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Clinical Trial Results:
Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Isatuximab Used in Combination With Chemotherapy in Pediatric Patients From 28 Days to Less Than 18 Years of Age With Relapsed/Refractory B or T Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia In First or Second Relapse

Summary
EudraCT number	2018-002697-45
Trial protocol	SE NO FI DK FR NL PT BE DE CZ GR Outside EU/EEA IT
Global end of trial date	26 May 2023

Results information
Results version number	v1
This version publication date	02 Dec 2023
First version publication date	02 Dec 2023
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ACT15378

ISRCTN number

US NCT number

NCT03860844

WHO universal trial number (UTN)

U1111-1202-1096

Sponsor organisation name

Sanofi aventis recherche & développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002205-PIP01-17

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 May 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 May 2023

Was the trial ended prematurely?

Main objective of the trial

To evaluate the anti-leukemic activity of isatuximab in combination with chemotherapies in pediatric participants of 28 days to less than 18 years of age with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL) or Acute Myeloid Leukemia (AML).

Protection of trial subjects

The study was conducted by investigators experienced in the treatment of pediatric participants. The parent (s) or guardian (s) as well as children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Aug 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Mexico: 3

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Norway: 3

Country: Number of subjects enrolled

Peru: 2

Country: Number of subjects enrolled

Portugal: 4

Country: Number of subjects enrolled

Sweden: 2

Country: Number of subjects enrolled

United States: 2

Country: Number of subjects enrolled

Denmark: 4

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Greece: 2

Country: Number of subjects enrolled

Hungary: 1

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Argentina: 7

Country: Number of subjects enrolled

Brazil: 12

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This Phase II, open-label, single-arm study was conducted in 3 separate cohorts at 41 investigational sites in 16 countries. A total of 67 participants were enrolled between 06 Aug 2019 and 08 Jun 2022.

Screening details

The study consisted of a screening period (up to 3 weeks prior to the first study treatment administration), treatment period (Day 1 to Day 57 for ALL; Day 1 to Day 22 for AML), a period of aplasia followed by recovery period; an end of treatment (EOT) visit within 30 days after hematological recovery and follow-up period.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Arm description

Participants with B-ALL received isatuximab 20 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and every 2 weeks (Q2W) during the consolidation period (i.e., on Days 29, 43, and 57). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Isatuximab was administered as 20 mg/kg weekly on Days 1, 8, 15, 22, 29, 43, and 57.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Dexamethasone was administered before each administration of isatuximab, at least 15 to 30 minutes (but no longer than 60 minutes) prior to infusion as premedication for prevention of infusion associated reactions consisting of dexamethasone 10 mg/meter square (m^2) (maximum 20 mg) IV or orally (PO) on Days -3, -2, and -1 before isatuximab administration, Days 1, 8, 15 to 19, 22, and 29 to 33 during the induction period, and on Days 43 to 47 and 57 during the consolidation period.

Investigational medicinal product name

Mitoxantrone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Mitoxantrone was administered as 10 mg/m^2 IV over 15 minutes on Days 8 and 9 of the induction period.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin was administered as 25 mg/m^2 IV over 15 minutes on Days 10, 17, 24, and 31 of the induction period.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Vincristine was administered as 1.5 mg/m^2 IV on Days 10, 17, 24, and 31 during the induction period (not exceeding 2 mg per infusion in any participant) and on Day 38 during the consolidation period.

Investigational medicinal product name

Pegaspargase

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use, Intravenous use

Dosage and administration details

Pegaspargase was administered as 1000 International units (IU)/m^2 on Days 10 and 24 during the induction period and Day 44 during the consolidation period.

Investigational medicinal product name

L-asparaginase

Investigational medicinal product code

Other name

Erwinase

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use, Intravenous use

Dosage and administration details

L-asparaginase was administered as 25000 IU/m^2 on Days 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 during induction and days 43, 45, 47, 50, 52, 54 during consolidation, only in case of confirmed hypersensitivity reaction to pegaspargase prior or during the study or loss of asparaginase activity and/or country availability and regulations.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 440 mg/m^2 was administered as a 1-hour infusion on Days 50 to 54 (inclusive) during the consolidation period.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Etoposide 100 mg/m^2 was administered as a 2-hour infusion on Days 50 to 54 (inclusive) during the consolidation period.

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Methotrexate 1000 mg/m^2 was infused over 36 hours and calcium folinate rescue started 48 hours from start of infusion on Day 43 during the consolidation period.

T-cell Acute Lymphoblastic Leukemia (T-ALL)

Arm description

Participants with T-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Isatuximab was administered as 20 mg/kg weekly on Days 1, 8, 15, 22, 29, 43, and 57.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Dexamethasone was administered before each administration of isatuximab, at least 15 to 30 minutes (but no longer than 60 minutes) prior to infusion as premedication for prevention of infusion associated reactions consisting of dexamethasone 10 mg/m^2 (maximum 20 mg) IV or PO on Days -3, -2, and -1 before isatuximab administration, Days 1, 8, 15 to 19, 22, and 29 to 33 during the induction period, and on Days 43 to 47 and 57 during the consolidation period.

