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This arm includes participants from 3 cohorts: AML, T-ALL and B-ALL.; AML: Weekly dosing of isatuximab with induction chemotherapy. The therapy may be repeated one more cycle; ALL: (Includes T-ALL and B-ALL) Weekly dosing of isatuximab with induction chemotherapy, then biweekly dosing of isatuximab with consolidation chemotherapy.

Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: Intravenous

Isatuximab

Pharmaceutical form: Solution for injection or tablet Route of administration: Intravenous or oral

Dexamethasone or equivalent

Pharmaceutical form: Solution for injection Route of administration: Intravenous

Liposomal daunorubicin

Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion

Daunorubicin (nonliposomal)

Filgrastim or equivalent

Pegaspargase (PEG) Asparaginase

Pharmaceutical form: Solution for injection Route of administration: Intramuscular

L - Asparginase

Pharmaceutical form: Solution for injection Route of administration: PO

L - Asparaginase (Erwinase)

Clinical Sciences & Operations

Primary Objective:

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

Secondary Objectives:

* Safety and tolerability assessments
* Assessment of infusion reactions (IRs)
* Pharmacokinetics (PK) of isatuximab
* Minimal residual disease
* Overall response rate
* Overall survival
* Event free survival
* Duration of response
* Relationship between clinical effects and CD38 receptor density and occupancy

The study included:

* a screening period of up to (up to 3 weeks prior to the first study treatment administration);
* a study treatment period \[Day 1 to Day 57 for Acute Lymphoblastic Leukemia (ALL); Day 1 to Day 22 for Acute Myeloid Leukemia (AML)\];
* the period of aplasia followed by a recovery period;
* an end of treatment (EOT) visit \[within 30 days after hematological recovery;
* a follow-up period (until final analysis cut off date).

Isatuximab in Combination With Chemotherapy in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia

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

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

The complete response rate (CR + CRi \[complete response with incomplete peripheral recovery\]) was defined as the percentage of participants achieving complete response (CR + CRi) assessed by the investigator per National Comprehensive Cancer Network (NCCN) guidelines version 1.2018 criteria. CR was defined as \<5% blasts in a 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 the physician documented transfusion dependency related to study treatment and not to the participant's underlying disease, CRi was reported. CRi met the same criteria as for CR, except neutrophils and/or platelets recovery (ANC \<1000/mcL or platelets \<100000/mcL).

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.

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.

Plasma samples were collected at specified timepoints to determine the AUC of isatuximab.

Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab.

Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.

MRD assessment was performed centrally 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 was analyzed. In AML indication, peripheral blood tissue is not representative of the tumor burden and cannot be used to assess MRD.

ORR:Percentage of participants with CR/CRi or partial response (PR) 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 the 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.

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.

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.

Duration of response was defined as the time from the date of the first response to the date of first disease progression or death from any cause, whichever happens 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.

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.

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 two murine monoclonal antibodies (MAbs), one competing with SAR650984 to determine the number of free CD38 receptors (MAb1) and one recognizing a different binding epitope on CD38 to measure the total number of receptors (MAb2) at the cell surface of the cancer cells. Cells were tagged with either MAb1 (Tube #1) or MAb2 (Tube #2). The percentage RO was calculated using the following equation: % CD38RO = \[(sABC MAb2 - sABC MAb1)/sABC MAb2\] X 100.

Sanofi

Analysis was performed on the AT population.

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.

B-cell Acute Lymphoblastic Leukemia (B-ALL)

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.

T-cell Acute Lymphoblastic Leukemia (T-ALL)

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.

Acute Myeloid Leukemia (AML)

All participants in the study were included in this cohort.

All Participants

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

The All-treated (AT) population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.

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

Trial Transparency Team

The evaluable population 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.

Percentage of Participants With Complete Response (CR) Rate

Any TEAE

Any TESAE

The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.

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

Number of Participants With Infusion Reactions (IRs)

Week 0 to Week 1

Week 0 to Week 5

Week 0 to Week 10

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.

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

Week 0 to Week 3

Week 0 to Week 8

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.

AML: AUC of Isatuximab

Cycle 1: Day 8

Cycle 1: Day 15

Cycle 1: Day 22

Cycle 1: Day 29

Cycle 2: Day 43

Cycle 2: Day 57

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

Cycle 2: Day 1

Cycle 2: Day 15

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

Cycle 1: Day 1

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

AML: Ceoi of Isatuximab

Blood, 10^-6

Bone marrow, 10^-6

Bone marrow, 10^-3

The evaluable population 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.

Number of Participants With Negative Minimal Residual Disease (MRD)

Overall Response Rate (ORR)

The evaluable population 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 were analyzed.

Overall Survival (OS)

Event-Free Survival (EFS)

The evaluable population 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.

Duration of Response (DoR)

Blood blast cells: CR/CRi

Blood blast cells: Non CR/CRi;

Blood immune cells (Natural Killer [NK] cells): CR/CRi

Blood immune cells (NK cells): Non CR/CRi

The evaluable population 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.

Cluster of Differentiation (CD)38 Receptor Density

Blood plasma cells: CR/CRi

Blood plasma cells: Non CR/CRi;

Blood NK cells: CR/CRi

Blood NK cells: Non CR/CRi

CD38 Receptor Occupancy

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Isatuximab in Combination With Chemotherapy in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia	NCT03860844	Acute Lymphobla... Acute Myeloid L...	Isatuximab Dexamethasone o... Fludarabine Cytarabine Liposomal dauno... Daunorubicin (n... Idarubicin Filgrastim or e... Mitoxantrone Doxorubicin Vincristine Pegaspargase (P... Cyclophosphamid... Etoposide Methotrexate L - Asparginase Hydroxyurea L - Asparaginas...	28 Days - 17 Years	Sanofi
Isatuximab in Combination With Chemotherapy in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia	NCT03860844	Acute Lymphobla... Acute Myeloid L...	Isatuximab Dexamethasone o... Fludarabine Cytarabine Liposomal dauno... Daunorubicin (n... Idarubicin Filgrastim or e... Mitoxantrone Doxorubicin Vincristine Pegaspargase (P... Cyclophosphamid... Etoposide Methotrexate L - Asparginase Hydroxyurea L - Asparaginas...	28 Days - 17 Years	Sanofi

Spots Global Cancer Trial Database for filgrastim or equivalent