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

• ClinicalTrials.gov Identifier: NCT03860844
• Recruitment Status: Terminated
• First Posted: March 4, 2019
• Results First Posted: November 15, 2023
• Last Update Posted: May 16, 2024
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: February 21, 2019
• First Posted Date: March 4, 2019
• Results First Submitted Date: September 7, 2023
• Results First Posted Date: November 15, 2023
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: August 6, 2019
• Actual Primary Completion Date: September 12, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2023)

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

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).

Original Primary Outcome Measures (submitted: February 28, 2019)

• Complete Response (CR) rate in acute myeloid leukemia (AML) cohort [ Time Frame: Baseline to Day 22 ]
  Morphological CR rate defined as the proportion of participants with CR or CRi (CR with incomplete peripheral recovery)
• Complete Response (CR) rate in B-cell acute lymphoblastic leukemia (B-ALL) cohort [ Time Frame: Baseline to Day 57 ]
  Morphological CR rate defined as the proportion of participants with CR or CRi
• Complete Response (CR) rate in T-cell acute lymphoblastic leukemia (T-ALL) cohort [ Time Frame: Baseline to Day 57 ]
  Morphological CR rate defined as the proportion of participants with CR or CRi

Current Secondary Outcome Measures (submitted: April 22, 2024)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: 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) ]
  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.
• Number of Participants With Infusion Reactions (IRs) [ Time Frame: 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) ]
  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.
• B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab [ Time Frame: From Week 0 to Week 1, Week 0 to Week 5, and Week 0 to Week 10 ]
  Plasma samples were collected at specified timepoints to determine the AUC of isatuximab.
• AML: AUC of Isatuximab [ Time Frame: From Week 0 to Week 1, Week 0 to Week 3, and Week 0 to Week 8 ]
  Plasma samples were collected at specified timepoints to determine the AUC of isatuximab.
• B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) [ Time Frame: Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 1 Day 29, Cycle 2 Day 43, Cycle 2 Day 57 ]
  Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab.
• AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) [ Time Frame: Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15 ]
  Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab.
• B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab [ Time Frame: At end of infusion on Cycle 1 Days 1 and 29 ]
  Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.
• AML: Ceoi of Isatuximab [ Time Frame: At end of infusion on Cycle 1 Days 1 and 15 ]
  Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.
• Number of Participants With Negative Minimal Residual Disease (MRD) [ Time Frame: From screening until the study completion date, approximately 45 months ]
  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.
• Overall Response Rate (ORR) [ Time Frame: From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks ]
  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 (OS) [ Time Frame: From first study treatment administration up to death due to any cause, a maximum of 45 months ]
  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.
• Event-Free Survival (EFS) [ Time Frame: From study treatment administration up to the date of first documented disease progression or death due to any cause, a maximum of 45 months ]
  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 (DoR) [ Time Frame: From first documented response up to the date of first documented disease progression or death due to any cause, a maximum of 45 months ]
  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.
• Cluster of Differentiation (CD)38 Receptor Density [ Time Frame: Pre-dose on Day 1 ]
  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.
• CD38 Receptor Occupancy [ Time Frame: Pre-dose on Day 15 ]
  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.

Original Secondary Outcome Measures (submitted: February 28, 2019)

• Safety and tolerability assessments: Adverse events [ Time Frame: Baseline to approximately 3 months ]
  Number of adverse events and serious adverse events
• Assessment of infusion reactions [ Time Frame: Time from isatuximab infusion to resolution (approximately 2 days) ]
  Incidence and severity of infusion reactions
• Pharmacokinetics of isatuximab: Cmax [ Time Frame: Day 1 to 30 days after hematological recovery ]
  Maximum observed concentration (Cmax)
• Pharmacokinetics of isatuximab: Ctrough [ Time Frame: Day 1 to 30 days after hematological recovery ]
  Concentration observed just before treatment administration during repeated dosing (Ctrough)
• Pharmacokinetics of isatuximab: AUC [ Time Frame: Day 1 to 30 days after hematological recovery ]
  Partial area under the serum concentration time curve: AUC
• Minimal residual disease [ Time Frame: On day 43 ]
  Estimation of minimal residual disease in participants achieving CR or CRi
• Overall response rate [ Time Frame: On day 43 ]
  The overall response rate is defined as the proportion of participants with CR or CRi for blood and bone marrow disease; Partial response (PR) based on the National Comprehensive Cancer Network (NCCN) guideline will be considered in case of lymphomatous extramedullary disease for T-ALL participants
• Overall survival [ Time Frame: Baseline to approximately 3 months ]
  Overall survival is defined as the time interval from the date of first study treatment administration to death from any cause
• Event free survival [ Time Frame: Baseline to approximately 3 months ]
  Event free survival is 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
• Duration of response [ Time Frame: Time from the first response to the first disease progression or death, up to Month 42 ]
  Duration of response is 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Isatuximab in Combination With Chemotherapy in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia
• Official Title: 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

Brief Summary

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

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
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia

Intervention

• 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: 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: Daunorubicin (nonliposomal)
  Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion
• Drug: Idarubicin
  Pharmaceutical form: Solution for injection Route of administration: Intravenous
• Drug: Filgrastim or equivalent
  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: Pegaspargase (PEG) Asparaginase
  Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion
• Drug: Cyclophosphamide
  Pharmaceutical form: Solution for injection Route of administration: Intravenous
• 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: L - Asparginase
  Pharmaceutical form: Solution for injection Route of administration: Intramuscular
• Drug: Hydroxyurea
  Pharmaceutical form: Solution for injection Route of administration: PO
• Drug: L - Asparaginase (Erwinase)
  Pharmaceutical form: Solution for injection Route of administration: Intramuscular

Study Arms

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.

Interventions:

• 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)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 26, 2023): 67
• Original Estimated Enrollment (submitted: February 28, 2019): 104
• Actual Study Completion Date: May 26, 2023
• Actual Primary Completion Date: September 12, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 28 Days to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Denmark, France, Germany, Greece, Hungary, Italy, Korea, Republic of, Mexico, Netherlands, Norway, Peru, Portugal, Sweden, United States
• Removed Location Countries: Belgium, Canada, Czechia, Finland

Administrative Information

• NCT Number: NCT03860844
• Other Study ID Numbers: ACT15378; PIP - 2018-002697-45; U1111-1202-1096 ( Other Identifier: UTN ); 2018-002697-45 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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

• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: April 2024