Isatuximab in Combination With Chemotherapy in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia
- Conditions
- Acute Lymphoblastic LeukemiaAcute Myeloid Leukemia
- Interventions
- Registration Number
- NCT03860844
- Lead Sponsor
- Sanofi
- 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).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 67
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Dexamethasone or equivalent 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Filgrastim or equivalent 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Daunorubicin (nonliposomal) 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Liposomal daunorubicin 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia L - Asparaginase (Erwinase) 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Pegaspargase (PEG) Asparaginase 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Cyclophosphamide 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia L - Asparginase 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Etoposide 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Isatuximab 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Fludarabine 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Cytarabine 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Idarubicin 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Mitoxantrone 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Doxorubicin 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Vincristine 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Methotrexate 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. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia Hydroxyurea 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
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.
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.
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.
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.
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.
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: 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: 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.
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.
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.
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.
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.
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.
Trial Locations
- Locations (41)
Children's Medical Center of Dallas-Site Number:8400002
🇺🇸Dallas, Texas, United States
Investigational Site Number :4840001
🇲🇽Monterrey, Nuevo León, Mexico
Investigational Site Number :0760007
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Investigational Site Number :0760009
🇧🇷Ribeirao Preto, São Paulo, Brazil
Investigational Site Number :0320005
🇦🇷Buenos Aires, Argentina
Investigational Site Number :0760010
🇧🇷Jau, São Paulo, Brazil
Investigational Site Number :0320002
🇦🇷Caba, Buenos Aires, Argentina
Investigational Site Number :0320004
🇦🇷Buenos Aires, Argentina
Investigational Site Number :0320006
🇦🇷Capital Federal, Buenos Aires, Argentina
Investigational Site Number :0760013
🇧🇷Curitiba, Paraná, Brazil
Sarah Cannon Research Institute-Site Number:8400001
🇺🇸Nashville, Tennessee, United States
Investigational Site Number :3000001
🇬🇷Athens, Greece
Investigational Site Number :6040001
🇵🇪Arequipa, Peru
Investigational Site Number :0760006
🇧🇷Curitiba, Paraná, Brazil
Investigational Site Number :0760001
🇧🇷Sao Paulo, São Paulo, Brazil
Investigational Site Number :5280001
🇳🇱Utrecht, Netherlands
Investigational Site Number :6200002
🇵🇹Coimbra, Portugal
Investigational Site Number :0760004
🇧🇷Sao Paulo, São Paulo, Brazil
Investigational Site Number :4840005
🇲🇽Col. Rancho Menchaca, Querétaro, Mexico
Investigational Site Number :6040002
🇵🇪Lima, Peru
Investigational Site Number :3800005
🇮🇹Verona, Veneto, Italy
Investigational Site Number :6200001
🇵🇹Lisboa, Portugal
Investigational Site Number :6200003
🇵🇹Porto, Portugal
Investigational Site Number :3480002
🇭🇺Budapest, Hungary
Investigational Site Number :2080001
🇩🇰Copenhagen, Denmark
Investigational Site Number :2500002
🇫🇷Lille, France
Investigational Site Number :2500001
🇫🇷PARIS Cedex 12, France
Investigational Site Number :2500003
🇫🇷Lyon, France
Investigational Site Number :2500004
🇫🇷PARIS Cedex 19, France
Investigational Site Number :2760003
🇩🇪Hamburg, Germany
Investigational Site Number :2760005
🇩🇪Erlangen, Germany
Investigational Site Number :2760006
🇩🇪Münster, Germany
Investigational Site Number :3800001
🇮🇹Monza, Lombardia, Italy
Investigational Site Number :4100001
🇰🇷Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :3800003
🇮🇹Torino, Piemonte, Italy
Investigational Site Number :4100002
🇰🇷Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :4100004
🇰🇷Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :5780002
🇳🇴Oslo, Norway
Investigational Site Number :5780001
🇳🇴Bergen, Norway
Investigational Site Number :7520001
🇸🇪Göteborg, Sweden
Investigational Site Number :3800002
🇮🇹Genova, Liguria, Italy