Trial Outcomes & Findings for First in Human Testing of Dose-escalation of SAR440234 in Patients With Acute Myeloid Leukemia, Acute Lymphoid Leukemia and Myelodysplastic Syndrome (NCT NCT03594955)

Last Updated: 2022-05-24

Results Overview

DLTs: occurrence of any of following related to investigational medicinal product (IMP): Any grade (G) greater than or equal to (\>=) 3 nonhematological adverse events (AE); G4 hematological toxicities (bone marrow hypocellularity, decreased neutrophils, febrile neutropenia, decreased platelet count and anemia) as defined in national cancer institute common terminology criteria for adverse events (NCI-CTCAE, v4.03); G3 or G4 cytokine release syndrome (CRS) (G1: fever, nausea, fatigue, headache, myalgias and malaise; G2: oxygen requirement less than \[\<\] 40 percent (%); G3: oxygen requirement greater than \[\>\] 40% ; G4: life-threatening symptoms, requirement for mechanical ventilation, organ toxicity, G5: death) graded by NCI Consensus Guidelines; Grade 2 CRS for \>48 hours or \<48 hours before IMP; any treatment-emergent AE of potential significance and IMP-related adverse reaction lasted \>2 weeks with failure to recover to baseline or improve to Grade less than or equal to (\<=1).

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

7 participants

Primary outcome timeframe

Cycle 1 (42 days)

Results posted on

2022-05-24

Participant Flow

Study was conducted at 4 sites in France and the United States. A total of 12 participants were screened, of whom 5 participants were screen failures, mainly due to not meeting inclusion criteria. A total of 7 participants were enrolled and treated in Dose Escalation Part before termination of study.

Study consisted of 2 parts: Dose Escalation and Expansion. Enrollment of participants in Dose Expansion Part was planned to start after completion of Dose Escalation Part. Due to early termination of study, Dose Expansion Part was not conducted.

Participant milestones

Participant milestones
Measure	SAR440234 SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Overall Study STARTED	7
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Reasons for withdrawal
Measure	SAR440234 SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Overall Study Adverse Event	1
Overall Study Progressive disease	5
Overall Study Sponsor's decision	1

Baseline Characteristics

First in Human Testing of Dose-escalation of SAR440234 in Patients With Acute Myeloid Leukemia, Acute Lymphoid Leukemia and Myelodysplastic Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SAR440234 n=7 Participants SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Age, Continuous	68.0 years STANDARD_DEVIATION 10.4 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 (42 days)

Population: Analysis was performed on dose-limiting toxicities (DLT) evaluable population which included all participants in dose escalation part, who received at least 5 out of 6, weekly IV administrations of SAR440234 and participants who discontinued IMP before completion of Cycle 1 because of DLT.

Outcome measures

Outcome measures
Measure	SAR440234 n=7 Participants SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Dose Escalation Part: Number of Participants With Dose Limiting Toxicities (DLTs)	1 Participants

PRIMARY outcome

Timeframe: First IMP administration (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)

Population: Analysis was performed on safety population.

In this outcome measure, number of participants with allergic reactions or hypersensitivity and CRS or acute infusion reactions is reported. CRS is a nonantigen specific toxicity that occurs as result of potent immune activation mediated by large, rapid release of cytokines into blood from immune cells affected by IMP. Grading and management of CRS was based on National Cancer Institute (NCI) Consensus Guidelines 2014. Allergic/Hypersensitivity reactions or acute infusion reactions are defined as disorder characterized by adverse local/general response from exposure to allergen; graded by NCI CTCAE v4.03.

Outcome measures

Outcome measures
Measure	SAR440234 n=7 Participants SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Dose Escalation Part: Number of Participants With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions	2 Participants

PRIMARY outcome

Timeframe: From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)

Population: Due to the early termination of the study, data for this outcome measure was not collected and analyzed.

