Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia
Conditions
Keywords
Anti-CD38 monoclonal antibody
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).
Interventions
DRUGMethotrexate
Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion
DRUGL - Asparaginase (Erwinase)
Pharmaceutical form: Solution for injection Route of administration: Intramuscular
DRUGCyclophosphamide
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGEtoposide
Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion
DRUGIsatuximab
Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: Intravenous
DRUGDexamethasone or equivalent
Pharmaceutical form: Solution for injection or tablet Route of administration: Intravenous or oral
DRUGFludarabine
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGCytarabine
Pharmaceutical form: Solution for injection Route of administration: Intravenous
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGDaunorubicin (nonliposomal)
Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion
DRUGIdarubicin
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGFilgrastim or equivalent
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGMitoxantrone
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGDoxorubicin
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGVincristine
Pharmaceutical form: Solution for injection Route of administration: Intravenous
DRUGPegaspargase (PEG) Asparaginase
Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion
DRUGL - Asparginase
Pharmaceutical form: Solution for injection Route of administration: Intramuscular
DRUGHydroxyurea
Pharmaceutical form: Solution for injection Route of administration: PO
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) Rate | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Infusion Reactions (IRs) | 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 | 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 | 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) | 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) | 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 | 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 | 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 Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | 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. |
| Overall Response Rate (ORR) | 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) | 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) | 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) | 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 | 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 | 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. |
| Number of Participants With Negative Minimal Residual Disease (MRD) | 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. |
Countries
Argentina, Brazil, Denmark, France, Germany, Greece, Hungary, Italy, Mexico, Netherlands, Norway, Peru, Portugal, South Korea, Sweden, United States
Participant flow
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.
Pre-assignment details
The study consisted of a screening period (up to 3 weeks prior to the first study treatment administration), treatment period \[Day 1 to Day 57 for Acute Lymphoblastic Leukemia(ALL); Day 1 to Day 22 for Acute Myeloid Leukemia(AML)\],a period of aplasia followed by recovery period;an end of treatment (EOT) visit within 30 days after hematological recovery and a follow-up period.The study was prematurely stopped due to sponsor decision (stage 2 efficacy criteria not met);not due to safety concerns.
Participants by arm
| Arm | Count |
|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) 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. | 27 |
| T-cell Acute Lymphoblastic Leukemia (T-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. | 13 |
| Acute Myeloid Leukemia (AML) 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. | 27 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse event, not related to Coronavirus Disease-2019 (COVID-19) | 3 | 2 | 3 |
| Overall Study | Other, Not related to COVID-19 | 0 | 1 | 0 |
| Overall Study | Progressive disease | 5 | 3 | 4 |
Baseline characteristics
| Characteristic | B-cell Acute Lymphoblastic Leukemia (B-ALL) | T-cell Acute Lymphoblastic Leukemia (T-ALL) | Acute Myeloid Leukemia (AML) | Total |
|---|---|---|---|---|
| Age, Continuous | 8.22 years STANDARD_DEVIATION 3.92 | 8.72 years STANDARD_DEVIATION 4.15 | 9.04 years STANDARD_DEVIATION 5.41 | 8.65 years STANDARD_DEVIATION 4.56 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) White | 17 Participants | 7 Participants | 15 Participants | 39 Participants |
| Sex: Female, Male Female | 10 Participants | 4 Participants | 12 Participants | 26 Participants |
| Sex: Female, Male Male | 17 Participants | 9 Participants | 15 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 27 | 8 / 13 | 18 / 27 | 43 / 67 |
| other Total, other adverse events | 26 / 27 | 12 / 13 | 24 / 27 | 62 / 67 |
| serious Total, serious adverse events | 19 / 27 | 12 / 13 | 17 / 27 | 48 / 67 |
Outcome results
Primary
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).
Time frame: From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Percentage of Participants With Complete Response (CR) Rate | 52.0 percentage of participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Percentage of Participants With Complete Response (CR) Rate | 45.5 percentage of participants |
| Acute Myeloid Leukemia (AML) | Percentage of Participants With Complete Response (CR) Rate | 60.9 percentage of participants |
Secondary
AML: AUC of Isatuximab
Plasma samples were collected at specified timepoints to determine the AUC of isatuximab.
