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

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

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

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Fludarabine; Drug: Cytarabine; Drug: Liposomal daunorubicin; Drug: Idarubicin; Drug: Mitoxantrone; Drug: Doxorubicin; Drug: Vincristine; Drug: Cyclophosphamide; Drug: L - Asparginase; Drug: L - Asparaginase (Erwinase); Drug: Isatuximab; Drug: Dexamethasone or equivalent; Drug: Daunorubicin (nonliposomal); Drug: Filgrastim or equivalent; Drug: Pegaspargase (PEG) Asparaginase; Drug: Etoposide; Drug: Methotrexate; Drug: Hydroxyurea

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1245AAM
    • Investigational Site Number :0320004
  • Buenos Aires, Argentina, C1118AAT
    • Investigational Site Number :0320005
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, C1181ACH
      • Investigational Site Number :0320002
    • Capital Federal, Buenos Aires, Argentina, C1425DUC
      • Investigational Site Number :0320006
• Brazil
  • Paraná
    • Curitiba, Paraná, Brazil, 80250-060
      • Investigational Site Number :0760013
    • Curitiba, Paraná, Brazil, 81520-060
      • Investigational Site Number :0760006
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035 003
      • Investigational Site Number :0760007
  • São Paulo
    • Jaú, São Paulo, Brazil, 17210-070
      • Investigational Site Number :0760010
    • Ribeirão Preto, São Paulo, Brazil, 14048-900
      • Investigational Site Number :0760009
    • São Paulo, São Paulo, Brazil, 08270-070
      • Investigational Site Number :0760001
    • São Paulo, São Paulo, Brazil, 4023-062
      • Investigational Site Number :0760004
• Denmark
  • Copenhagen, Denmark, 2100
    • Investigational Site Number :2080001
• France
  • Lille, France, 59037
    • Investigational Site Number :2500002
  • Lyon, France, 69008
    • Investigational Site Number :2500003
  • Paris, France, 75571
    • Investigational Site Number :2500001
  • Paris, France, 75935
    • Investigational Site Number :2500004
• Germany
  • Erlangen, Germany, 91054
    • Investigational Site Number :2760005
  • Hamburg, Germany, 20246
    • Investigational Site Number :2760003
  • Münster, Germany, 48149
    • Investigational Site Number :2760006
• Greece
  • Athens, Greece, 115 27
    • Investigational Site Number :3000001
• Hungary
  • Budapest, Hungary, 1094
    • Investigational Site Number :3480002
• Italy
  • Liguria
    • Genoa, Liguria, Italy, 16147
      • Investigational Site Number :3800002
  • Lombardy
    • Monza, Lombardy, Italy, 20900
      • Investigational Site Number :3800001
  • Piedmont
    • Turin, Piedmont, Italy, 10126
      • Investigational Site Number :3800003
  • Veneto
    • Verona, Veneto, Italy, 37126
      • Investigational Site Number :3800005
• Mexico
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • Investigational Site Number :4840001
  • Querétaro
    • Col. Rancho Menchaca, Querétaro, Mexico, 76140
      • Investigational Site Number :4840005
• Netherlands
  • Utrecht, Netherlands, 3584 CS
    • Investigational Site Number :5280001
• Norway
  • Bergen, Norway, 5021
    • Investigational Site Number :5780001
  • Oslo, Norway, 0342
    • Investigational Site Number :5780002
• Peru
  • Arequipa, Peru
    • Investigational Site Number :6040001
  • Lima, Peru, 34
    • Investigational Site Number :6040002
• Portugal
  • Coimbra, Portugal, 3000-602
    • Investigational Site Number :6200002
  • Lisbon, Portugal, 1099-023
    • Investigational Site Number :6200001
  • Porto, Portugal, 4200-162
    • Investigational Site Number :6200003
• South Korea
  • Seoul-teukbyeolsi
    • Seoul, Seoul-teukbyeolsi, South Korea, 03080
      • Investigational Site Number :4100001
    • Seoul, Seoul-teukbyeolsi, South Korea, 06351
      • Investigational Site Number :4100002
    • Seoul, Seoul-teukbyeolsi, South Korea, 137-701
      • Investigational Site Number :4100004
• Sweden
  • Gothenburg, Sweden, 416 85
    • Investigational Site Number :7520001
• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute-Site Number:8400001
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center of Dallas-Site Number:8400002

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Participant 28 days to less than 18 years of age, at the time of signing the informed consent.
• Participants must have had a confirmed diagnosis of relapsed Acute Lymphoblastic Leukemia (ALL) of T- or B-cell origin including T-lymphoblastic lymphoma (LBL), or relapsed Acute Myeloblastic Leukemia (AML) including participants with history of myelodysplasia.
• Participants must have been previously treated for their disease and have relapsed or are refractory to most recent treatment. Participants in first or second relapse were eligible regardless of the remission duration.
• Participants who had no more than 1 prior salvage therapy.
• White Blood Cell (WBC) counts below 20 x10^9/L on Day 1 before isatuximab administration

