Study Evaluating Safety and Efficacy of UCART123 in Patients With Acute Myeloid Leukemia

This study's primary objective is to assess the safety and tolerability of Universal Chimeric
Antigen Receptor (CAR) T-cells targeting Cluster of Differentiation (CD) 123 (UCART123)
administered to patients with relapsed/refractory and newly diagnosed high-risk acute myeloid
leukemia (AML), and to determine the Maximum Tolerated Dose (MTD) of UCART123. The primary
benefit expected from UCART123 for participating patients is a high degree of T-cell
expansion that could induce high and sustained anti-CD123 activity, leading to durable
remission in poor-prognosis patients with AML. Also, patients are expected to benefit from
the immediate availability of UCART123 cells and the higher, more homogenous transduction
success rate expected from healthy allogeneic cells, compared to autologous T-cells. The
absence of cell-surface expression of the TCR complex on UCART123 eliminates the
TCR-recognition of histocompatibility antigens, the primary mechanism of GVHD, and confers a
"universal" character to UCART123, which circumvents the necessity of human leukocyte antigen
(HLA) matching between donor and recipient.

Main Inclusion Criteria:

- AML blast cells expressing CD123 by flow cytometry performed as per standard practice

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

- Estimated life expectancy >12 weeks

- Adequate organ function, including renal and hepatic function based on the last
assessment performed within the Screening Period

i. Creatinine clearance ≥60 mL/min (assessed as glomerular filtration rate using the
Cockcroft & Gault formula or MDRD); ii. Alanine aminotransferase or aspartate
aminotransferase <3 × upper limit of normal (ULN); iii. Total bilirubin <2 × ULN
(except for patients with documented history of Gilbert's Syndrome confirmed by UGT1A1
mutation); iv. Left ventricular ejection fraction (LVEF) ≥50% as assessed by
echocardiography or Multi Gated Acquisition Scan (MUGA); and v. Must have a minimum
level of pulmonary reserve defined as Grade <2 dyspnea and pulse oxygenation ≥92% on
room air.

Patients enrolled in the Dose-Escalation Phase of the Study:

- Patients with acute promyelocytic leukemia (APL) are not eligible;

- Patients who are considered primary refractory to treatment must have received
induction therapy with at least two cycles of an anthracyclinewith standard-dose
cytarabine, or at least one cycle of induction including intermediate-dose or
high-dose cytarabine;

- Patients who are considered to have relapsed after treatment must have achieved
pathologically documented CR after treatment and must have received at least one
course of treatment with an anthracycline/cytarabine combination OR one course of
treatment with a hypomethylating agent (note: one course is defined as at least 4
five-day cycles of eitherdecitabine or azacitidine);

- Patients relapsing after an autologous or allogeneic stem cell transplantation is
eligible if they have recovered from all transplantrelated toxicities and are off all
immunosuppression for at least 6 weeks,with no evidence of acute or chronic
graft-versus-host disease (GvHD); and

- Patients enrolled into the dose-escalation phase of the study must have an identified
donor and transplant strategy prior to initiation of the lymphodepletion regimen. This
will ensure that HSCs are available for a potential urgent allogeneic stem cell
transplantation to be performed (including matched related or unrelated donor, cord
blood transplant, orhaploidentical donor) in the event of persistent marrow aplasia
without evidence of residual leukemia. The potential donor will have been evaluated at
the transplant center and cleared for donation, per transplant center policies.
Suitability of unrelated donors implies that human leukocyte antigen typing has been
confirmed, and that the donor has expressed willingness and availability to donate.
Suitability for cord blood donors implies that a qualifying cord blood unit - as per
the center's criteria - has been identified and reserved.

Patients enrolled in the Dose-Expansion Phase of the Study:

Relapsed/Refractory Cohort

• Patients with relapsed or primary refractory (i.e., never having achieved Complete
Remission) AML (as defined in World Health Organization (WHO) criteria) with >5% bone
marrow blasts.

Newly Diagnosed Cohort

• Patients with newly diagnosed, untreated AML (as defined by WHO criteria), who meet
criteria for the ELN adverse genetics prognostic group. This includes de novo leukemia,
therapy-related leukemia after prior chemotherapy and/or radiation, and secondary leukemia
arising from an antecedent hematologic disorder.

Eligibility criteria for UCART123 administration

- No active uncontrolled infections

- Afebrile (<38°C per CTCAE v4.03)

- Normal organ function since eligibility screening, and no new clinical or laboratory
findings that, in the opinion of the investigator, might jeopardize the patient's
safety

- Off all but replacement dose of corticosteroids from Day 0 to Day 28 of the considered
UCART123 administration (replacement dose is the patient's individualized dose defined
for physiological replacement)

Main Exclusion Criteria:

- Previous treatment with investigational gene or chimeric antigen receptor therapy.

- Active or previous central nervous system leukemia involvement.

- Presence of active and clinically relevant Central Nervous System (CNS) disorder.

- Use of rituximab and other anti-cluster of differentiation 20 (CD20) antibodies known
to have the same epitope as rituximab or anti-CD20 antibodies for which the epitope is
unknown within 3 months prior to start of lymphodepletion.

- Patients may not receive ≥ 20 mg of prednisone or equivalent between Days -7 and +28
of UCART123 infusion. Hydrocortisone required for mineralocorticoid replacement
therapy is authorized at all times as needed clinically. Topical, inhaled, or nasal
route of steroids are permitted.

- Known infection with Human Immunodeficiency Virus (HIV) or Human T-cell
leukemia/lymphoma virus type 1 (HTLV-1).

- A known hypersensitivity to any of the test materials or related compounds including
murine and bovine products.

- Any known uncontrolled cardiovascular disease.

- Active bacterial, fungal or viral infection not controlled by adequate treatment, at
enrollment.