Acute Lymphocytic Leukaemia, Acute Myeloid Leukaemia Refractory, Blastic Plasmacytoid Dendritic Cell Neoplasia, Myelodysplastic Syndromes
Conditions
Brief summary
This is an open-label, multicenter, Phase 1/Phase 2, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics and anti-leukemic activity of SAR443579 in various hematological malignancies.
Detailed description
Study duration per participant is 2.5 years.
Interventions
DRUGSAR443579
Powder for solution for infusion; by IV infusion
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be at least 1 year (for France: 2 years) old at the time the trial participant or legal guardian signs the informed consent form and will be assigned as follows: * Adult arm: aged at least 18 years old. * Pediatric arm: aged 1 (for France: 2 years) to less than 18 years old. * Adult and Pediatric Arms: Escalation and Expansion/Optimization Cohorts A1, A2, C, D: Confirmed diagnosis of primary or secondary AML (any subtype) according to World Health Organization (WHO) 2022 classification. Participants with AML must meet one of the following criteria, a), b), c) or d) and are limited to those with no available (or are ineligible) therapy with known clinical benefit. a) Primary Induction Failure (PIF) AML, defined as disease refractory to one of the following, i or ii. i) An intensive induction attempt, per institution. Induction attempts include high-dose and/or standard-dose cytarabine ± an anthracyclines/anthracenedione ± an anti-metabolite, with or without growth factor or targeted therapy containing regimens. ii) For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; PIF is defined as AML refractory to one of the following less intensive regimens, 1 or 2: 1. 4 cycles of hypomethylating agents (HMA) or 2. 2 cycles HMA + venetoclax b) Early relapse (ER) AML, defined as AML in relapse with CR, CRh or CRi duration less than 6 months on prior induction treatment c) Leukemia in first or higher relapse d) For participants aged 1 (for France: 2 years) to less than 18 years old, primary induction failure is defined as disease refractory after two cycles of induction therapy. * Adult Arm (Escalation and Expansion/Optimization Cohorts B and Japan Cohort C only): Confirmed diagnosis of MDS, meeting the following criteria: 1. intermediate or high-risk category as per a Revised International Prognostic Scoring System (IPSS-R) AND 2. confirmed CD123 + expression status determined by local institutional standards AND 3. limited to those with no available (or are ineligible) therapy with known clinical benefit. * Pediatric arms escalation part and Japan Cohort C only: Confirmed diagnosis of CD123+ BALL without extramedullary lesions that have no available (or are ineligible) therapy with known clinical benefit. Participants with non-CNS chloromatous disease are not allowed in the study. * Body weight at least 10 kg. * Pediatric arm and escalation part only: Confirmed diagnosis of BPDCN according to World Health Organization (WHO) 2022 classification, who have relapsed or refractory disease with no available (or are ineligible) therapy with known clinical benefit. * Japan participants (Cohort C): Participant must be at least 18 years old at the time the trial participant signs the informed consent form
Exclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status greater than 2 (at least 18 years-old). Karnofsky Scale (16 to 17 years-old) less than 50% or Lansky Scale (less than 16 years-old) less than 50%. * Ongoing or recent (within 5 years) evidence of significant autoimmune disease that requires or required treatment with systemic immunosuppressive treatments, which may suggest a risk for immune-related adverse events. The following are not exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that required only hormone replacement or psoriasis that does not require systemic treatment. * History of an invasive malignancy within the last 3 years prior to first IMP administration that requires active therapy (adjuvant hormonal therapy is allowed) other than the one treated in this study. * Evidence of active central nervous system leukemia at the time of enrollment as evidenced by cytology or pathology. Except for participants aged 1 (for France: 2 years) to less than 18 years, central nervous system 1 disease (CNS1) and CNS2 disease are allowed. * Known acquired immunodeficiency syndrome (AIDS-related illnesses) or human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. * Prior treatment with an anti-CD123-directed agent (except for participants with BPDCN in the pediatric arm). * Prior HSCT with relapse beyond 3 months or prior CAR-T therapy in B-ALL with relapse beyond 2 months may be included only if off immunosuppression for a minimum of 4 weeks and no evidence of GVHD. * Receiving at the time of first investigational medicinal product (IMP) administration corticosteroid as a concomitant medication with corticosteroid dose more than 10 mg/day of oral prednisone or the equivalent. * AML, BPDCN, or HR-MDS participants with prior treatment with cellular therapy, eg, chimeric antigen receptor T cell (CAR-T) or chimeric antigen receptor NK cell (CAR-NK). Prior CAR-T therapy is allowed for participants with B-ALL. * Concurrent treatment with other investigational drugs. * Pregnant and breast-feeding women. * History of solid organ transplant, including corneal transplant. * Average QTc (using the Fridericia correction calculation) greater than 470 millisecond (msec) at screening. * Pediatric arm only: Participants with known inherited bone marrow failure syndromes (e.g., bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome). Participants with Down syndrome with adequate organ function as per Investigator discretion are allowed to participate in the study. * Adult arm Expansion/Optimization- Participants with MDS evolving from a pre-existing myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), unclassifiable MDS/MPN and therapy-related MDS (t-MDS). * Confirmed diagnosis of acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML) according to WHO 2022 classification. The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 Day 1 up to Cycle 1 Day 28. Each cycle duration in induction period was 28 days. | The DLT was defined as any of the following events during Cycle 1 (first 28 days) using NCI CTCAE v5.0 or ASTCT criteria, whether related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to disease progression. Hematologic DLTs included hematologic toxicities, bone marrow hypocellularity, decreased neutrophils lasting, febrile neutropenia, decreased platelet count lasting, anemia (all Grade 4), and Grade 3 thrombocytopenia. Non-hematologic DLTs included any Grade \>=3 toxicities except alopecia, Grade 3 fatigue, asthenia, fever, anorexia, constipation, nausea, vomiting, diarrhea, total parenteral nutrition, hospitalization related events, infection, bleeding, Grade 3 infusion related reaction and laboratory abnormalities, Grade 3 or 4 tumor lysis syndrome and isolated electrolyte abnormalities. Also, DLTs were any treatment related toxicity causing \>2 week delay in recovery to baseline/Grade \<=1 or requiring dose reduction. |
| Dose Escalation (Cohort C): Number of Participants With Dose Limiting Toxicities | Cycle 1 Day 1 to Cycle 1 Day 28. Each cycle duration in induction period was 28 days. | The DLT was defined as any of the following events during Cycle 1 (first 28 days) using NCI CTCAE v5.0 or ASTCT criteria, whether related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to disease progression. Hematologic DLTs included hematologic toxicities, bone marrow hypocellularity, decreased neutrophils lasting, febrile neutropenia, decreased platelet count lasting, anemia (all Grade 4), and Grade 3 thrombocytopenia. Non-hematologic DLTs included any Grade \>=3 toxicities except alopecia, Grade 3 fatigue, asthenia, fever, anorexia, constipation, nausea, vomiting, diarrhea, total parenteral nutrition, hospitalization related events, infection, bleeding, Grade 3 infusion related reaction and laboratory abnormalities, Grade 3 or 4 tumor lysis syndrome and isolated electrolyte abnormalities. Also, DLTs were any treatment related toxicity causing \>2 week delay in recovery to baseline/Grade \<=1 or requiring dose reduction. |
| Dose Expansion (Cohorts A1, A2 and D): Composite Complete Remission (CRc) Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | The CRc rate was defined as the percentage of participants who had a response of complete remission (CR), CR with partial hematologic recovery (CRh) or CR with incomplete hematologic recovery (CRi) according to modified AML International Working Group (IWG) 2003 response criteria. |
| Dose Expansion (Cohort B): Overall Response Rate (ORR) | Tumors were planned to assess on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. | The ORR was defined as the percentage of participants who had a response of CR, CR equivalent, partial remission (PR), CR with limited count recovery (CRL), CRh or hematologic improvement (HI) according to IWG 2023 myelodysplastic syndrome (MDS) response criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Expansion (Cohorts A1, A2, B and D): Recommended Dose for Expansion (RDE) | Cycle 1 Day 1 up to Cycle 1 Day 28. Each cycle duration in induction period was 28 days. | The RDE of SAR443579 was determined based on the occurrence of DLTs in Cycle 1. |
