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

Acute Myeloid Leukemia Clinical Trial

— ISAKIDS  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03860844
• Other study ID #: ACT15378
• Secondary ID: PIP - 2018-00269
• Status: Terminated
• Phase: Phase 2
• Start date: August 6, 2019
• Est. completion date: May 26, 2023

Study information

• Verified date: April 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Terminated
• Enrollment: 67
• Est. completion date: May 26, 2023
• Est. primary completion date: September 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 28 Days to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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

Locations

Country	Name	City	State
Argentina	Investigational Site Number :0320004	Buenos Aires
Argentina	Investigational Site Number :0320005	Buenos Aires
Argentina	Investigational Site Number :0320002	Caba	Buenos Aires
Argentina	Investigational Site Number :0320006	Capital Federal	Buenos Aires
Brazil	Investigational Site Number :0760006	Curitiba	Paraná
Brazil	Investigational Site Number :0760013	Curitiba	Paraná
Brazil	Investigational Site Number :0760010	Jau	São Paulo
Brazil	Investigational Site Number :0760007	Porto Alegre	Rio Grande Do Sul
Brazil	Investigational Site Number :0760009	Ribeirao Preto	São Paulo
Brazil	Investigational Site Number :0760001	Sao Paulo	São Paulo
Brazil	Investigational Site Number :0760004	Sao Paulo	São Paulo
Denmark	Investigational Site Number :2080001	Copenhagen
France	Investigational Site Number :2500002	Lille
France	Investigational Site Number :2500003	Lyon
France	Investigational Site Number :2500001	PARIS Cedex 12
France	Investigational Site Number :2500004	PARIS Cedex 19
Germany	Investigational Site Number :2760005	Erlangen
Germany	Investigational Site Number :2760003	Hamburg
Germany	Investigational Site Number :2760006	Münster
Greece	Investigational Site Number :3000001	Athens
Hungary	Investigational Site Number :3480002	Budapest
Italy	Investigational Site Number :3800002	Genova	Liguria
Italy	Investigational Site Number :3800001	Monza	Lombardia
Italy	Investigational Site Number :3800003	Torino	Piemonte
Italy	Investigational Site Number :3800005	Verona	Veneto
Korea, Republic of	Investigational Site Number :4100001	Seoul	Seoul-teukbyeolsi
Korea, Republic of	Investigational Site Number :4100002	Seoul	Seoul-teukbyeolsi
Korea, Republic of	Investigational Site Number :4100004	Seoul	Seoul-teukbyeolsi
Mexico	Investigational Site Number :4840005	Col. Rancho Menchaca	Querétaro
Mexico	Investigational Site Number :4840001	Monterrey	Nuevo León
Netherlands	Investigational Site Number :5280001	Utrecht
Norway	Investigational Site Number :5780001	Bergen
Norway	Investigational Site Number :5780002	Oslo
Peru	Investigational Site Number :6040001	Arequipa
Peru	Investigational Site Number :6040002	Lima
Portugal	Investigational Site Number :6200002	Coimbra
Portugal	Investigational Site Number :6200001	Lisboa
Portugal	Investigational Site Number :6200003	Porto
Sweden	Investigational Site Number :7520001	Göteborg
United States	Children's Medical Center of Dallas-Site Number:8400002	Dallas	Texas
United States	Sarah Cannon Research Institute-Site Number:8400001	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Denmark,  France,  Germany,  Greece,  Hungary,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Norway,  Peru,  Portugal,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
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.	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)
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.	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)
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.	From Week 0 to Week 1, Week 0 to Week 5, and Week 0 to Week 10
Secondary	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
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.	Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 1 Day 29, Cycle 2 Day 43, Cycle 2 Day 57
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.	Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15
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.	At end of infusion on Cycle 1 Days 1 and 29
Secondary	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
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.	From screening until the study completion date, approximately 45 months
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.	From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
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.	From first study treatment administration up to death due to any cause, a maximum of 45 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.	From study treatment administration up to the date of first documented disease progression or death due to any cause, a maximum of 45 months
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.	From first documented response up to the date of first documented disease progression or death due to any cause, a maximum of 45 months
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.	Pre-dose on Day 1
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.	Pre-dose on Day 15