Exclusion criteria:

• Any serious active disease or co-morbid condition which, in the opinion of the Investigator, may interfere with the safety of the study treatment or the compliance with the study protocol.
• Participants must have been off prior treatment with immunotherapy/investigational agents and chemotherapy for >2 weeks and must have recovered from acute toxicity before the first study treatment administration. Exceptions were participants who needed to receive cytoreductive chemotherapy in order to decrease tumor burden (the study treatment may have started earlier if necessitated by the patient's medical condition (eg, rapidly progressive disease) following discussion with the Sponsor).
• Prior stem cell transplant within 3 months and/or evidence of active systemic Graft versus Host Disease (GVHD) and/or immunosuppressive therapy for GVHD within 1 week before the first study treatment administration.
• Participants with LBL with bone marrow blasts <5%.
• Participants with Burkitt-type ALL.
• Acute leukemia with testicular or central nerve system involvement alone.
• Participants who had developed therapy related acute leukemia.
• Live vaccine(s) within 30 days prior to the first IMP administration or plans to receive such vaccines during the study until 90 days after the last IMP administration.
• Participants with white blood cell count > 50 x10^9/L at the time of screening visit.
• Participants who had been exposed to anti-CD38 therapies within 6 months prior to Day-1.

The above information was not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia; 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.

Drug: Fludarabine; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Cytarabine; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Liposomal daunorubicin; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Idarubicin; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Mitoxantrone; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Doxorubicin; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Vincristine; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Cyclophosphamide; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: L - Asparginase; Pharmaceutical form: Solution for injection Route of administration: Intramuscular; Drug: L - Asparaginase (Erwinase); Pharmaceutical form: Solution for injection Route of administration: Intramuscular; Drug: Isatuximab; Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: Intravenous; Other Names: SAR650984; Sarclisa; Drug: Dexamethasone or equivalent; Pharmaceutical form: Solution for injection or tablet Route of administration: Intravenous or oral; Drug: Daunorubicin (nonliposomal); Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion; Drug: Filgrastim or equivalent; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Drug: Pegaspargase (PEG) Asparaginase; Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion; Drug: Etoposide; Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion; Drug: Methotrexate; Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion; Drug: Hydroxyurea; Pharmaceutical form: Solution for injection Route of administration: PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Complete Response (CR) Rate	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).	From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	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.	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)
Number of Participants With Infusion Reactions (IRs)	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.	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)
B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab	Plasma samples were collected at specified timepoints to determine the AUC of isatuximab.	From Week 0 to Week 1, Week 0 to Week 5, and Week 0 to Week 10
AML: AUC of Isatuximab	Plasma samples were collected at specified timepoints to determine the AUC of isatuximab.	From Week 0 to Week 1, Week 0 to Week 3, and Week 0 to Week 8
B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)	Plasma samples were collected at specified timepoints to determine the Ctrough 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
AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)	Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab.	Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15
B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab	Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.	At end of infusion on Cycle 1 Days 1 and 29
AML: Ceoi of Isatuximab	Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.	At end of infusion on Cycle 1 Days 1 and 15
Overall Response Rate (ORR)	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.	From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
Cluster of Differentiation (CD)38 Receptor Density	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.	Pre-dose on Day 1
CD38 Receptor Occupancy	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.	Pre-dose on Day 15
Number of Participants With Negative Minimal Residual Disease (MRD)	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.	From screening until the study completion date, approximately 45 months
Overall Survival (OS)	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.	From first study treatment administration up to death due to any cause, a maximum of 45 months
Event-Free Survival (EFS)	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.	From study treatment administration up to the date of first documented disease progression or death due to any cause, a maximum of 45 months
Duration of Response (DoR)	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.	From first documented response up to the date of first documented disease progression or death due to any cause, a maximum of 45 months

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

Helpful Links

• ACT15378 Plain Language Results Summary

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2019
• Primary Completion (Actual): September 12, 2022
• Study Completion (Actual): May 26, 2023

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: February 28, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Estimated): September 9, 2025
• Last Update Submitted That Met QC Criteria: September 8, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Anti-CD38 monoclonal antibody
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Leukemia, Lymphoid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Amides; Hydrolases; Enzymes; Enzymes and Coenzymes; Indoles; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Pterins; Pteridines; Intercellular Signaling Peptides and Proteins; Pregnadienetriols; Amidohydrolases; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Anthraquinones; Anthrones; Anthracenes; Quinones; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Granulocyte Colony-Stimulating Factor; Urea; Dexamethasone; Methotrexate; Cyclophosphamide; Cytarabine; Etoposide; Doxorubicin; Vincristine; Daunorubicin; Asparaginase; Mitoxantrone; Idarubicin; Hydroxyurea; fludarabine; Filgrastim; pegaspargase; isatuximab
• Other Study ID Numbers: ACT15378; PIP - 2018-002697-45; U1111-1202-1096 (Other Identifier: UTN); 2018-002697-45 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No