| Dose Escalation and Dose Expansion (Cohort A1): Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (SAEs) | From the first dose of study drug administration (Day 1) up to early termination of the study, maximum treatment duration was 117.3 weeks for dose escalation (adult), 12 weeks for dose escalation (pediatric) and 20.9 for dose expansion (Cohort A1). | An adverse event (AE) was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any AE that: resulted in death; or was life-threatening; or required inpatient hospitalization or prolongation of existing hospitalization; or resulted in persistent or significant disability/incapacity; or was a congenital anomaly/birth defect; or was an important medical event. The TEAEs were defined as events that were newly reported or reported to worsen in severity after the first administration of study treatment up to 30 days after the last administration of study treatment. |
| Dose Escalation and Dose Expansion (Cohort A1): Minimum Plasma Concentration (Ctrough) of SAR443579 | At Days 1, 4, 8, 11, 15, 22, and 28 of Cycle 1 | Blood samples are collected just before treatment administration during repeated dosing to determine the Ctrough of SAR443579. |
| Dose Escalation and Dose Expansion (Cohort A1): Percentage of Participants With Anti-drug Antibodies (ADA) Against SAR443579 | From the first dose of study drug administration (Day 1) up to early termination of the study, maximum treatment duration was 117.3 weeks for dose escalation (adult), 12 weeks for dose escalation (pediatric) and 20.9 for dose expansion (Cohort A1). | Plasma samples were collected to assess the antibodies to SAR443579. Treatment-emergent ADA was defined as a participant with at least 1 treatment-induced or treatment-boosted ADA-positive sample at any time during the treatment or follow-up observation period. Non-treatment emergent ADA was defined as participant without any treatment-induced, treatment-boosted ADA-positive or ADA-inconclusive sample during the treatment or follow-up observation period. |
| Dose Escalation and Dose Expansion (Cohort C): Composite Complete Remission Rate Assessed by Acute Myeloid Leukemia 2003 Modified International Working Group Response Criteria and National Comprehensive Cancer Network (NCCN) | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapse, unacceptable AE, discontinuation or death. Maximum treatment duration: 117.3 weeks (adults) and 12 weeks (pediatrics) in dose escalation phase. | The CRc rate was defined as the percentage of participants who had a response of CR, CRh or CRi according to modified AML IWG 2003 response criteria. For Dose Expansion (Cohort C), the CRc rate was planned to be assessed according to NCCN. |
| Dose Escalation and Dose Expansion (Cohort C): Alternative Complete Remission Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapse, unacceptable AE, discontinuation or death. Maximum treatment duration: 117.3 weeks (adults) and 12 weeks (pediatrics) in dose escalation phase. | Alternative CR rate was defined as percentage of participants with CR and CRh according to modified AML IWG 2003 response criteria. |
| Dose Escalation and Dose Expansion (Cohort C): Overall Response Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapse, unacceptable AE, discontinuation or death. Maximum treatment duration: 117.3 weeks (adults) and 12 weeks (pediatrics) in dose escalation phase. | Overall response rate was defined as percentage of participants who had a CR or CRi or CRh or PR or morphological leukemia-free state (MLFS) according to modified AML IWG 2003 response criteria. |
| Dose Expansion (Cohorts A1, A2 and D): Overall Response Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | Overall response rate was defined as percentage of participants who had a CR or CRi or CRh or PR or MLFS according to modified AML IWG 2003 response criteria. |
| Dose Expansion (Cohorts A1, A2 and D): Duration of Composite Complete Remission Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | Duration of CRc was defined as the time interval from first documented evidence of CRc (CR, CRh or CRi) until disease relapse (DR) or death due to any cause, whichever comes first. |