Response: assessed by IWG 2003 recommendations for acute myeloid leukemia (AML) and revised 2000 criteria for myelodysplastic syndrome (MDS). MDS - OR: complete remission (CR)/marrow CR/partial remission (PR), CR: repeat bone marrow show \<5% myeloblasts and peripheral blood evaluations lasting \>=2 months hemoglobin (\>11 grams per deciliter), neutrophils 1500 per cubic millimeter (mm\^3), platelets \>=100000/mm\^3, blasts 0% and no dysplasia, PR: all CR criteria except blasts decreased by \>=50% over pretreatment or less advanced than pretreatment. AML - OR:CR/CR with incomplete hematological recovery(CRi)/PR, CR:absolute neutrophil count (ANC) \>=1000 per microliter (mcL), platelets \>=100000/mcL, \<5% blast cells in bone marrow; auer rods should not be detectable; no platelet/whole blood transfusions for 7 days prior hematology test. CRi:all criteria of CR except platelets and/or ANC. PR:all CR criteria except blasts decreased by \>=50% over pretreatment or less advanced than pretreatment.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: From 1st documentation of response to date of first documentation of disease progression or death, whichever came earlier (up to 42 days)

Population: Due to the early termination of the study, data for this outcome measure was not collected and analyzed.

DOR: time from first tumor assessment at which the overall response was recorded as CR, marrow CR, or PR (MDS) and CR/CRi (AML) until documented progressive disease (PD) determined by IWG criteria, or death from any cause, whichever occurred first. Per IWG criteria, relapse was defined as reappearance of blasts in blood or bone marrow (\>5%) or in any extramedullary site after a CR. CR:\<= 5% myeloblasts in bone marrow with no evidence of persistent dysplasia; peripheral blood showing hemoglobin\>=11g/dL. Marrow CR: no circulating blasts, \<5% blast, absolute neutrophil count \>1000/mcL, platelets \>100000/mcL, no recurrence for 4 weeks. CRi: meet all criteria for CR except platelet count and/or ANC. PR: all CR criteria except blasts decreased by \>=50% over pretreatment or less advanced than pretreatment. Progression: at least 50% decrease from maximum remission/response in granulocytes/platelets; reduction in Hgb by \>=2 g/dL; transfusion dependence.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: First IMP administration to date of first documentation of disease progression or relapse or death, whichever came earlier (up to 42 days)

Population: Due to the early termination of the study, data for this outcome measure was not collected and analyzed.

Disease-free survival was defined as the time from date of first administration of study intervention until the earliest of any of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response whichever occurred first.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)

Population: Analysis was performed on safety population.

An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious AEs (SAEs) were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as the AEs that developed or worsened or became serious during the TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days).

Outcome measures

Outcome measures
Measure	SAR440234 n=7 Participants SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Dose Escalation Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Any TEAE	7 Participants
Dose Escalation Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Any TESAE	6 Participants

SECONDARY outcome

Timeframe: From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)

Population: Due to the early termination of the study, data for this outcome measure was not collected and analyzed.

Objective response was defined as the percentage of participants who had a marrow CR, or PR (MDS) and CR/CRi (AML) per IWG criteria. For MDS, CR: repeat bone marrow show \<5% myeloblasts and peripheral blood evaluations lasting \>=2 months of hemoglobin (\>11 g/dL), neutrophils 1500/mm\^3, platelets \>=100000/mm\^3, blasts 0% and no dysplasia, PR: all CR criteria except blasts decreased by \>=50% over pretreatment or less advanced than pretreatment. For AML, CR: ANC \>=1000/mcL, platelet count \>=100000/mcL, bone marrow should contain \<5% blast cells; auer rods should not be detectable; no platelet/whole blood transfusions for 7 days prior to date of hematology assessment. CRi: morphologic complete remission but ANC count might be \<1000/mcL or platelet \<100000/mcL.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)

Population: Analysis was performed on ADA population which included all participants who had given their informed consent, had received at least 1 dose (even incomplete) of SAR440234 and had at least 1 available ADA result after IMP administration.

ADA response categories: 1) Treatment-induced ADA: Participants without pre-existing ADA and without pre-treatment samples and who developed ADAs during the TEAE period. 2) Treatment-boosted ADA: Participant with pre-existing ADAs that was increased at least a 4-fold in titer compared to Baseline during the TEAE period. 2) Treatment-emergent ADA: Participants with at least one treatment-induced/boosted ADA sample. TEAE period was defined as the time from the first dose of the IMP to the last dose of the IMP + 30 days.