Investigational medicinal product name

Mitoxantrone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Mitoxantrone was administered as 10 mg/m^2 IV over 15 minutes on Days 8 and 9 of the induction period.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin was administered as 25 mg/m^2 IV over 15 minutes on Days 10, 17, 24, and 31 of the induction period.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Pegaspargase

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use, Intravenous use

Dosage and administration details

Pegaspargase was administered as 1000 IU/m^2 on Days 10 and 24 during the induction period and Day 44 during the consolidation period.

Investigational medicinal product name

L-asparaginase

Investigational medicinal product code

Other name

Erwinase

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use, Intravenous use

Dosage and administration details

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 440 mg/m^2 was administered as a 1-hour infusion on Days 50 to 54 (inclusive) during the consolidation period.

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Methotrexate 1000 mg/m^2 was infused over 36 hours and calcium folinate rescue started 48 hours from start of infusion on Day 43 during the consolidation period.

Acute Myeloid Leukemia (AML)

Arm description

Participants with AML received isatuximab 20 mg/kg IV infusion on Days 1, 8, and 15 of each Cycle (up to 2 treatment cycles, each cycle 28 days). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Isatuximab was administered as 20 mg/kg weekly on Days 1, 8, 15 (mandatory for Cycles 1 and 2).

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Solution for injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Dexamethasone was administered as a premedication for prevention of infusion associated reactions before each administration of isatuximab, at least 15 to 30 minutes (but no longer than 60 minutes) prior to infusion consisting of dexamethasone 10 mg/m^2 (maximum 20 mg) IV or PO on Days 1, 8, and 15 during the induction period (mandatory for Cycle 1 and before first isatuximab infusion Cycle 2). It was optionally used for rapid control of tumor burden on Days -3, -2 and -1. When dexamethasone was administered at 10 mg/m^2 orally, it could have been divided in 2 daily doses.

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Fludarabine 30 mg/m^2 IV was administered as 30-minute infusion after granulocyte colony-stimulating factor (G-CSF) administration, if any on Days 8 to 12 (inclusive) (mandatory for Cycles 1 and 2).

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Cytarabine 2 gram (g)/m^2 was administered as a 4-hour infusion, beginning 4 hours after start of fludarabine on Days 8 to 12 (inclusive) (mandatory for Cycles 1 and 2)

Investigational medicinal product name

Anthracycline

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Anthracycline (a choice of liposomal daunorubicin 60 mg/m^2, non-liposomal daunorubicin 60 mg/m^2, or idarubicin 10 mg/m^2) was given after administration of fludarabine. Anthracycline administration on Day 8 in Cycle 1 was mandatory. Administrations on Cycle 1 Days 10 and 12 and on Cycle 2 were at the Investigator’s discretion.

Investigational medicinal product name

Filgrastim

Investigational medicinal product code

Other name

Granulocyte colony-stimulating factor

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Filgrastim (optional for Cycles 1 and 2) was administered as 200 microgram/m^2/day on Days 7 to 12 (inclusive) and was continued until neutrophil recovery.

Number of subjects in period 1	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Started	27	13	27
Completed	19	7	20
Not completed	8	6	7
Other, Not related to COVID-19	-	1	-
Adverse event, unrelated to Coronavirus Disease-19	3	2	3
Progressive disease	5	3	4

Baseline characteristics

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Reporting group title

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Reporting group description

Reporting group title

T-cell Acute Lymphoblastic Leukemia (T-ALL)

Reporting group description

Reporting group title

Acute Myeloid Leukemia (AML)

Reporting group description

Reporting group values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)	Total
Number of subjects	27	13	27	67
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	8.22 ( 3.92 )	8.72 ( 4.15 )	9.04 ( 5.41 )	-
Gender categorical
Units: Subjects
Female	10	4	12	26
Male	17	9	15	41
Race
Units: Subjects
American Indian or Alaska Native	3	0	0	3
Asian	1	1	4	6
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	1	1	2	4
White	17	7	15	39
More than one race	1	0	0	1
Unknown or Not Reported	4	4	6	14

End points

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Reporting group title

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Reporting group description

Reporting group title

T-cell Acute Lymphoblastic Leukemia (T-ALL)

Reporting group description

Reporting group title

Acute Myeloid Leukemia (AML)

Reporting group description

Primary: Percentage of Participants With Complete Response (CR) Rate

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End point title

Percentage of Participants With Complete Response (CR) Rate ^[1]

End point description

The CR rate (CR+CRi [CR with incomplete peripheral recovery]): % of participants achieving CR assessed by investigator per National Comprehensive Cancer Network (NCCN) guidelines version 1.2018 criteria. CR:<5% blasts in bone marrow aspirate (BMA)with spicules;no circulating blasts(ALL)/no blasts with Auer rods(AML)or extramedullary disease,no lymphadenopathy, splenomegaly,skin/gum infiltration/testicular mass/central nervous system involvement(ALL),trilineage hematopoiesis(ALL);Absolute neutrophil count(ANC)>=1000/microliter (mcL);platelets >100000/mcL;red blood cell transfusion independence.If physician documented transfusion dependency related to study treatment;not participant’s underlying disease, CRi was reported.CRi=CR, except neutrophils (<1000/mcL) and/or platelets recovery(<100000/mcL). Evaluable population(EP):Evaluable participants from All-treated (AT) population who received atleast 1 full dose of isatuximab in Cycle 1 and who had atleast 1 valid response value evaluable

