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)

The intensive first-line treatment for AML usually includes cytosine
arabinoside and anthracycline induction therapy, followed by consolidation
chemotherapy with cytarabine or other agents. Recent innovations for first-line
therapy include the use of liposomal daunorubicin/cytarabine or the addition of
an FLT3 inhibitor. For patients who cannot tolerate initial intensive
chemotherapy combinations, the BCL2 inhibitor venetoclax in combination with a
hypomethylating agent or low dose cytarabine (LDAC) provides better results
than previous monotherapy regimens. Allogeneic stem cell transplantation is
offered to patients with high-risk disease in first or subsequent remission,
provided they have adequate organ function and a suitable source of stem cells.
Despite this aggressive therapeutic approach, the most recent 5-year US
survival rate based on 2011-2017 data was 29.5%. Despite advances in
understanding the pathophysiology of AML and recognizing its molecular
heterogeneity, it is challenging to develop viable therapies for patients with
AML. New agents are needed to achieve a better response that prolongs overall
survival, especially for patients with relapsed or refractory disease, and to
improve quality of life.
Recent studies support the need for more tolerable and highly effective
therapies for hematologic malignancies. As for AML, the most effective
therapies for B-ALL and HR-MDS include intensive multi-agent chemotherapy
and/or allogeneic stem cell transplantation. However, many patients with these
diseases are of advanced age or have co-morbidities that preclude these
aggressive, highly toxic therapies. In addition, not all patients recover with
intensive therapy and/or allogeneic transplantation and the risk of
treatment-related toxicity is high. Although approximately 15% of patients >60
years and 40% of patients <60 years who receive intensive induction
chemotherapy and/or allogeneic stem cell transplantation for AML are cured, AML
patients with relapsed or refractory disease have a poor prognosis after
initial therapy . The most recent 5-year US survival rate based on 2011-2017
data is 29.5%. There has been progress in understanding the pathophysiology of
AML and recognizing its molecular heterogeneity, but developing viable
therapies for patients with AML remains challenging.
Despite advances in understanding the pathophysiology of AML and recognizing
its molecular heterogeneity, it is challenging to develop viable therapies for
patients with AML. New agents are needed to achieve a better response that
prolongs overall survival, especially for patients with relapsed or refractory
disease, and to improve quality of life.
Recent studies support the need for more tolerable and highly effective
therapies for hematologic malignancies. As for AML, the most effective
therapies for B-ALL and HR-MDS include intensive multi-agent chemotherapy
and/or allogeneic stem cell transplantation. However, many patients with these
diseases are of advanced age or have co-morbidities that preclude these
aggressive, highly toxic therapies. In addition, not all patients recover with
intensive therapy and/or allogeneic transplantation and the risk of
treatment-related toxicity is high. Although approximately 15% of patients >60
years and 40% of patients <60 years who receive intensive induction
chemotherapy and/or allogeneic stem cell transplantation for AML are cured, AML
patients with relapsed or refractory disease have a poor prognosis after
initial therapy . The most recent 5-year US survival rate based on 2011-2017
data is 29.5%. There has been progress in understanding the pathophysiology of
AML and recognizing its molecular heterogeneity, but developing viable
therapies for patients with AML remains challenging. New agents are needed to
achieve a better response that prolongs overall survival, especially for
patients with relapsed or refractory disease, and to improve quality of life.
But despite the development of several new agents for relapsed or refractory
AML, it is mostly incurable. Short remission duration (ie < 6 months), adverse
genetic factors, prior allogeneic transplantation, advanced age, and poor
general health are factors associated in part with poorer survival outcomes in
the setting of R/R AML, in part because these factors affect the limit the
possibility of further intensive treatment.
As with AML, healing of B-ALL requires aggressive therapy that can be
associated with significant toxicity. For B-ALL, a two-year course of intensive
multi-agent chemotherapy and/or allogeneic stem cell transplantation can cure a
significant proportion of younger patients (aged <40 years), but the outcomes
for older adults are much worse. Although treatment with a CD19-targeted
chimeric antigen receptor T (CAR-T) has resulted in durable remissions, it is
not approved for administration to patients older than 25 years of age. In
addition, CD123 is frequently expressed on B-ALL cells both at diagnosis and
relapse, indicating that CD123-targeted therapy could be effective in this
indication, even in disease resistant to CD19-targeted therapy. For HR-MDS,
hypomethylating agents were the main treatment, while other treatment options
are limited. Allogeneic stem cell transplantation provides the only known cure
for HR-MDS, but is not always a treatment option, given the patient's age and
possible co-morbidities.
The haematological indications selected for the dose escalation (B-ALL, HR-MDS,
AML) and dose expansion (AML) have a high prevalence of CD123 positivity. This
supports not to pre-screen for CD123 expression.
There are several reasons to justify the inclusion of adolescents with relapsed
or refractory AML, B-ALL and HR-MDS. In accordance with recent FDA draft
guidelines, adolescent participants (12-17 years of age) are included in this
study when the first adult to be treated with DL3 has completed Cycle 1 without
the occurrence of a DLT and upon availability of sufficient PK data.
demonstrate exposure. In this study, adolescents will be included with relapsed
or refractory disease for which standard therapies with curative intent are
available. However, there are no CD123-targeted therapies approved for children
or adolescents. For patients with relapsed or refractory disease who are
currently ineligible for allogeneic stem cell transplantation (all indications)
or for CAR-T therapy (B-ALL), there are no standard therapies available with
curative intent, so participation in clinical trials is encouraged.
Initiation of maintenance treatment is supported by recent evidence suggesting
that long-term therapy in which CR or CRi is not achieved may provide a benefit
in overall survival or disease-free survival, especially for patients with R/R
AML. Once CR or CRi is achieved, the effector:target ratio will be
significantly improved, which will improve both efficacy and exposure after a
dose of SAR443579. Thus, dosing of SAR443579 every 8 weeks is expected to be
sufficient for maintenance dosing, but the dose and schedule for maintenance
therapy can be refined based on clinical data.

