Trial Outcomes & Findings for Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Combination With Standard Chemotherapy During Induction and Consolidation Followed by 12 Months of Maintenance Monotherapy in Patients With Newly-diagnosed FMS-like Tyrosine 3 (FLT3) Kinase Receptor-mutated Acute Myeloid Leukemia. (NCT NCT03379727)

Last Updated: 2024-02-29

Results Overview

Safety of Midostaurin was represented by various types of AEs, SAEs \& death up to M24. AE: the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained. AE grades to characterize the severity of AEs were based on the Common Terminology Criteria for AEs ver. 4.03 with Grade (Gr) 1: mild; Gr 2: moderate; Gr 3: severe; Gr 4: life-threatening; Gr 5: death related to AE. AEs not related to hematological toxicities were generally of grade 1 or 2 severity. SAE: 1 of the following: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, i.e. an event that jeopardizes the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed above, requires inpatient hospitalization or prolongation of existing hospitalization with a few exceptions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

301 participants

Primary outcome timeframe

Baseline up to approximatly 24 months

Results posted on

2024-02-29

Participant Flow

Participants took part in 88 investigative sites in 15 countries.

Investigators had to obtain locally approved FMS-like tyrosine kinase 3 (FLT3) testing results prior to informed consent form signature to allow subjects to initiate Midostaurin treatment per protocol.

Participant milestones

Participant milestones
Measure	Midostaurin Patients went through 3 phases: Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles
Overall Study STARTED	301
Overall Study Entered Induction Phase	301
Overall Study Entered Consolidation Phase	210
Overall Study Entered Maintenance Phase	93
Overall Study COMPLETED	52
Overall Study NOT COMPLETED	249

Reasons for withdrawal

Reasons for withdrawal
Measure	Midostaurin Patients went through 3 phases: Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles
Overall Study Lack of Efficacy	73
Overall Study Adverse Event	32
Overall Study Death	18
Overall Study Patient/guardian decision	17
Overall Study Physician Decision	104
Overall Study Protocol Violation	4
Overall Study Lost to Follow-up	1

Baseline Characteristics

Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Combination With Standard Chemotherapy During Induction and Consolidation Followed by 12 Months of Maintenance Monotherapy in Patients With Newly-diagnosed FMS-like Tyrosine 3 (FLT3) Kinase Receptor-mutated Acute Myeloid Leukemia.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Midostaurin n=301 Participants Patients went through 3 phases: Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles
Age, Continuous	55.8 years STANDARD_DEVIATION 13.82 • n=5 Participants
Sex: Female, Male Female	160 Participants n=5 Participants
Sex: Female, Male Male	141 Participants n=5 Participants
Race/Ethnicity, Customized White	225 Participants n=5 Participants
Race/Ethnicity, Customized Other	18 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	56 Participants n=5 Participants
Race/Ethnicity, Customized Missing	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to approximatly 24 months

Population: Safety Set: The safety set comprises all subjects who received at least one dose of midostaurin

Outcome measures

Outcome measures
Measure	Midostaurin n=301 Participants Patients went through 3 phases: Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles
Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24). Adverse events (AEs) - all grades	295 Participants
Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24). Grade >=3 AEs	254 Participants
Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24). Serious adverse events (SAEs) - all grades	137 Participants
Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24). AEs leading to discontinuation - all grades	40 Participants
Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24). Deaths	19 Participants

SECONDARY outcome

Timeframe: Baseline up to approximately 24 months

Population: The full analysis set (FAS) comprises all subjects who received at least one dose of midostaurin and have a documented FLT3 mutation (ITD or TKD).

CR/CRi rate is defined as the percentage of patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per local assessment in Induction, Consolidation and Maintenance phases. CR/CRi rate was calculated based on the full analysis set (FAS). Complete remission (CR): Bone marrow blasts \<5% with spicules; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) \>1.0 x109/L; platelet count \>100 x 109/L; independence of red cell transfusions. CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (\<1.0 x109/L) or thrombocytopenia (\<100 x 109/L)

Outcome measures

Outcome measures
Measure	Midostaurin n=300 Participants Patients went through 3 phases: Induction phase - Day (D)8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles; Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles; Maintenance phase - D1 to D28 up to 12 cycles
Percentage of Patients With Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (CRi) as Per Local Assessment Complete remission (CR)	196 Participants
Percentage of Patients With Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (CRi) as Per Local Assessment Complete remission with incomplete recovery (CRi)	46 Participants