Time frame: From Week 0 to Week 1, Week 0 to Week 3, and Week 0 to Week 8
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: AUC of Isatuximab | Week 0 to Week 1 | 28592 mg*h/L | Standard Deviation 6858 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: AUC of Isatuximab | Week 0 to Week 3 | 130862 mg*h/L | Standard Deviation 40827 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: AUC of Isatuximab | Week 0 to Week 8 | 291962 mg*h/L | Standard Deviation 112222 |
Secondary
AML: Ceoi of Isatuximab
Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.
Time frame: At end of infusion on Cycle 1 Days 1 and 15
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: Ceoi of Isatuximab | Cycle 1: Day 1 | 363 mcg/mL | Standard Deviation 110 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: Ceoi of Isatuximab | Cycle 1: Day 15 | 562 mcg/mL | Standard Deviation 176 |
Secondary
AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)
Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab.
Time frame: Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 8 | 126 mcg/mL | Standard Deviation 41 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 15 | 217 mcg/mL | Standard Deviation 60.6 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 2: Day 1 | 115 mcg/mL | Standard Deviation 94.2 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 2: Day 15 | 420 mcg/mL | Standard Deviation 205 |
Secondary
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.
Time frame: From Week 0 to Week 1, Week 0 to Week 5, and Week 0 to Week 10
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab | Week 0 to Week 1 | 31703 mg*hour (h)/Liter (L) | Standard Deviation 10048 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab | Week 0 to Week 5 | 299071 mg*hour (h)/Liter (L) | Standard Deviation 127581 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab | Week 0 to Week 10 | 582686 mg*hour (h)/Liter (L) | Standard Deviation 316749 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab | Week 0 to Week 1 | 29057 mg*hour (h)/Liter (L) | Standard Deviation 8294 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab | Week 0 to Week 5 | 289167 mg*hour (h)/Liter (L) | Standard Deviation 93095 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab | Week 0 to Week 10 | 540375 mg*hour (h)/Liter (L) | Standard Deviation 233411 |
Secondary
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.
Time frame: At end of infusion on Cycle 1 Days 1 and 29
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab | Cycle 1: Day 29 | 835 mcg/mL | Standard Deviation 366 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab | Cycle 1: Day 1 | 452 mcg/mL | Standard Deviation 344 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab | Cycle 1: Day 29 | 745 mcg/mL | Standard Deviation 330 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab | Cycle 1: Day 1 | 259 mcg/mL | Standard Deviation 120 |
Secondary
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.
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
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 8 | 114 microgram/milliliter (mcg/mL) | Standard Deviation 45.7 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 15 | 272 microgram/milliliter (mcg/mL) | Standard Deviation 118 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 22 | 388 microgram/milliliter (mcg/mL) | Standard Deviation 163 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 29 | 475 microgram/milliliter (mcg/mL) | Standard Deviation 174 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 2: Day 43 | 504 microgram/milliliter (mcg/mL) | Standard Deviation 296 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 2: Day 57 | 531 microgram/milliliter (mcg/mL) | Standard Deviation 224 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 2: Day 43 | 357 microgram/milliliter (mcg/mL) | — |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 8 | 127 microgram/milliliter (mcg/mL) | Standard Deviation 49.9 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 29 | 426 microgram/milliliter (mcg/mL) | Standard Deviation 209 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 15 | 263 microgram/milliliter (mcg/mL) | Standard Deviation 103 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 2: Day 57 | 478 microgram/milliliter (mcg/mL) | Standard Deviation 261 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) | Cycle 1: Day 22 | 323 microgram/milliliter (mcg/mL) | Standard Deviation 206 |
Secondary
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.
Time frame: Pre-dose on Day 15
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | CD38 Receptor Occupancy | Blood plasma cells: Non CR/CRi; | 44.0 percent receptor occupancy | — |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | CD38 Receptor Occupancy | Blood NK cells: Non CR/CRi | 61.3 percent receptor occupancy | Standard Deviation 3.5 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | CD38 Receptor Occupancy | Blood NK cells: CR/CRi | 55.6 percent receptor occupancy | Standard Deviation 6.9 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | CD38 Receptor Occupancy | Blood NK cells: Non CR/CRi | 70.0 percent receptor occupancy | — |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | CD38 Receptor Occupancy | Blood plasma cells: Non CR/CRi; | 55.0 percent receptor occupancy | — |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | CD38 Receptor Occupancy | Blood plasma cells: CR/CRi | 40.5 percent receptor occupancy | Standard Deviation 30.4 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | CD38 Receptor Occupancy | Blood NK cells: CR/CRi | 66.7 percent receptor occupancy | Standard Deviation 2.1 |
Secondary
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.