End point type

Primary

End point timeframe

From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	25	11	23
Units: percentage of participants
number (not applicable)	52.0	45.5	60.9

No statistical analyses for this end point

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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End point title

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

End point description

An AE was defined as any untoward medical occurrence in a participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. SAEs were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as an AE which occurred after the first dose of study treatment administration until the last dose plus 30 days, or until the start of hematological recovery period or a new anti-leukemia/lymphoma therapy, whichever occurred first. The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.

End point type

Secondary

End point timeframe

From the time of the first treatment administration (Day 1) up to 30 days after the last treatment (maximum duration of exposure of 13.1 weeks for B-ALL cohort, 10.7 weeks for T-ALL cohort and 7.1 weeks for AML cohort)

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	27	13	27
Units: participants
number (not applicable)
Any TEAEs	27	13	26
Any TESAEs	19	12	17

No statistical analyses for this end point

Secondary: Number of Participants With Infusion Reactions (IRs)

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End point title

Number of Participants With Infusion Reactions (IRs)

End point description

An IR was an AE related to isatuximab typically with onset within 24 hours from the start of the isatuximab infusion and was reported by the investigator. The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.

End point type

Secondary

End point timeframe

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	27	13	27
Units: participants
number (not applicable)	9	5	15

No statistical analyses for this end point

Secondary: B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab

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End point title

B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab ^[2]

End point description

Plasma samples were collected at specified timepoints to determine the AUC of isatuximab. The Pharmacokinetic (PK) population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed.

End point type

Secondary

End point timeframe

From Week 0 to Week 1, Week 0 to Week 5, and Week 0 to Week 10

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from B-ALL and T-ALL cohort were included in this endpoint.

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)
Number of subjects analysed	27	12
Units: mg*hour (h)/Liter (L)
arithmetic mean (standard deviation)
Week 0 to Week 1	31703 ( 10048 )	29057 ( 8294 )
Week 0 to Week 5	299071 ( 127581 )	289167 ( 93095 )
Week 0 to Week 10	582686 ( 316749 )	540375 ( 233411 )

No statistical analyses for this end point

Secondary: AML: AUC of Isatuximab

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End point title

AML: AUC of Isatuximab ^[3]

End point description

Plasma samples were collected at specified timepoints to determine the AUC of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed.

End point type

Secondary

End point timeframe

From Week 0 to Week 1, Week 0 to Week 3, and Week 0 to Week 8

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from AML cohort were included in this endpoint.

End point values	Acute Myeloid Leukemia (AML)
Number of subjects analysed	26
Units: mg*h/L
arithmetic mean (standard deviation)
Week 0 to Week 1	28592 ( 6858 )
Week 0 to Week 3	130862 ( 40827 )
Week 0 to Week 8	291962 ( 112222 )

No statistical analyses for this end point

Secondary: B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

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End point title

B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) ^[4]

End point description

Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed and are denoted by 'n' in the categories. 99999= Standard deviation (SD) could not be derived for a single participant.

End point type

Secondary

End point timeframe

Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 1 Day 29, Cycle 2 Day 43, Cycle 2 Day 57

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from B-ALL and T-ALL cohort were included in this endpoint.

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)
Number of subjects analysed	27	13
Units: microgram/milliliter (mcg/mL)
arithmetic mean (standard deviation)
Cycle 1: Day 8 (n=25, 11)	114 ( 45.7 )	127 ( 49.9 )
Cycle 1: Day 15 (n=23, 11)	272 ( 118 )	263 ( 103 )
Cycle 1: Day 22 (n=15, 8)	388 ( 163 )	323 ( 206 )
Cycle 1: Day 29 (n=18, 9)	475 ( 174 )	426 ( 209 )
Cycle 2: Day 43 (n=5, 1)	504 ( 296 )	357 ( 99999 )
Cycle 2: Day 57 (n=8, 2)	531 ( 224 )	478 ( 261 )

No statistical analyses for this end point

Secondary: AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

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End point title

AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) ^[5]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from AML cohort were included in this endpoint.

End point values	Acute Myeloid Leukemia (AML)
Number of subjects analysed	27
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1: Day 8 (n=19)	126 ( 41.0 )
Cycle 1: Day 15 (n=24)	217 ( 60.6 )
Cycle 2: Day 1 (n=10)	115 ( 94.2 )
Cycle 2: Day 15 (n=8)	420 ( 205 )

No statistical analyses for this end point

Secondary: B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab

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End point title

B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab ^[6]

End point description

Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed and are denoted by 'n' in the categories.

End point type

Secondary

End point timeframe

At end of infusion on Cycle 1 Days 1 and 29

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from B-ALL and T-ALL cohort were included in this endpoint.