Adverse Events

Induction Phase

Serious events: 76 serious events

Other events: 253 other events

Deaths: 16 deaths

Consolidation Phase

Serious events: 67 serious events

Other events: 179 other events

Deaths: 3 deaths

Maintenance Phaase

Serious events: 7 serious events

Other events: 48 other events

Deaths: 0 deaths

Overall

Serious events: 137 serious events

Other events: 277 other events

Deaths: 19 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Induction Phase n=301 participants at risk 1 - 2 cycles; 28 day cycles	Consolidation Phase n=210 participants at risk up to 4 cycles; 28 day cycles	Maintenance Phaase n=93 participants at risk up to 12 cycles; 28 day cycles	Overall n=301 participants at risk Patients from all 3 Phases (Induction, Consolidation and Maintenance).
Blood and lymphatic system disorders Cytopenia	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.9% 4/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.3% 4/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Febrile neutropenia	2.0% 6/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	12.4% 26/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	10.6% 32/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Neutropenia	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Atrial fibrillation	1.3% 4/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.3% 4/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Cardiac arrest	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.95% 2/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Cardiac dysfunction	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Cardiac failure	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Cardio-respiratory arrest	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Cardiopulmonary failure	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Myocardial infarction	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Pericardial effusion	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Pericarditis	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Stress cardiomyopathy	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Tachycardia	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Ventricular dysfunction	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Cardiac disorders Ventricular fibrillation	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Colitis	1.7% 5/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.7% 5/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Diarrhoea	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Enteritis	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Enterocolitis	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Ileus	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Ileus paralytic	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Large intestinal obstruction	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Neutropenic colitis	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Oesophagitis	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Stomatitis	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Subileus	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders General physical health deterioration	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.95% 2/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.00% 3/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders Impaired healing	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders Multiple organ dysfunction syndrome	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders Pyrexia	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.4% 3/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.00% 3/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Hepatobiliary disorders Autoimmune hepatitis	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Hepatobiliary disorders Cholelithiasis	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Hepatobiliary disorders Drug-induced liver injury	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Hepatobiliary disorders Hepatitis cholestatic	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Immune system disorders Hypersensitivity	0.00% 0/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.48% 1/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.33% 1/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.

Other adverse events
Measure	Induction Phase n=301 participants at risk 1 - 2 cycles; 28 day cycles	Consolidation Phase n=210 participants at risk up to 4 cycles; 28 day cycles	Maintenance Phaase n=93 participants at risk up to 12 cycles; 28 day cycles	Overall n=301 participants at risk Patients from all 3 Phases (Induction, Consolidation and Maintenance).
Blood and lymphatic system disorders Anaemia	11.3% 34/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	17.1% 36/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.3% 4/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	17.3% 52/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Febrile neutropenia	22.3% 67/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	21.0% 44/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	29.2% 88/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Neutropenia	11.0% 33/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	23.8% 50/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	12.9% 12/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	23.3% 70/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Blood and lymphatic system disorders Thrombocytopenia	9.0% 27/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	19.0% 40/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.5% 6/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	16.9% 51/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Abdominal pain	8.0% 24/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.2% 11/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	11.3% 34/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Abdominal pain upper	4.7% 14/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.2% 13/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	8.3% 25/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Constipation	10.6% 32/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	19.5% 41/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	2.2% 2/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	21.6% 65/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Diarrhoea	32.2% 97/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	19.0% 40/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	8.6% 8/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	40.2% 121/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Haemorrhoids	5.3% 16/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.8% 10/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	8.3% 25/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Nausea	25.2% 76/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	31.9% 67/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	19.4% 18/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	40.2% 121/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Stomatitis	17.9% 54/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	11.9% 25/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	23.9% 72/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Gastrointestinal disorders Vomiting	18.9% 57/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	15.7% 33/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	22.9% 69/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders Asthenia	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	7.6% 16/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	2.2% 2/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	10.0% 30/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders Oedema peripheral	7.6% 23/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.2% 13/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	12.3% 37/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
General disorders Pyrexia	30.9% 93/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	34.3% 72/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	46.2% 139/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Infections and infestations Device related infection	5.6% 17/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.9% 4/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.3% 19/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Infections and infestations Oral herpes	2.0% 6/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.7% 12/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Infections and infestations Pneumonia	5.3% 16/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.2% 11/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.0% 27/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Infections and infestations Sepsis	3.3% 10/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.8% 10/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Investigations Alanine aminotransferase increased	5.0% 15/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	8.1% 17/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.5% 6/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	10.6% 32/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Investigations Aspartate aminotransferase increased	2.7% 8/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.8% 10/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Investigations Electrocardiogram QT prolonged	6.3% 19/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	2.4% 5/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	8.0% 24/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Investigations Platelet count decreased	2.3% 7/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.2% 11/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.6% 17/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Metabolism and nutrition disorders Hypokalaemia	15.0% 45/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.0% 19/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	19.3% 58/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Musculoskeletal and connective tissue disorders Arthralgia	0.66% 2/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.2% 11/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.3% 16/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Musculoskeletal and connective tissue disorders Back pain	1.3% 4/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.5% 20/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.0% 27/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	3.0% 9/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.8% 8/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.6% 17/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Nervous system disorders Headache	8.0% 24/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	22.4% 47/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	19.6% 59/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Psychiatric disorders Anxiety	2.7% 8/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.2% 11/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.3% 16/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Psychiatric disorders Insomnia	4.7% 14/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	2.4% 5/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Cough	6.6% 20/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.3% 9/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.0% 27/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.3% 16/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	7.6% 16/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.6% 29/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.0% 6/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	5.7% 12/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Skin and subcutaneous tissue disorders Erythema	4.3% 13/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.3% 9/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.6% 20/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Skin and subcutaneous tissue disorders Petechiae	2.3% 7/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.2% 13/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.0% 18/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Skin and subcutaneous tissue disorders Pruritus	2.7% 8/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.7% 14/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	0.00% 0/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.3% 19/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Skin and subcutaneous tissue disorders Rash	12.6% 38/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	13.8% 29/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	3.2% 3/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	21.3% 64/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Vascular disorders Hypertension	5.0% 15/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	4.3% 9/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.5% 6/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	9.3% 28/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Vascular disorders Hypotension	3.3% 10/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	6.7% 14/210 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	1.1% 1/93 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.	8.0% 24/301 • Adverse Events were reported from first dose of study treatment until end of treatment plus 30 days, up to a maximum duration of 25 months (24 months plus 1 month (30 days) post treatment). Adverse Events (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.