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) SAR443579

What's the purpose of this trial?

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.

This trial is currently open and accepting patients.


What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

Inclusion Criteria:

- Participant must be at least 1 year 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 12 years old.
  • Pediatric arm: aged 1 to 17 years old.

For participants of the Escalation Part only:

- Adult and Pediatric Arms: Confirmed diagnosis of primary or secondary AML [any subtype except acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML)] 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.

Examples include but are not limited to:

  • One cycle of high dose cytarabine (HiDAC) containing regimen
  • One cycle of liposomal cytarabine and daunorubicin
  • Two cycles of standard dose cytarabine containing regimen

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 duration < 6 months on prior induction treatment

c) Leukemia in first or higher relapse

d) For participants aged 1 to 17 years old, primary induction failure is defined as disease refractory after two cycles of induction therapy.

  • Adult arm only: Confirmed diagnosis of cluster of differentiation 123 (CD123) + HR-MDS, with a Revised International Prognostic Scoring System (IPSS-R) risk category of intermediate or higher and are limited to those with no available (or are ineligible) therapy with known clinical benefit.

    • Not eligible for induction therapy and having completed ≥2 cycles of any of the following: hypomethylating agent (eg, 5 azacitidine or decitabine) and/or venetoclax, chemotherapy, or targeted agents.
    • Not eligible for autologous stem cell transplant (ASCT) and having completed ≥1 course of induction therapy.
  • Adult and Pediatric arms and escalation part only: Confirmed diagnosis of CD123+ B-ALL without extramedullary lesions that have no available (or are ineligible) therapy with known clinical benefit.

For Participants in the Expansion Part Only (Adults only):

  • For participants in Cohort A: Participants meeting inclusion criteria for AML participants that have been primary refractory (PIF) to prior induction treatment or who have had ER occurring 6 months or less after an initial remission on prior induction treatment.
  • For participants in Cohort B: Participants meeting inclusion criteria for AML participants that have had late relapse (LR), occurring more than 6 months after an initial remission on prior induction treatment.
  • 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.
  • Pediatric arm and expansion part only: For participants in Cohort C: Participants with AML who have relapsed according to inclusion criteria for AML or have recurrent disease resistant or intolerant to available therapies.

Exclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status >2 (≥18 years-old). Karnovsky Scale (16-17 years-old) <50% or Lansky Scale (<16 years-old) <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 that requires active therapy (adjuvant hormonal therapy is allowed) other than the one treated in this study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment.
  • Evidence of active central nervous system leukemia at the time of enrollment as evidenced by cytology or pathology. Except for participants aged 1 to 17 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 graft-versus-host disease (GVHD).
  • Receiving at the time of first investigational medicinal product (IMP) administration corticosteroid as a concomitant medication with corticosteroid dose >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.
  • Radiotherapy, even if palliative in intent, may not be given during the study.
  • Prophylactic use of hematopoietic growth factors (eg, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin) during the DLT observation period in the Dose Escalation Part only. - Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
  • Pregnant and breast-feeding women.
  • History of solid organ transplant, including corneal transplant.
  • Average QTc (using the Fridericia correction calculation) greater than 470 milliseconds (msec) at screening. For pediatric arm participants only, inadequate ejection fraction as per institutional standards at screening or any clinically significant cardiac conditions (including but not limited to congestive heart failure, myocarditis, pericarditis, arrythmias).
  • 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.

The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.


Additional Trial Information

Phase 1/2

Enrollment: 126 patients (estimated)

View More

Published Results

A first-in-human study of CD123 NK cell engager SAR443579 in relapsed or refractory acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or high-risk myelodysplasia

January 27, 2023

With a cutoff date of January 27, 2023, total 23 patients with R/R AML across 6 DLs (3 patients DL1 and 4 each in DL2 - DL6) were included in the safety population. The median age was 70 years (range: 21 - 80) with 9 patients (39.1%) reporting prior hematopoietic stem cell transplantation (HSCT) and 16 (69.6%) had prior exposure to venetoclax. Patients received a median of 2 cycles (range: 1 – 7) for median duration of 7 weeks (range: 1 - 25) and escalating doses of SAR’579 between 10 - 3000 µg/kg/dose in cycle 1 and 100 - 3000 µg/kg QW for the rest of induction cycles. No dose limiting toxicities (DLTs) were observed among the 21 DLT-evaluable patients, until highest dose of 3000 µg/kg QW. The most common treatment emergent adverse events (TEAEs) included infusion-related reactions (n = 10 [43.5%]) and nausea (n = 7 [30.4%]). TEAEs were reported in 22 patients (95.7%) with grade 3/4 adverse events (AEs) in 18 (78.3%) and treatment-related AEs in 16 patients (69.6%), respectively. There were 2 cases of cytokine release syndrome (n = 1 grade 1 and n = 1 grade 2) and no case of immune effector cell-associated neurotoxicity syndrome. No patient reported TEAE leading to permanent discontinuation of SAR’579. The CRc rate was 13.0% (3/23 patients evaluable for response). In DLs with a highest dose of 1000 µg/kg QW, 3/8 (37.5%) patients achieved a CR (2 CR/1 CRi). The median time to first CR/CRi was 16.1 weeks 95% confidence interval (8.1 – Not Estimable [NE]), and the median duration of CR/CRi is NE due to limited follow-up time. Conclusions: SAR’579 was well tolerated up to doses of 3000 µg/kg QW with observed clinical benefit in patients with R/R AML. The trial continues to accrue patients.

Trial Locations

All Trial Locations

View all clinical trial locations sorted by state.

California

City of Hope Comprehensive Cancer Center Beckman Research Institute

Duarte, CA

Open and Accepting

Georgia

Winship Cancer Institute Emory University

Atlanta, GA

Open and Accepting

Massachusetts

Beth Israel Deaconess Medical Center

Boston, MA

Open and Accepting

New York

Montefiore Medical Center

Bronx, NY

Open and Accepting

Weill Cornell

New York, NY

Open and Accepting

Ohio

Oregon

Oregon Health and Science University OHSU Knight Cancer Institute

Portland, OR

Open and Accepting

Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, PA

Open and Accepting

Texas

MD Anderson Cancer Center The University of Texas

Houston, TX

Open and Accepting

Washington

Seattle Children's Hospital

Seattle, WA

Open and Accepting
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