15/100 (15.00%) 
Dyspepsia * 1  0/4 (0.00%)  0/4 (0.00%)  2/6 (33.33%)  0/7 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Abdominal pain lower * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Abdominal pain upper * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  12/100 (12.00%) 
Ascites * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  7/100 (7.00%) 
Abdominal discomfort * 1  0/4 (0.00%)  1/4 (25.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Cheilitis * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Dental caries * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Dysphagia * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  4/100 (4.00%) 
Gastritis * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Stomatitis * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  2/100 (2.00%) 
Toothache * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Gastrointestinal disorder * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Gastrooesophageal reflux disease * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  1/6 (16.67%)  2/100 (2.00%) 
Haemorrhoids * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  1/100 (1.00%) 
Dry mouth * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Gastrointestinal haemorrhage * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Gastrointestinal oedema * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Melaena * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Small intestinal obstruction * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Haematemesis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Haematochezia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Impaired gastric emptying * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Lip dry * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
General disorders                   
Fatigue * 1  3/4 (75.00%)  3/4 (75.00%)  4/6 (66.67%)  4/7 (57.14%)  5/7 (71.43%)  4/7 (57.14%)  8/10 (80.00%)  5/6 (83.33%)  47/100 (47.00%) 
Oedema peripheral * 1  2/4 (50.00%)  1/4 (25.00%)  3/6 (50.00%)  0/7 (0.00%)  3/7 (42.86%)  2/7 (28.57%)  2/10 (20.00%)  1/6 (16.67%)  14/100 (14.00%) 
Pyrexia * 1  2/4 (50.00%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  3/7 (42.86%)  0/7 (0.00%)  3/10 (30.00%)  2/6 (33.33%)  13/100 (13.00%) 
Asthenia * 1  1/4 (25.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  5/100 (5.00%) 
Early satiety * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  2/7 (28.57%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Catheter thrombosis * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Chest pain * 1  0/4 (0.00%)  1/4 (25.00%)  1/6 (16.67%)  1/7 (14.29%)  0/7 (0.00%)  1/7 (14.29%)  2/10 (20.00%)  0/6 (0.00%)  6/100 (6.00%) 
Chills * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  6/100 (6.00%) 
Chest discomfort * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  1/6 (16.67%)  1/100 (1.00%) 
Crepitations * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Gait disturbance * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Nodule * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Pain * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  4/100 (4.00%) 
Catheter site related reaction * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Local swelling * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Oedema * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  6/100 (6.00%) 
Temperature intolerance * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Feeling hot * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Localised oedema * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hepatobiliary disorders                   
Hyperbilirubinaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  11/100 (11.00%) 
Infections and infestations                   
Urinary tract infection * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  10/100 (10.00%) 
Bronchitis * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Influenza * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  1/100 (1.00%) 
Laryngitis * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Oral herpes * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Postoperative wound infection * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Skin infection * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Nasopharyngitis * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Viral pharyngitis * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Pneumonia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  5/100 (5.00%) 
Septic shock * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Sinusitis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  2/100 (2.00%) 
Staphylococcal infection * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Upper respiratory tract infection * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  5/100 (5.00%) 
Injury, poisoning and procedural complications                   
Incision site pain * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Post procedural complication * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Procedural pain * 1  1/4 (25.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Procedural site reaction * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Excoriation * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Overdose * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  1/100 (1.00%) 
Spinal compression fracture * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Arthropod bite * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Contrast media reaction * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Drug toxicity * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Fall * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  2/100 (2.00%) 
Transfusion reaction * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Wound * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Investigations                   
Weight decreased * 1  0/4 (0.00%)  0/4 (0.00%)  2/6 (33.33%)  3/7 (42.86%)  3/7 (42.86%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  16/100 (16.00%) 
Aspartate aminotransferase increased * 1  0/4 (0.00%)  0/4 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  0/7 (0.00%)  2/7 (28.57%)  2/10 (20.00%)  0/6 (0.00%)  16/100 (16.00%) 
Breath sounds abnormal * 1  0/4 (0.00%)  1/4 (25.00%)  2/6 (33.33%)  0/7 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Alanine aminotransferase increased * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/7 (14.29%)  2/7 (28.57%)  3/10 (30.00%)  0/6 (0.00%)  14/100 (14.00%) 
Blood bilirubin increased * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Electrocardiogram QT prolonged * 1  1/4 (25.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Electrocardiogram T wave abnormal * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Blood alkaline phosphatase increased * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  14/100 (14.00%) 
Pulmonary function test decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
White blood cell count increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  0/100 (0.00%) 
Activated partial thromboplastin time prolonged * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  4/100 (4.00%) 
