Clinical trial NCT05086315: First-in-human Study of SAR443579 Infusion in Male and Female Children and Adult Participants With Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-cell Acute Lymphoblastic Leukemia (B-ALL), High Risk-myelodysplasia (HR-MDS), or Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Official title: An Open-label, First-in-human, Dose-escalation/Expansion Study of SAR443579 Administered as Single Agent by Intravenous Infusion in Adult and Pediatric Participants With Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-cell Acute Lymphoblastic Leukemia (B-ALL), High Risk-myelodysplasia (HR-MDS), or Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Lymphocytic Leukaemia
Acute Myeloid Leukaemia Refractory
Myelodysplastic Syndromes
Blastic Plasmacytoid Dendritic Cell Neoplasia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2021-10-20
Enrollment: 169
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Escalation Part: Incidence of dose-limiting toxicity (DLT)
timeFrame: Day 1 to Day 28
measure: Japan Cohort C: Incidence of DLT in Japanese participants
timeFrame: Day 1 to Day 28
measure: Expansion/Optimization part (Cohorts A1, A2 & D), AML: Proportion of participants who have a CR + CRh + CRi according to the modified AML IWG 2003 criteria
timeFrame: Up to 6 months
measure: Expansion/Optimization part (Cohort B), MDS: Overall response rate (CR + CR equivalent + PR + CRL + CRh + HI) according to the IWG 2023 MDS response criteria
timeFrame: Up to 6 months
Secondary outcomes:
measure: Expansion/Optimization part - Cohorts A, B and D: Recommended dose for expansion (RDE)
timeFrame: Up to 12 months
measure: Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Number of participants with TEAEs
timeFrame: Up to 30 months
measure: Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Ctrough
timeFrame: Day 1 to end of trial (maximum up to 30 months)
measure: Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Incidence of ADA
timeFrame: Up to 30 months
measure: Escalation and Expansion/Optimization parts - Japan Cohort C, AML: Rate of CR + CRh + CRi per AML 2003 modified IWG response criteria
timeFrame: Up to 6 months
measure: Escalation and expansion/Optimization parts - Japan Cohort C, MDS: CR rate and ORR rate per IWG 2023 MDS response criteria for escalation part and ORR rate per IWG 2023
timeFrame: Up to 6 months
measure: Escalation and Expansion/Optimization parts - Japan Cohort C, B-ALL: Rate of CR + CRh + CRi as defined by National Comprehensive Cancer Network (NCCN)
timeFrame: Up to 6 months
measure: Expansion/Optimization part - Cohorts A and D: Overall response rate (ORR)
timeFrame: Up to 6 months
measure: Expansion/Optimization part - Cohorts A and D: Duration of CR + CRh + CRi (Duration of CRc)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohorts A and D: Duration of CR + CRi + CRh + PR + MLFS (Duration of overall response rate)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohorts A and D: Alternative CR rate
timeFrame: Up to 6 months
measure: Expansion/Optimization part - Cohorts A and D: Duration of CR + CRh (Duration of alternative CR)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohorts A and D: Event-free survival (EFS)
timeFrame: Up to 6 months
measure: Expansion/Optimization part - Cohorts A and D: Overall survival (OS)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohorts A and D: Rate of hematopoietic stem cell transplantation (HSCT)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohorts A and D: Time to treatment failure (TTF)
timeFrame: Up to 6 months
measure: Expansion/Optimization part - Cohorts A and D: Rate of conversion from transfusion dependence
timeFrame: Day 0 to Day 56
measure: Expansion/Optimization part - Cohorts A and D: Rate of participants who are transfusion independent at baseline and remain independent during 56-day postbaseline period
timeFrame: Day 0 to Day 56
measure: Expansion/Optimization part - Cohort B: Alternative CR rate
timeFrame: Up to 6 months
measure: Expansion/Optimization part - Cohort B: Duration of ORR
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohort B: Event-free survival (EFS)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohort B: Overall survival (OS)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohort B: Rate of hematopoietic stem cell transplantation (HSCT)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohort B: Time to treatment failure (TTF)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohort B: Duration of alternative CR (CR + CR equivalent + CRL + CRh)
timeFrame: Up to 30 months
measure: Expansion/Optimization part - Cohort B: Progression free survival (PFS)
timeFrame: Up to 30 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope-Site Number:8400002
state: California
city: Atlanta
country: United States
facility: Emory University- Site Number : 8400006
state: Georgia
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center-Site Number:8400004
state: Massachusetts
city: Bronx
country: United States
facility: Montefiore Medical Center - Einstein Campus- Site Number : 8400012
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College-Site Number:8400003
state: New York
city: Columbus
country: United States
facility: The Ohio State University- Site Number : 8400009
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University-Site Number:8400011
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia-3401 Civic Center Blvd Site Number : 8400013
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia- Site Number : 8400013
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center-Site Number:8400001
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital- Site Number : 8400014
state: Washington
city: Melbourne
country: Australia
facility: Investigational Site Number :0360002
state: Victoria
city: Melbourne
country: Australia
facility: Investigational Site Number :0360001
state: Victoria
city: Tianjin
country: China
facility: Investigational Site Number : 1560001
city: Zhengzhou
country: China
facility: Investigational Site Number : 1560003
city: Marseille
country: France
facility: Investigational Site Number :2500002
city: Paris
country: France
facility: Investigational Site Number :2500001
city: Paris
country: France
facility: Investigational Site Number : 2500004
city: Villejuif
country: France
facility: Investigational Site Number :2500003
city: Amsterdam
country: Netherlands
facility: Investigational Site Number :5280002
city: Groningen
country: Netherlands
facility: Investigational Site Number :5280003
city: Nijmegen
country: Netherlands
facility: Investigational Site Number : 5280005
city: Rotterdam
country: Netherlands
facility: Investigational Site Number :5280001
city: Utrecht
country: Netherlands
facility: Investigational Site Number :5280004
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: