Trial Outcomes & Findings for Comparison of Pixantrone + Rituximab With Gemcitabine + Rituximab in Patients With Aggressive B-cell Non-Hodgkin Lymphoma or Follicular Grade 3 Lymphoma Who Have Relapsed After Therapy and Are Not Eligible for Stem Cell Transplant (NCT NCT01321541)

Last Updated: 2021-11-19

Results Overview

PFS is defined as the time of randomization to the date of disease progression or death due to any cause (whichever occurs first)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

312 participants

Primary outcome timeframe

From the date of randomization to the date of progressive disease or death due to any cause (whichever is first reported) (Up to 100 weeks)

Results posted on

2021-11-19

Participant Flow

Participant milestones

Participant milestones
Measure	Pixantrone + Rituximab Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Overall Study STARTED	155	157
Overall Study COMPLETED	72	61
Overall Study NOT COMPLETED	83	96

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Comparison of Pixantrone + Rituximab With Gemcitabine + Rituximab in Patients With Aggressive B-cell Non-Hodgkin Lymphoma or Follicular Grade 3 Lymphoma Who Have Relapsed After Therapy and Are Not Eligible for Stem Cell Transplant

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pixantrone + Rituximab n=155 Participants Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=157 Participants Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Total n=312 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	36 Participants n=5 Participants	30 Participants n=7 Participants	66 Participants n=5 Participants
Age, Categorical >=65 years	119 Participants n=5 Participants	127 Participants n=7 Participants	246 Participants n=5 Participants
Sex: Female, Male Female	86 Participants n=5 Participants	90 Participants n=7 Participants	176 Participants n=5 Participants
Sex: Female, Male Male	69 Participants n=5 Participants	67 Participants n=7 Participants	136 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) White	147 Participants n=5 Participants	155 Participants n=7 Participants	302 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
IPI Score IPI Score 0-2	73 Participants n=5 Participants	73 Participants n=7 Participants	146 Participants n=5 Participants
IPI Score IPI Score 3 or more	82 Participants n=5 Participants	84 Participants n=7 Participants	166 Participants n=5 Participants
Ann Arbor Stage I-III	81 Participants n=5 Participants	76 Participants n=7 Participants	157 Participants n=5 Participants
Ann Arbor Stage IV	74 Participants n=5 Participants	81 Participants n=7 Participants	155 Participants n=5 Participants
Number ofprior lines of therapy 0-2	137 Participants n=5 Participants	139 Participants n=7 Participants	276 Participants n=5 Participants
Number ofprior lines of therapy 3 or more	18 Participants n=5 Participants	18 Participants n=7 Participants	36 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the date of randomization to the date of progressive disease or death due to any cause (whichever is first reported) (Up to 100 weeks)

PFS is defined as the time of randomization to the date of disease progression or death due to any cause (whichever occurs first)

Outcome measures

Outcome measures
Measure	Pixantrone + Rituximab n=155 Participants Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=157 Participants Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Progression Free Survival (PFS)	7.3 Months Interval 5.2 to 8.4	6.3 Months Interval 4.4 to 8.1

SECONDARY outcome

Timeframe: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)

Overall survival is from randomization to death due to any cause

Outcome measures

Outcome measures
Measure	Pixantrone + Rituximab n=155 Participants Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=157 Participants Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Overall Survival	13.3 Months Interval 10.1 to 19.8	19.6 Months Interval 12.4 to 31.9

SECONDARY outcome

Timeframe: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)

CRR is defined as the proportion of patients who achieve a Complete Response (CR) without additional therapy. CR is defined as the disappearance of all target lesions.

Outcome measures

Outcome measures
Measure	Pixantrone + Rituximab n=155 Participants Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=157 Participants Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Complete Response Rate	55 Participants	34 Participants

SECONDARY outcome

Timeframe: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)

ORR is defined as the proportion of patients who achieve a CR or PR without additional therapy.

Outcome measures

Outcome measures
Measure	Pixantrone + Rituximab n=155 Participants Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=157 Participants Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Overall Response Rate	61.9 percentage of patients Interval 53.8 to 69.6	43.9 percentage of patients Interval 36.0 to 52.1

SECONDARY outcome

Timeframe: From date of randomization to the date of the patient's death due to any cause (Up to 100 weeks)

Population: Safety Population

The number of Participants with Treatment Emergent Adverse Events (TEAE) related to study drug (pixantrone or gemcitabine)

Outcome measures

Outcome measures
Measure	Pixantrone + Rituximab n=153 Participants Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=146 Participants Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Number of Treatment Emergent Adverse Events (TEAE) Related to Study Drug	140 Participants	140 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: within 1 hour of initiation of infusion to 24-48 hours after start of pixantrone infusion