With PA#5, patients with BPDCN were added to the research group. Treatment
options for BPDCN typically include a combination of chemotherapy (usually
ALL-targeted), targeted therapy, stem cell transplantation, and supportive
care. Tagraxofusp (Elzonris) is an FDA-approved targeted therapy that
specifically targets CD123, a surface marker expressed in BPDCN cells. Notably,
participants with BPDCN treated with tagraxofusp were shown to maintain CD123
expression across disease progression, supporting the inclusion of participants
with prior tagraxofusp treatment. Tagraxofusp validates the use of a
CD123-targeted agent in BPDCN and warrants further investigation of this
SAR443579 in this indication.

This study has been transitioned to CTIS with ID 2023-508357-58-00 check the CTIS register for the current data.

The aim of the escalation portion of this study, in which SAR443579 is
administered for the first time in humans, is to establish the safety profile,
determine the maximum tolerated dose (MTD/MAD) and recommended phase II dose
(RP2D), and determine the PK profile. to characterize. The expansion portion of
the study assesses preliminary clinical activity at the RP2D in participants
with AML. Assessment of preliminary activity in HR-MDS or other indications may
be considered later in this study.

An open-label, first-in-human, dose-escalation study

SAR443579 will be administered as a single agent by intravenous (IV) infusion
in participants aged >=12 years with R/R AML, B-ALL, HR-MDS or (BPDCN).
Treatment consists of 3 cycles of 28 days in the Induction Phase, followed by
up to 13 cycles of 56 days in the Maintenance Phase.

The study includes a dose Escalation Part and a dose Expansion Part.
During the Escalation Part, dose escalation is planned through up to 6 main
doselevels (DLs). Depending on the DL, SAR443579 will be administered twice
weekly or once weekly in the first 1 or 2 weeks of Cycle 1 on Days 1, 4, 8 and
11 and once-weekly during the last 2 weeks of Cycle 1 (Day 15 and Day 22) and
all subsequent induction cycles (Days 1, 8, 15, and 22). When supported by PK
data, alternative schedules may be tested.

In the Expansion Part, the recommended phase II dose will be confirmed.

The risks are related to the blood samples and the biopies taken, and also the
possible side effects of the study drug and infusion reactions.

The burden for the patient are the frequent visits to the hospital including
the hospitalization on day 1 to 12 of the first cycle.