Time frame: Pre-dose on Day 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood blast cells: CR/CRi | 20345.6 sABC | Standard Deviation 23439.7 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood blast cells: Non CR/CRi; | 31080.0 sABC | Standard Deviation 2397.1 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood immune cells (Natural Killer [NK] cells): CR/CRi | 13506.2 sABC | Standard Deviation 3018.6 |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood immune cells (NK cells): Non CR/CRi | 16650.0 sABC | Standard Deviation 851.4 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood immune cells (NK cells): Non CR/CRi | 33859.0 sABC | — |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood blast cells: CR/CRi | 12780.0 sABC | Standard Deviation 15559.2 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood immune cells (Natural Killer [NK] cells): CR/CRi | 22639.0 sABC | Standard Deviation 1796.1 |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Cluster of Differentiation (CD)38 Receptor Density | Blood blast cells: Non CR/CRi; | 22952.0 sABC | — |
| Acute Myeloid Leukemia (AML) | Cluster of Differentiation (CD)38 Receptor Density | Blood immune cells (NK cells): Non CR/CRi | 22530.0 sABC | Standard Deviation 685.9 |
| Acute Myeloid Leukemia (AML) | Cluster of Differentiation (CD)38 Receptor Density | Blood blast cells: Non CR/CRi; | 9815.0 sABC | Standard Deviation 4203 |
| Acute Myeloid Leukemia (AML) | Cluster of Differentiation (CD)38 Receptor Density | Blood immune cells (Natural Killer [NK] cells): CR/CRi | 11220.3 sABC | Standard Deviation 3764.6 |
| Acute Myeloid Leukemia (AML) | Cluster of Differentiation (CD)38 Receptor Density | Blood blast cells: CR/CRi | 19502.0 sABC | Standard Deviation 20919.7 |
Secondary
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.
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Duration of Response (DoR) | 7.26 months |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Duration of Response (DoR) | 1.18 months |
| Acute Myeloid Leukemia (AML) | Duration of Response (DoR) | 4.40 months |
Secondary
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.
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Event-Free Survival (EFS) | 2.23 months |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Event-Free Survival (EFS) | 2.14 months |
| Acute Myeloid Leukemia (AML) | Event-Free Survival (EFS) | 5.65 months |
Secondary
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.
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)
Population: The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Number of Participants With Infusion Reactions (IRs) | 9 Participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Number of Participants With Infusion Reactions (IRs) | 5 Participants |
| Acute Myeloid Leukemia (AML) | Number of Participants With Infusion Reactions (IRs) | 15 Participants |
Secondary
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.
Time frame: From screening until the study completion date, approximately 45 months
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Number of Participants With Negative Minimal Residual Disease (MRD) | Blood, 10^-6 | 3 Participants |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Number of Participants With Negative Minimal Residual Disease (MRD) | Bone marrow, 10^-6 | 0 Participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Number of Participants With Negative Minimal Residual Disease (MRD) | Blood, 10^-6 | 1 Participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Number of Participants With Negative Minimal Residual Disease (MRD) | Bone marrow, 10^-6 | 2 Participants |
| Acute Myeloid Leukemia (AML) | Number of Participants With Negative Minimal Residual Disease (MRD) | Bone marrow, 10^-6 | 0 Participants |
| Acute Myeloid Leukemia (AML) | Number of Participants With Negative Minimal Residual Disease (MRD) | Bone marrow, 10^-3 | 0 Participants |
Secondary
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.
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)
Population: The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TEAE | 27 Participants |
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TESAE | 19 Participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TEAE | 13 Participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TESAE | 12 Participants |
| Acute Myeloid Leukemia (AML) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TEAE | 26 Participants |
| Acute Myeloid Leukemia (AML) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TESAE | 17 Participants |
Secondary
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.
Time frame: From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Overall Response Rate (ORR) | 52.0 percentage of participants |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Overall Response Rate (ORR) | 54.5 percentage of participants |
| Acute Myeloid Leukemia (AML) | Overall Response Rate (ORR) | 65.2 percentage of participants |
Secondary
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.
Time frame: From first study treatment administration up to death due to any cause, a maximum of 45 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| B-cell Acute Lymphoblastic Leukemia (B-ALL) | Overall Survival (OS) | 12.09 months |
| T-cell Acute Lymphoblastic Leukemia (T-ALL) | Overall Survival (OS) | 6.85 months |
| Acute Myeloid Leukemia (AML) | Overall Survival (OS) | 9.40 months |