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)
Number of subjects analysed	27	13
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1: Day 1 (n=21, 8)	452 ( 344 )	259 ( 120 )
Cycle 1: Day 29 (n=19, 7)	835 ( 366 )	745 ( 330 )

No statistical analyses for this end point

Secondary: AML: Ceoi of Isatuximab

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End point title

AML: Ceoi of Isatuximab ^[7]

End point description

End point type

Secondary

End point timeframe

At end of infusion on Cycle 1 Days 1 and 15

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from AML cohort were included in this endpoint.

End point values	Acute Myeloid Leukemia (AML)
Number of subjects analysed	27
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1: Day 1 (n=19)	363 ( 110 )
Cycle 1: Day 15 (n=20)	562 ( 176 )

No statistical analyses for this end point

Secondary: Number of Participants With Negative Minimal Residual Disease (MRD)

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End point title

Number of Participants With Negative Minimal Residual Disease (MRD)

End point description

The MRD assessment was performed by next generation sequencing using clonoSEQ and T-cell receptor assays for B-ALL and T-ALL cohorts respectively. It was performed by flow cytometry for AML cohort. Number of participants with CR or CRi who achieved negative MRD in bone marrow and blood were analyzed. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only those participants who achieved CR/CRi were analyzed. 9999 = In AML indication, peripheral blood tissue is not representative of the tumor burden and cannot be used to assess MRD.

End point type

Secondary

End point timeframe

From screening until the study end date, approximately 45 months

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	13	5	14
Units: participants
number (not applicable)
Blood, 1 in 10^6	3	1	9999
Bone marrow, 1 in 10^6	0	2	0

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

ORR:Percentage of participants with CR/CRi or partial response for blood and bone marrow disease based on NCCN guideline. CR: <5% blasts in BMA with spicules; no circulating blasts (ALL)/no blasts with Auer rods (AML) or extramedullary disease, no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/central nervous system involvement (ALL), trilineage hematopoiesis (ALL);ANC >=1000/mcL; platelets >100000/mcL; RBC transfusion independence. If physician documented transfusion dependency related to study treatment;not to participant’s underlying disease, CRi was reported. CRi met the same criteria as CR, except neutrophils and/or platelets recovery (ANC <1000/mcL or platelets <100000/mcL). PR: >50% decrease in the sum of the product of the greatest perpendicular diameters of the mediastinal enlargement. For participants with a previous positive positron emission tomography (PET) scan, a post-treatment PET was to be positive in at least 1 previously involved site. The EP.

End point type

Secondary

End point timeframe

From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	25	11	23
Units: percentage of participants
number (confidence interval 80%)	52.0 (37.5 to 66.2)	54.5 (31.8 to 75.9)	65.2 (49.7 to 78.6)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival was defined as the time interval from the date of first study treatment administration to death from any cause. It was estimated using the Kaplan-Meier method. Confidence interval (CI) for Kaplan-Meier estimates were calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. 99999 = Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

End point type

Secondary

End point timeframe

From first study treatment administration up to death due to any cause, a maximum of 45 months

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	25	11	23
Units: months
median (confidence interval 95%)	12.09 (3.975 to 99999)	6.85 (2.201 to 99999)	9.40 (5.947 to 99999)

No statistical analyses for this end point

Secondary: Event-Free Survival (EFS)

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End point title

Event-Free Survival (EFS)

End point description

The EFS was defined as the time interval from the date of first study treatment administration to the date of the first of: completion or going off protocol induction/consolidation therapy without CR, relapse from CR, or death due to any cause, whichever occurred first. It was estimated using the Kaplan-Meier method. CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. 99999 = Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

End point type

Secondary

End point timeframe

From study treatment administration up to the date of first documented disease progression or death due to any cause, a maximum of 45 months

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	25	11	23
Units: months
median (confidence interval 95%)	2.23 (1.413 to 99999)	2.14 (1.347 to 99999)	5.65 (1.347 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DoR)

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End point title

Duration of Response (DoR)

End point description

The DoR was defined as the time from the date of the first complete response to the event date of first disease progression or death from any cause, whichever happened first. It was estimated using the Kaplan-Meier method. CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only responders were included in this analysis. -99999= Lower limit of CI not estimable due to insufficient number of participants with events at study closure. 99999= Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

End point type

Secondary

End point timeframe

From first documented response up to the date of first documented disease progression or death due to any cause, a maximum of 45 months

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	13	5	14
Units: months
median (confidence interval 95%)	7.26 (-99999 to 99999)	1.18 (0.887 to 99999)	4.40 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Cluster of Differentiation (CD)38 Receptor Density

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End point title

Cluster of Differentiation (CD)38 Receptor Density

End point description

Blood samples were collected to assess CD38 receptor density as a predictive biomarker. It was assessed across complete responders and non-complete responders. The Antibody Binding Capacity (ABC) was calculated using the following equation: ABC = 10^(Logarithm(Mean Fluorescence Intensity)*a+b) where “a” was the slope and “b” was the Y-intercept of the calibration curve equation. Specific and absolute quantitative values (specific antibody-binding capacity [sABC]) of binding of the selected antibodies were calculated after subtraction of the negative isotypic immunoglobulin G (IgG) control. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only those participants with data available at specified timepoints were analyzed and denoted by 'n' in the categories . 99999 = SD cannot be derived for a single participant. NK=Natural killer cells.