| Dose Expansion (Cohorts A1, A2, B and D): Duration of Overall Response Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | Duration of overall response rate was defined as the time from the first documented evidence of CR or CRi or CRh or PR or MLFS until DR or death due to any cause, whichever comes first. |
| Dose Expansion (Cohorts A1, A2, B and D): Alternative Complete Remission Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | Alternative CR rate was defined as percentage of participants with CR and CRh according to modified AML IWG 2003 response criteria. |
| Dose Expansion (Cohorts A1, A2, B and D): Duration of Alternative Complete Remission Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | Duration of alternative CR was defined as the time from the first documented evidence of CR or CRh until DR or death due to any cause, whichever comes first. |
| Dose Expansion (Cohorts A1, A2, B and D): Event-Free Survival (EFS) | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | The EFS was defined as the time interval from the first day of treatment assignment to the date of earliest evidence of relapse, treatment failure, or death. |
| Dose Expansion (Cohorts A1, A2, B and D): Overall Survival (OS) | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | The OS was defined as time interval from the first day of treatment assignment to death from any cause. |
| Dose Expansion (Cohorts A1, A2, B and D): Rate of Hematopoietic Stem Cell Transplantation (HSCT) | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | The HSCT rate was defined as the percentage of participants who had received HSCT immediately following study treatment administration but prior to subsequent therapy for treatment of AML. |
| Dose Expansion (Cohorts A1, A2, B and D): Time to Treatment Failure (TTF) | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | The TTF was defined as the time from first day of treatment assignment to discontinuation for any reason excluding remission, example, relapsed disease, refractory disease, unacceptable AE, participant preference or death. |
| Dose Expansion (Cohorts A1, A2 and D): Transfusion Independence (TI) Rate | Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks. | The TI rate was defined differently for participants who were transfusion dependency (TD) at baseline and participants who were transfusion independency (TI) at baseline. For subgroup of participants with TD at baseline, the TI rate was defined as the percentage of participants who convert from baseline TD to TI during on treatment period; For subgroup of participants with TI at baseline, the TI rate was defined as the percentage of participants who remain TI during 56-day post baseline period during treatment. |
| Dose Expansion (Cohort B): Progression Free Survival (PFS) | Tumors were planned to assess on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. | The PFS was defined as the time interval from the first day of treatment assignment to the date of disease progression, relapse from CR (or CR equivalent), PR, CRL, CRh, or HI, death due to any cause, whichever comes first. |
Countries
Australia, China, France, Netherlands, United States
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
The study was conducted at 21 centers across 5 countries between 08 December 2021 and 13 June 2025. A total of 101 eligible participants were enrolled, including 69 in the Dose Escalation - Adult arm, 12 in the Dose Escalation - Pediatric arm, and 20 in the Dose Expansion - Adult arm. All enrolled participants received the study treatment.
Pre-assignment details
Study included adult (\>=18 years) and pediatric (1 to \<18 years; \>=2 years in France) arms with dose escalation and dose expansion/optimization phases. Study was terminated after completion of dose escalation phase of adult and pediatric arms and dose expansion/optimization phase of adult arm (Cohort A1), for non-safety related reasons. Dose expansion/optimization part of adult (Cohorts A2, B and C) and pediatric arms (Cohort D) were not initiated. Only results from completed parts are reported.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 54.2 years STANDARD_DEVIATION 23.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 4 | 5 / 6 | 5 / 10 | 3 / 4 | 3 / 4 | 4 / 8 | 6 / 6 | 3 / 4 | 4 / 4 | 5 / 8 | 8 / 8 | 5 / 6 | 6 / 6 | 16 / 20 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 6 / 6 | 9 / 10 | 3 / 4 | 4 / 4 | 8 / 8 | 5 / 6 | 4 / 4 | 4 / 4 | 6 / 8 | 8 / 8 | 5 / 6 | 6 / 6 | 19 / 20 |
| serious Total, serious adverse events | 2 / 3 | 3 / 4 | 4 / 6 | 7 / 10 | 3 / 4 | 3 / 4 | 3 / 8 | 5 / 6 | 2 / 4 | 3 / 4 | 5 / 8 | 2 / 8 | 4 / 6 | 5 / 6 | 14 / 20 |
Outcome results
None listed