Outcome measures

Outcome measures
Measure	SAR440234 n=7 Participants SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Immunogenicity: Number of Participants With Treatment-Emergent Anti-drug Antibodies (ADA) Response	1 Participants

SECONDARY outcome

Timeframe: Cycle 1: D 1: SOI, EOI, 1, 2, 5, 7, 24, 48, 72 H post EOI; D 8: SOI, MOI, EOI, 2, 5, 168 H post EOI; D 15: MOI, EOI, 2, 5, 24 H post EOI; D 22: SOI, MOI, EOI, 2, 5, 24, 48, 72, 96, 168 H post EOI; D 29: EOI, 2 H post EOI; D 36: SOI, EOI, 2 H post EOI

Population: Analyzed on PK population which included participants who had given their informed consent and had received at least one dose (even incomplete) of SAR440234 with at least 1 evaluable drug concentration after IMP administration. Here, number analyzed = participants with available data for each specified category.

Cmax was the maximum observed plasma concentration. Cmax was obtained by a non-compartmental analysis. Here in the time frame, Day = D, start of infusion = SOI, mid of infusion = MOI, end of infusion = EOI and hours = H.

Outcome measures

Outcome measures
Measure	SAR440234 n=7 Participants SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 Cycle 1 Day 1	64.7 picograms per milliliter Standard Deviation 171
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 Cycle 1 Day 8	NA picograms per milliliter Standard Deviation NA Mean and standard deviation (SD) were not estimable as no participant had plasma concentration greater than lower limit of quantification.
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 Cycle 1 Day 15	99.1 picograms per milliliter Standard Deviation 115
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 Cycle 1 Day 22	57.1 picograms per milliliter Standard Deviation 22.6
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 Cycle 1 Day 29	74.5 picograms per milliliter Standard Deviation 90.3
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 Cycle 1 Day 36	70.4 picograms per milliliter

Adverse Events

SAR440234

Serious events: 6 serious events

Other events: 7 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	SAR440234 n=7 participants at risk SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Investigations Alanine Aminotransferase Increased	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Blood and lymphatic system disorders Febrile Neutropenia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Blood and lymphatic system disorders Thrombocytopenia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Vomiting	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Infections and infestations Perirectal Abscess	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Infections and infestations Pneumonia Moraxella	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Vascular disorders Hypotension	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Immune system disorders Cytokine Release Syndrome	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Disease Progression	42.9% 3/7 • Number of events 3 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Pyrexia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.

Other adverse events

Other adverse events
Measure	SAR440234 n=7 participants at risk SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Injury, poisoning and procedural complications Infusion Related Reaction	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Investigations Alanine Aminotransferase Increased	28.6% 2/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Investigations Blood Alkaline Phosphatase Increased	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Blood and lymphatic system disorders Febrile Neutropenia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Blood and lymphatic system disorders Pancytopenia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Blood and lymphatic system disorders Thrombocytopenia	14.3% 1/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Nervous system disorders Dizziness	28.6% 2/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Nervous system disorders Headache	28.6% 2/7 • Number of events 5 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Ear and labyrinth disorders Deafness	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Abdominal Pain	28.6% 2/7 • Number of events 3 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Constipation	42.9% 3/7 • Number of events 3 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Diarrhoea	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Gastrointestinal Haemorrhage	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Gingival Bleeding	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Gingival Hypertrophy	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Nausea	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Odynophagia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Oral Disorder	14.3% 1/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Gastrointestinal disorders Proctalgia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Renal and urinary disorders Micturition Urgency	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Dry Skin	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Ecchymosis	14.3% 1/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Erythema	28.6% 2/7 • Number of events 4 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Pruritus	28.6% 2/7 • Number of events 3 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Purpura	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Back Pain	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Bone Pain	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Pain In Extremity	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Metabolism and nutrition disorders Decreased Appetite	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Metabolism and nutrition disorders Hypertriglyceridaemia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Metabolism and nutrition disorders Hypo Hdl Cholesterolaemia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Metabolism and nutrition disorders Hypocalcaemia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Metabolism and nutrition disorders Hypophosphataemia	28.6% 2/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Infections and infestations Oral Candidiasis	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Infections and infestations Staphylococcal Bacteraemia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Infections and infestations Urinary Tract Infection	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Vascular disorders Deep Vein Thrombosis	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Vascular disorders Haematoma	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Immune system disorders Cytokine Release Syndrome	28.6% 2/7 • Number of events 2 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Asthenia	42.9% 3/7 • Number of events 3 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Chest Discomfort	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Chills	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Fatigue	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Gait Disturbance	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Oedema Peripheral	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Pyrexia	28.6% 2/7 • Number of events 5 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
General disorders Tenderness	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Psychiatric disorders Insomnia	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Epistaxis	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Pulmonary Mass	14.3% 1/7 • Number of events 1 • From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days) Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.

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