Blood albumin decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Blood creatinine increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  12/100 (12.00%) 
Blood phosphorus decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Body temperature increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Haemoglobin decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  10/100 (10.00%) 
International normalised ratio increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Urine analysis abnormal * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
White blood cells urine positive * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Blood phosphorus increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Blood urea decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Cardiac murmur * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Gamma-glutamyltransferase increased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  4/100 (4.00%) 
Platelet count decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  3/100 (3.00%) 
Urine output decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Metabolism and nutrition disorders                   
Anorexia * 1  3/4 (75.00%)  1/4 (25.00%)  2/6 (33.33%)  2/7 (28.57%)  4/7 (57.14%)  1/7 (14.29%)  5/10 (50.00%)  5/6 (83.33%)  43/100 (43.00%) 
Hypokalaemia * 1  1/4 (25.00%)  3/4 (75.00%)  0/6 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/7 (0.00%)  3/10 (30.00%)  1/6 (16.67%)  6/100 (6.00%) 
Dehydration * 1  2/4 (50.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  3/10 (30.00%)  2/6 (33.33%)  21/100 (21.00%) 
Hypomagnesaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  2/7 (28.57%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Hypocalcaemia * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Decreased appetite * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  2/10 (20.00%)  1/6 (16.67%)  12/100 (12.00%) 
Hyperglycaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  8/100 (8.00%) 
Hypoglycaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  5/100 (5.00%) 
Hyponatraemia * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  6/100 (6.00%) 
Hypercalcaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Hyperkalaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  5/100 (5.00%) 
Hypernatraemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hypovolaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Lactic acidosis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Metabolic alkalosis * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hypoalbuminaemia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  5/100 (5.00%) 
Musculoskeletal and connective tissue disorders                   
Back pain * 1  0/4 (0.00%)  0/4 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  2/7 (28.57%)  2/7 (28.57%)  0/10 (0.00%)  4/6 (66.67%)  12/100 (12.00%) 
Arthralgia * 1  2/4 (50.00%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  2/7 (28.57%)  2/7 (28.57%)  1/10 (10.00%)  2/6 (33.33%)  9/100 (9.00%) 
Musculoskeletal chest pain * 1  2/4 (50.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  5/100 (5.00%) 
Pain in extremity * 1  2/4 (50.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  2/10 (20.00%)  2/6 (33.33%)  8/100 (8.00%) 
Flank pain * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  1/7 (14.29%)  0/10 (0.00%)  2/6 (33.33%)  2/100 (2.00%) 
Joint swelling * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Muscle spasms * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  4/100 (4.00%) 
Musculoskeletal pain * 1  1/4 (25.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  3/100 (3.00%) 
Neck mass * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Neck pain * 1  1/4 (25.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  2/10 (20.00%)  0/6 (0.00%)  2/100 (2.00%) 
Muscular weakness * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Myalgia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Joint range of motion decreased * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                   
Cervix neoplasm * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Haemangioma * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Basal cell carcinoma * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Melanocytic naevus * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Metastases to central nervous system * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  0/100 (0.00%) 
Nervous system disorders                   
Dizziness * 1  3/4 (75.00%)  1/4 (25.00%)  2/6 (33.33%)  4/7 (57.14%)  0/7 (0.00%)  2/7 (28.57%)  3/10 (30.00%)  2/6 (33.33%)  11/100 (11.00%) 
Headache * 1  1/4 (25.00%)  0/4 (0.00%)  2/6 (33.33%)  2/7 (28.57%)  3/7 (42.86%)  1/7 (14.29%)  5/10 (50.00%)  1/6 (16.67%)  16/100 (16.00%) 
Cervical cord compression * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Hypoaesthesia * 1  1/4 (25.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Migraine * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Neuralgia * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Somnolence * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  2/100 (2.00%) 
Amnesia * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Ataxia * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  1/100 (1.00%) 
Dysgeusia * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  5/100 (5.00%) 
Neuropathy peripheral * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  1/6 (16.67%)  3/100 (3.00%) 
Paraesthesia * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Sinus headache * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Transient ischaemic attack * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Convulsion * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Memory impairment * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  1/100 (1.00%) 
Peripheral sensory neuropathy * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Lethargy * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/10 (10.00%)  0/6 (0.00%)  1/100 (1.00%) 
Psychiatric disorders                   
Insomnia * 1  2/4 (50.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  1/7 (14.29%)  6/7 (85.71%)  2/10 (20.00%)  2/6 (33.33%)  11/100 (11.00%) 
Depression * 1  1/4 (25.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  4/10 (40.00%)  2/6 (33.33%)  3/100 (3.00%) 
Anxiety * 1  1/4 (25.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/10 (10.00%)  2/6 (33.33%)  4/100 (4.00%) 
Confusional state * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  4/100 (4.00%) 
Agitation * 1  0/4 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  1/10 (10.00%)  0/6 (0.00%)  2/100 (2.00%) 
Restlessness * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Anger * 1  0/4 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  0/100 (0.00%) 
Mood altered * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/10 (0.00%)  1/6 (16.67%)  0/100 (0.00%) 
Mental status changes * 1  0/4 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/10 (0.00%)  0/6 (0.00%)  3/100 (3.00%) 
Renal and urinary disorders                   
Haematuria * 1  1/4 (25.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/7 (0.00%)