End point type

Secondary

End point timeframe

Pre-dose on Day 1

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	25	11	23
Units: specific antibody-binding capacity
arithmetic mean (standard deviation)
Blood blast cells: CR/CRi (n=5,2,3)	20345.6 ( 23439.7 )	12780.0 ( 15559.2 )	19502.0 ( 20919.7 )
Blood blast cells: Non CR/CRi (n=2,1,2)	31080.0 ( 2397.1 )	22952.0 ( 99999 )	9815.0 ( 4203.0 )
Blood immune cells (NK cells): CR/CRi (n=5,2,3)	13506.2 ( 3018.6 )	22639.0 ( 1796.1 )	11220.3 ( 3764.6 )
Blood immune cells (NK cells):Non CR/CRi (n=2,1,2)	16650.0 ( 851.4 )	33859.0 ( 99999 )	22530.0 ( 685.9 )

No statistical analyses for this end point

Secondary: CD38 Receptor Occupancy

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End point title

CD38 Receptor Occupancy

End point description

Blood samples were collected to assess CD38 receptor occupancy as a pharmacodynamics marker. It was assessed across complete responders and non-complete responders. Multicolor flow cytometry assay was validated for CD38 receptor occupancy (CD38RO) quantification, based on the use of 2 murine monoclonal antibodies (MAbs), one competing with SAR650984 to determine number of free CD38 receptors (MAb1) and one recognizing a different binding epitope on CD38 to measure total number of receptors (MAb2) at cell surface of the cancer cells. Cells were tagged with either MAb1 (Tube #1) or MAb2 (Tube #2). The percentage RO was calculated using following equation: % CD38RO = [(sABC MAb2 - sABC MAb1)/sABC MAb2] X 100. The EP consisted of evaluable participants from AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only those participants with data available at specified timepoints were analyzed; denoted by 'n'.

End point type

Secondary

End point timeframe

Pre-dose on Day 15

End point values	B-cell Acute Lymphoblastic Leukemia (B-ALL)	T-cell Acute Lymphoblastic Leukemia (T-ALL)	Acute Myeloid Leukemia (AML)
Number of subjects analysed	25	11	23
Units: percent receptor occupancy
arithmetic mean (standard deviation)
Blood plasma cells: CR/CRi (n=0,2,0)	9999 ( 9999 )	40.5 ( 30.4 )	9999 ( 9999 )
Blood plasma cells: Non CR/CRi (n=1,1,0)	44.0 ( 99999 )	55.0 ( 99999 )	9999 ( 9999 )
Blood NK cells: CR/CRi (n=5,3,0)	55.6 ( 6.9 )	66.7 ( 2.1 )	9999 ( 9999 )
Blood NK cells: Non CR/CRi (n=3,1,0)	61.3 ( 3.5 )	70.0 ( 99999 )	9999 ( 9999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event reporting additional description

Analysis was performed on the AT population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Reporting group description

Participants with B-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

Reporting group title

All Participants

Reporting group description

All participants in the study were included in this cohort.

Reporting group title

Acute Myeloid Leukemia (AML)

Reporting group description

Reporting group title

T-cell Acute Lymphoblastic Leukemia (T-ALL)