To characterize the PK profile of pixantrone when co-administered with rituximab. Plasma samples for PK analysis will be collected relative to the D-1 dose of pixantrone in one of the 6 treatment cycles for each participating patient. The goal is to enroll approx. 20 patients, active at 20 sites- Beatson West of Scotland Cancer Center, Uni. Hospital Kralovske Vinohrady, Uni. Hospital Hradec Kralove Hematooncology, Hospital Nuernberg, St. Marien Hospital Hamm, Puerta del Mar Hospital, Tokuda Hospital Sofia, National Center of Hematology \& Transfusiology, UMHAT "SV. IVAN RILSKI", Moritz Kaposi General Hospital, Uni. of Debrecen, Polish Red Cross Marine Hospital, Kharkiv Regional Clinical Oncology Center, National Inst. of Cancer Ukraine, Cherkasy Regional Oncology Center, Inst. of Blood Pathology \& Transfusion Medicine, Uni. Hospital Martin, National Onclogy Inst., Uni. Hospital with Outpatient Clinic F.D. Roosevelt Banska Bystrica, Uni. Hospital J.A. Reiman Presov

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: within 1 hour of initiation of infusion to 24-48 hours after start of pixantrone infusion

Outcome measures

Outcome data not reported

Adverse Events

Pixantrone + Rituximab

Serious events: 59 serious events

Other events: 153 other events

Deaths: 12 deaths

Gemcitabine + Rituximab

Serious events: 57 serious events

Other events: 148 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Anton Egorov, Associate Project Director Clinical Development

Institut de Recherches Internationales Servier

Phone: +33 1 55 72 31 94

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Pixantrone + Rituximab n=153 participants at risk Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=149 participants at risk Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Infections and infestations Pneumonia	5.2% 8/153 • Number of events 8 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.7% 4/149 • Number of events 4 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Sepsis	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Septic shock	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Urinary tract infection	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Staphylococcal bacteremia	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Cellulitis	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Erysipelas	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Upper respiratory tract infection	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Anemia	3.3% 5/153 • Number of events 5 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	5.4% 8/149 • Number of events 8 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Febrile neutropenia	3.3% 5/153 • Number of events 5 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Thrombocytopenia	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Cardiac disorders Cardiac failure	2.0% 3/153 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Cardiac disorders Atrial fibrillation	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Cardiac disorders Cytotoxic cardiomyopathy	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Cardiac disorders Supraventricular tachycardia	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Cardiac disorders Cardiac failure acute	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Cardiac disorders Cardiac failure congestive	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Pyrexia	2.6% 4/153 • Number of events 4 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	5.4% 8/149 • Number of events 8 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Asthenia	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Chest pain	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Generalized edema	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Respiratory, thoracic and mediastinal disorders Dyspnea	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Diarrhea	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Nausea	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	2.0% 3/153 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Nervous system disorders Syncope	2.0% 3/153 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Renal and urinary disorders Hematuria	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Renal and urinary disorders Renal failure acute	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Renal and urinary disorders Hydronephrosis	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Metabolism and nutrition disorders Dehydration	1.3% 2/153 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Catheter related infection	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Infection	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Neutropenic sepsis	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Pleural infection	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Pneumonia bacterial	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Staphylococcal infection	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Staphylococcal sepsis	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Urinary tract infection bacterial	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.00% 0/149 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations

Other adverse events
Measure	Pixantrone + Rituximab n=153 participants at risk Pixantrone and Rituximab Pixantrone + Rituximab: Pixantrone + Rituximab: Rituximab 375 mg/m2 IV on day 1 and pixantrone 50 mg/m2 (equivalent to 85mg/m2 pixantrone dimaleate)IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.	Gemcitabine + Rituximab n=149 participants at risk Gemcitabine and Rituximab Gemcitabine + Rituximab: Gemcitabine + Rituximab: Rituximab 375 mg/m2 IV on day 1 and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15. Regimen is given in 28-day cycles. Up to 6 cycles may be administered.
Blood and lymphatic system disorders Neutropenia	68.6% 105/153 • Number of events 105 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	58.4% 87/149 • Number of events 87 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Anaemia	24.2% 37/153 • Number of events 37 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	45.0% 67/149 • Number of events 67 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Thrombocytopenia	15.0% 23/153 • Number of events 23 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	63.8% 95/149 • Number of events 95 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Leukopenia	7.8% 12/153 • Number of events 12 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	12.8% 19/149 • Number of events 19 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Blood and lymphatic system disorders Lymphopenia	6.5% 10/153 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	3.4% 5/149 • Number of events 5 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Fatigue	29.4% 45/153 • Number of events 45 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	22.8% 34/149 • Number of events 34 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Pyrexia	13.1% 20/153 • Number of events 20 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	20.1% 30/149 • Number of events 30 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Asthenia	13.1% 20/153 • Number of events 20 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	12.1% 18/149 • Number of events 18 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Oedema peripheral	12.4% 19/153 • Number of events 19 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	20.1% 30/149 • Number of events 30 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
General disorders Chills	7.2% 11/153 • Number of events 11 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.7% 10/149 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Nausea	24.8% 38/153 • Number of events 38 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	14.8% 22/149 • Number of events 22 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Constipation	22.9% 35/153 • Number of events 35 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	13.4% 20/149 • Number of events 20 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Diarrhoea	15.0% 23/153 • Number of events 23 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	12.8% 19/149 • Number of events 19 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Vomiting	13.7% 21/153 • Number of events 21 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	11.4% 17/149 • Number of events 17 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Stomatitis	10.5% 16/153 • Number of events 16 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.7% 10/149 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Gastrointestinal disorders Abdominal pain	4.6% 7/153 • Number of events 7 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	7.4% 11/149 • Number of events 11 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Skin and subcutaneous tissue disorders Alopecia	19.0% 29/153 • Number of events 29 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	1.3% 2/149 • Number of events 2 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Skin and subcutaneous tissue disorders Skin discolouration	9.8% 15/153 • Number of events 15 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Skin and subcutaneous tissue disorders Rash	3.3% 5/153 • Number of events 5 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	9.4% 14/149 • Number of events 14 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Upper respiratory tract infection	8.5% 13/153 • Number of events 13 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.7% 10/149 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Pneumonia	6.5% 10/153 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.0% 9/149 • Number of events 9 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Infections and infestations Urinary tract infection	5.9% 9/153 • Number of events 9 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	8.1% 12/149 • Number of events 12 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Metabolism and nutrition disorders Anorexia	18.3% 28/153 • Number of events 28 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	10.7% 16/149 • Number of events 16 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Metabolism and nutrition disorders Hypokalaemia	9.2% 14/153 • Number of events 14 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	7.4% 11/149 • Number of events 11 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Metabolism and nutrition disorders Hypomagnesaemia	6.5% 10/153 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	4.0% 6/149 • Number of events 6 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Metabolism and nutrition disorders Dehydration	5.2% 8/153 • Number of events 8 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.7% 4/149 • Number of events 4 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Metabolism and nutrition disorders Hyperuricaemia	2.0% 3/153 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.0% 9/149 • Number of events 9 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.8% 18/153 • Number of events 18 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	8.1% 12/149 • Number of events 12 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Respiratory, thoracic and mediastinal disorders Cough	12.4% 19/153 • Number of events 19 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	12.8% 19/149 • Number of events 19 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Nervous system disorders Dizziness	9.8% 15/153 • Number of events 15 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	4.7% 7/149 • Number of events 7 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Nervous system disorders Headache	7.8% 12/153 • Number of events 12 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	4.0% 6/149 • Number of events 6 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Nervous system disorders Dysgeusia	7.2% 11/153 • Number of events 11 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.0% 3/149 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Investigations Weight decreased	7.8% 12/153 • Number of events 12 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.7% 4/149 • Number of events 4 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Investigations Ejection fraction decreased	5.2% 8/153 • Number of events 8 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	0.67% 1/149 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Investigations Blood creatinine increased	2.0% 3/153 • Number of events 3 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.7% 10/149 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Investigations Platelet count decreased	0.65% 1/153 • Number of events 1 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.0% 9/149 • Number of events 9 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Investigations Alanine aminotransferase increased	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.0% 9/149 • Number of events 9 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Investigations Aspartate aminotransferase increased	0.00% 0/153 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.0% 9/149 • Number of events 9 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Musculoskeletal and connective tissue disorders Arthralgia	8.5% 13/153 • Number of events 13 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	2.7% 4/149 • Number of events 4 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations
Musculoskeletal and connective tissue disorders Back pain	7.8% 12/153 • Number of events 12 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations	6.7% 10/149 • Number of events 10 • From the time of Informed Consent until 30 days after the last dose of study treatment. (Up to 100 weeks) Safety will be assessed by monitoring and recording adverse events, serious adverse events, cardiac, hematologic and blood chemistry parameters, vital signs, performance status, and any abnormal findings observed on physical examinations