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

Study Overview
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Brief Summary
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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

Detailed Description
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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).

Official Title
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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

Conditions
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Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Isatuximab
* Drug: Dexamethasone or equivalent
* Drug: Fludarabine
* Drug: Cytarabine
* Drug: Liposomal daunorubicin
* Drug: Daunorubicin (nonliposomal)
* Drug: Idarubicin
* Drug: Filgrastim or equivalent
* Drug: Mitoxantrone
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Pegaspargase (PEG) Asparaginase
* Drug: Cyclophosphamide
* Drug: Etoposide
* Drug: Methotrexate
* Drug: L - Asparginase
* Drug: Hydroxyurea
* Drug: L - Asparaginase (Erwinase)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia<br>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: Isatuximab<br>* Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: Intravenous<br>* Other names: Sarclisa;Drug: Dexamethasone or equivalent<br>* Pharmaceutical form: Solution for injection or tablet Route of administration: Intravenous or oral<br>Drug: Fludarabine<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Cytarabine<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Liposomal daunorubicin<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Daunorubicin (nonliposomal)<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion<br>Drug: Idarubicin<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Filgrastim or equivalent<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Mitoxantrone<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Doxorubicin<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Vincristine<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Pegaspargase (PEG) Asparaginase<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion<br>Drug: Cyclophosphamide<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous<br>Drug: Etoposide<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion<br>Drug: Methotrexate<br>* Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion<br>Drug: L - Asparginase<br>* Pharmaceutical form: Solution for injection Route of administration: Intramuscular<br>Drug: Hydroxyurea<br>* Pharmaceutical form: Solution for injection Route of administration: PO<br>Drug: L - Asparaginase (Erwinase)<br>* Pharmaceutical form: Solution for injection Route of administration: Intramuscular<br>|

What is the study measuring?
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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 | 
| Number of Participants With Negative Minimal Residual Disease (MRD) | MRD assessment was performed by next generation sequencing (NGS) using clonoSEQ and T-cell receptor (TCR) 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. | From screening until the study completion date, approximately 46 months | 
| 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 | 
| Overall Survival (OS) | Overall survival was defined as the time interval from the date of first study treatment administration to death from any cause. | From first study treatment administration up to death due to any cause, approximately 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. | From study treatment administration up to the date of first documented disease progression or death due to any cause, approximately 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. | From first documented response up to the date of first documented disease progression or death due to any cause, approximately 45 months | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-CD38 monoclonal antibody