Reporting group description

Serious adverse events	B-cell Acute Lymphoblastic Leukemia (B-ALL)	All Participants	Acute Myeloid Leukemia (AML)	T-cell Acute Lymphoblastic Leukemia (T-ALL)
Total subjects affected by serious adverse events
subjects affected / exposed	19 / 27 (70.37%)	48 / 67 (71.64%)	17 / 27 (62.96%)	12 / 13 (92.31%)
number of deaths (all causes)	17	43	18	8
number of deaths resulting from adverse events	3	5	2	0
Injury, poisoning and procedural complications
Infusion Related Reaction
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	3 / 3	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic Aneurysm
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac Failure
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised Tonic-Clonic Seizure
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukoencephalopathy
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile Bone Marrow Aplasia
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile Neutropenia
subjects affected / exposed	10 / 27 (37.04%)	22 / 67 (32.84%)	7 / 27 (25.93%)	5 / 13 (38.46%)
occurrences causally related to treatment / all	11 / 12	26 / 29	9 / 11	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 27 (7.41%)	4 / 67 (5.97%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 2	1 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Haemophagocytic Lymphohistiocytosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic Shock
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytokine Release Syndrome
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Gastrointestinal disorders
Neutropenic Colitis
subjects affected / exposed	1 / 27 (3.70%)	2 / 67 (2.99%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis Acute
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	2 / 27 (7.41%)	2 / 67 (2.99%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth Haemorrhage
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal Fissure
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic Failure
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone Pain
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated Aspergillosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device Related Infection
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Catheter Site Infection
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial Sepsis
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Sepsis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Genital Herpes Zoster
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fungal Sepsis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Fungal Infection
subjects affected / exposed	1 / 27 (3.70%)	2 / 67 (2.99%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fournier's Gangrene
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Neutropenic Sepsis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis Externa
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal Bacteraemia
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis Fungal
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic Shock
subjects affected / exposed	3 / 27 (11.11%)	8 / 67 (11.94%)	3 / 27 (11.11%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	2 / 3	6 / 8	3 / 3	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 27 (3.70%)	4 / 67 (5.97%)	1 / 27 (3.70%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	0 / 1	2 / 4	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Rhinovirus Infection
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal Sepsis
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 3	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis Jirovecii Pneumonia
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal Infection
subjects affected / exposed	1 / 27 (3.70%)	1 / 67 (1.49%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	B-cell Acute Lymphoblastic Leukemia (B-ALL)	All Participants	Acute Myeloid Leukemia (AML)	T-cell Acute Lymphoblastic Leukemia (T-ALL)
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 27 (96.30%)	62 / 67 (92.54%)	24 / 27 (88.89%)	12 / 13 (92.31%)
Vascular disorders
Flushing
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	1	3	1	1
Hypertension
subjects affected / exposed	0 / 27 (0.00%)	8 / 67 (11.94%)	3 / 27 (11.11%)	5 / 13 (38.46%)
occurrences all number	0	10	3	7
Hypotension
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	1	3	2	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	10 / 27 (37.04%)	26 / 67 (38.81%)	12 / 27 (44.44%)	4 / 13 (30.77%)
occurrences all number	14	43	23	6
Oedema Peripheral
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	0	2	2	0
Fatigue
subjects affected / exposed	2 / 27 (7.41%)	6 / 67 (8.96%)	3 / 27 (11.11%)	1 / 13 (7.69%)
occurrences all number	2	8	5	1
Face Oedema
subjects affected / exposed	2 / 27 (7.41%)	3 / 67 (4.48%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	2	3	0	1
Chills
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	0	2	1	1
Catheter Site Pain
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	0	3	2	1
Immune system disorders
Food Allergy
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Drug Hypersensitivity
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 27 (0.00%)	3 / 67 (4.48%)	3 / 27 (11.11%)	0 / 13 (0.00%)
occurrences all number	0	5	5	0
Cough
subjects affected / exposed	6 / 27 (22.22%)	8 / 67 (11.94%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	8	10	1	1
Dyspnoea
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	0	2	2	0
Rhinorrhoea
subjects affected / exposed	2 / 27 (7.41%)	2 / 67 (2.99%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences all number	2	2	0	0
Oropharyngeal Pain
subjects affected / exposed	2 / 27 (7.41%)	5 / 67 (7.46%)	2 / 27 (7.41%)	1 / 13 (7.69%)
occurrences all number	2	5	2	1
Hypoxia
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	0	3	3	0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Anxiety
subjects affected / exposed	1 / 27 (3.70%)	4 / 67 (5.97%)	2 / 27 (7.41%)	1 / 13 (7.69%)
occurrences all number	1	4	2	1
Irritability
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Insomnia
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	0	2	1	1
Investigations
Weight Decreased
subjects affected / exposed	2 / 27 (7.41%)	4 / 67 (5.97%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	2	4	1	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Infusion Related Reaction
subjects affected / exposed	8 / 27 (29.63%)	26 / 67 (38.81%)	14 / 27 (51.85%)	4 / 13 (30.77%)
occurrences all number	12	33	16	5
Cardiac disorders
Tachycardia
subjects affected / exposed	2 / 27 (7.41%)	5 / 67 (7.46%)	2 / 27 (7.41%)	1 / 13 (7.69%)
occurrences all number	2	5	2	1
Nervous system disorders
Dysaesthesia
subjects affected / exposed	1 / 27 (3.70%)	2 / 67 (2.99%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	2	0	1
Dysgeusia
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	0	2	2	0
Facial Paralysis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Headache
subjects affected / exposed	3 / 27 (11.11%)	15 / 67 (22.39%)	9 / 27 (33.33%)	3 / 13 (23.08%)
occurrences all number	3	21	14	4
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Seizure
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Tremor
subjects affected / exposed	2 / 27 (7.41%)	4 / 67 (5.97%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	2	5	1	2
Dizziness
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	1	3	1	1
Blood and lymphatic system disorders
Haemolysis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Febrile Neutropenia
subjects affected / exposed	4 / 27 (14.81%)	10 / 67 (14.93%)	5 / 27 (18.52%)	1 / 13 (7.69%)
occurrences all number	6	12	5	1
Anaemia
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	1	6	5	0
Eye disorders
Eyelid Oedema
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	2	0	2
Periorbital Oedema
subjects affected / exposed	2 / 27 (7.41%)	2 / 67 (2.99%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences all number	2	2	0	0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	6 / 27 (22.22%)	12 / 67 (17.91%)	5 / 27 (18.52%)	1 / 13 (7.69%)
occurrences all number	6	17	8	3
Anal Fissure
subjects affected / exposed	3 / 27 (11.11%)	5 / 67 (7.46%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	5	7	2	0
Abdominal Pain Upper
subjects affected / exposed	1 / 27 (3.70%)	4 / 67 (5.97%)	2 / 27 (7.41%)	1 / 13 (7.69%)
occurrences all number	1	4	2	1
Anal Inflammation
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	0 / 27 (0.00%)	2 / 13 (15.38%)
occurrences all number	1	4	0	3
Constipation
subjects affected / exposed	3 / 27 (11.11%)	12 / 67 (17.91%)	7 / 27 (25.93%)	2 / 13 (15.38%)
occurrences all number	3	13	7	3
Diarrhoea
subjects affected / exposed	4 / 27 (14.81%)	15 / 67 (22.39%)	8 / 27 (29.63%)	3 / 13 (23.08%)
occurrences all number	5	17	9	3
Dyspepsia
subjects affected / exposed	0 / 27 (0.00%)	5 / 67 (7.46%)	4 / 27 (14.81%)	1 / 13 (7.69%)
occurrences all number	0	7	6	1
Gastritis
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	0	3	2	1
Nausea
subjects affected / exposed	9 / 27 (33.33%)	18 / 67 (26.87%)	6 / 27 (22.22%)	3 / 13 (23.08%)
occurrences all number	17	31	9	5
Oral Pain
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	1 / 27 (3.70%)	1 / 13 (7.69%)
occurrences all number	0	2	1	1
Pancreatitis
subjects affected / exposed	1 / 27 (3.70%)	2 / 67 (2.99%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	2	0	1
Stomatitis
subjects affected / exposed	10 / 27 (37.04%)	22 / 67 (32.84%)	8 / 27 (29.63%)	4 / 13 (30.77%)
occurrences all number	10	23	8	5
Vomiting
subjects affected / exposed	6 / 27 (22.22%)	19 / 67 (28.36%)	10 / 27 (37.04%)	3 / 13 (23.08%)
occurrences all number	7	25	15	3
Colitis
subjects affected / exposed	1 / 27 (3.70%)	5 / 67 (7.46%)	2 / 27 (7.41%)	2 / 13 (15.38%)
occurrences all number	1	5	2	2
Hepatobiliary disorders
Hepatic Steatosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Hepatic Failure
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Skin and subcutaneous tissue disorders
Dry Skin
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	0	2	2	0
Alopecia
subjects affected / exposed	2 / 27 (7.41%)	3 / 67 (4.48%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	2	3	0	1
Erythema
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	1	4	3	0
Rash
subjects affected / exposed	0 / 27 (0.00%)	6 / 67 (8.96%)	6 / 27 (22.22%)	0 / 13 (0.00%)
occurrences all number	0	7	7	0
Rash Maculo-Papular
subjects affected / exposed	1 / 27 (3.70%)	3 / 67 (4.48%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	1	7	6	0
Renal and urinary disorders
Nephropathy Toxic
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Renal Tubular Necrosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Urinary Retention
subjects affected / exposed	2 / 27 (7.41%)	6 / 67 (8.96%)	1 / 27 (3.70%)	3 / 13 (23.08%)
occurrences all number	2	7	1	4
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	0 / 27 (0.00%)	4 / 67 (5.97%)	3 / 27 (11.11%)	1 / 13 (7.69%)
occurrences all number	0	4	3	1
Bone Pain
subjects affected / exposed	2 / 27 (7.41%)	3 / 67 (4.48%)	1 / 27 (3.70%)	0 / 13 (0.00%)
occurrences all number	2	3	1	0
Neck Pain
subjects affected / exposed	0 / 27 (0.00%)	3 / 67 (4.48%)	3 / 27 (11.11%)	0 / 13 (0.00%)
occurrences all number	0	3	3	0
Pain In Extremity
subjects affected / exposed	4 / 27 (14.81%)	8 / 67 (11.94%)	2 / 27 (7.41%)	2 / 13 (15.38%)
occurrences all number	6	13	5	2
Infections and infestations
Conjunctivitis
subjects affected / exposed	1 / 27 (3.70%)	4 / 67 (5.97%)	2 / 27 (7.41%)	1 / 13 (7.69%)
occurrences all number	1	4	2	1
Device Related Infection
subjects affected / exposed	0 / 27 (0.00%)	3 / 67 (4.48%)	2 / 27 (7.41%)	1 / 13 (7.69%)
occurrences all number	0	3	2	1
Lip Infection
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Oral Candidiasis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Oral Herpes
subjects affected / exposed	1 / 27 (3.70%)	2 / 67 (2.99%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	2	0	1
Respiratory Syncytial Virus Infection
subjects affected / exposed	2 / 27 (7.41%)	2 / 67 (2.99%)	0 / 27 (0.00%)	0 / 13 (0.00%)
occurrences all number	2	2	0	0
Skin Infection
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 27 (0.00%)	2 / 67 (2.99%)	2 / 27 (7.41%)	0 / 13 (0.00%)
occurrences all number	0	2	2	0
Viral Rhinitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 27 (3.70%)	11 / 67 (16.42%)	8 / 27 (29.63%)	2 / 13 (15.38%)
occurrences all number	1	11	8	2
Increased Appetite
subjects affected / exposed	0 / 27 (0.00%)	1 / 67 (1.49%)	0 / 27 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1

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Were there any global substantial amendments to the protocol? Yes

11 Mar 2019

Clarified the suspected unexpected serious adverse reactions and sponsor responsibilities to submit any change(s) considered substantial to the regulatory authorities for notification and approval. Clarified the contraception and pregnancy testing for females and males of childbearing potential, as well as the criteria for discontinuation of the study by the Sponsor. Updated the PK follow-up assessment from 60 to 90 days after last isatuximab administration to align with other isatuximab studies. Improved the feasibility of the study procedures. Clarified that administrative and editorial updates and corrections to the protocol will be performed.

04 Dec 2019

Clarified the definition of CR, in order to avoid participants being ‘not evaluable’ if still dependent on red blood cell transfusions. Included dexamethasone as an intervention for ALL cohort as part of study treatment. Further clarified the difference that for AML cohort dexamethasone is optional, except as premedication for isatuximab. Updated the duration for contraception. Added Montelukast as a systematic premedication, the objective being to decrease the incidence and severity of IRs; it should not be at Investigator's discretion. Added hematological criteria for ALL participants before starting the consolidation period. Simplified some procedures in order to be closer to clinical practice. Added recommendations in case of pegaspargase hypersensitivity. Added analysis of CD38 receptor density and occupancy, in order to better understand the response profile at the end of the trial. Clarified on the first interim analysis that was to be performed on first 20 participants. Clarified that administrative and editorial updates and corrections to the protocol will be performed.

30 Jul 2020

Protocol was amended to implement changes following health Authorities comments and to mitigate the risk of hepatitis reactivation identified in the SAR650984 Investigator’s Brochure edition 11 (30-Apr-2020).

24 Nov 2020

Implemented data monitoring committee (DMC) recommendations following the occurrence of first fatal case as an outcome of a Cytokine Release Syndrome (CRS) event. On 01 October 2020, due to the occurrence of first fatal CRS event, the study DMC had evaluated the safety profile of the first 9 treated participants and recommended the continuation of the study with changes to be implemented in an amendment to the protocol. The main changes were: White blood cell (WBC) counts to be below 20 x 10^9/L before isatuximab administration. Participants with high WBC counts between 20 and 50 x 10^9/L at screening and with high tumor burden in relation to extramedullary disease should receive a rescue cytoreductive therapy with a short half-life in order to potentially reach the 20 x 10^9/L WBC threshold before first isatuximab administration. As consequence, the list of cytoreductive drugs with suggested doses were proposed in this amendment in order to have less heterogeneity in the participants’ cytoreductive therapy management across participating sites. Guidance was added to clarify the CRS events with inclusion of a specific section and table describing criteria for diagnosis, grading, as well as management of these events. Prospective determinations of CRS biomarkers at different time points were included. Cytokines panel, ferritin, and C-reactive protein (CRP) were added at baseline and at different time points in order to better assess events like CRS, hemophagocytic lymphohistiocytosis (HLH), infections, etc. Moreover, specific guidance for hematology, vital signs, radiology were added in case of high tumor burden or CRS events. Anti-interleukin 6 as concomitant or rescue medication in case of CRS Grade 2 or above was added. Clarified that seizures >=Grade 3 should be reported as adverse events of special interest (AESI).

14 Oct 2021

Protocol was amended to allow the enrollment of children <2 years old as after PK assessment, the dose of 20 mg/kg was confirmed in this young subpopulation. The main changes were: Justification of the dose (20 mg/kg) for children <2 years old. Definition of evaluable participant update. Clarification on coagulation test frequency. Added the possibility to perform a positron emission tomography (PET)-magnetic resonance imaging instead of PET-computed tomography when needed.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The study was prematurely stopped due to sponsor decision (stage 2 efficacy criteria not met) and not due to safety concerns.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Complete Response (CR) Rate

Primary: Percentage of Participants With Complete Response (CR) Rate

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Secondary: Number of Participants With Infusion Reactions (IRs)

Secondary: Number of Participants With Infusion Reactions (IRs)

Secondary: B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab

Secondary: B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab

Secondary: AML: AUC of Isatuximab

Secondary: AML: AUC of Isatuximab

Secondary: B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

Secondary: B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

Secondary: AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

Secondary: AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

Secondary: B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab

Secondary: B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab

Secondary: AML: Ceoi of Isatuximab

Secondary: AML: Ceoi of Isatuximab

Secondary: Number of Participants With Negative Minimal Residual Disease (MRD)

Secondary: Number of Participants With Negative Minimal Residual Disease (MRD)

Secondary: Overall Response Rate (ORR)

Secondary: Overall Response Rate (ORR)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Event-Free Survival (EFS)

Secondary: Event-Free Survival (EFS)

Secondary: Duration of Response (DoR)

Secondary: Duration of Response (DoR)

Secondary: Cluster of Differentiation (CD)38 Receptor Density

Secondary: Cluster of Differentiation (CD)38 Receptor Density

Secondary: CD38 Receptor Occupancy

Secondary: CD38 Receptor Occupancy

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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