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Study Evaluating Safety and Efficacy of UCART123 in Patients With Acute Myeloid Leukemia (AML123)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03190278
Recruitment Status : Recruiting
First Posted : June 16, 2017
Last Update Posted : December 28, 2018
Information provided by (Responsible Party):
Cellectis S.A.

Brief Summary:
Phase I, first-in-human, open-label, dose-finding study of UCART123 administered intravenously to patients with Acute Myeloid Leukemia (AML), followed by a dose escalation phase in relapsed or refractory AML patients and a dose-expansion phase in relapsed/refractory AML patients, and in poor-prognosis, newly diagnosed AML patients in the European Leukemia Net (ELN) adverse genetic risk group.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Biological: UCART123 Phase 1

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I, Open Label Dose Escalation and Dose-Expansion Study to Evaluate the Safety, Expansion, Persistence, and Clinical Activity of UCART123 (Allogeneic Engineered T-cells Expressing Anti-CD123 Chimeric Antigen Receptor), Administered in Patients With Relapsed/Refractory Acute Myeloid Leukemia, and Patients With Newly Diagnosed High-Risk Acute Myeloid Leukemia
Actual Study Start Date : June 19, 2017
Estimated Primary Completion Date : June 15, 2021
Estimated Study Completion Date : December 15, 2021

Arm Intervention/treatment
Experimental: Part 1: Dose Escalation
A single IV administration of UCART123 in the dose escalation phase will explore 4 doses of UCART123 ranging from 1.25x10^5 cells/kg to 5.05x10^6 cells/kg and continue until the Recommended Phase 2 Dose (RP2D) is identified.
Biological: UCART123
Allogeneic engineered T-cells expressing anti-CD123 Chimeric Antigen Receptor given as a single dose following a lymphodepleting regimen

Experimental: Part 2: Dose Expansion
A single IV administration of UCART123. 2 Cohorts: Relapsed/Refractory AML, and in poor-prognosis, newly diagnosed AML patients in the ELN adverse genetic risk group.
Biological: UCART123
Allogeneic engineered T-cells expressing anti-CD123 Chimeric Antigen Receptor given as a single dose following a lymphodepleting regimen

Primary Outcome Measures :
  1. Incidence, nature, and severity of adverse events and serious adverse events [ Time Frame: Through Day 84 (+/- 7 days), dose limiting toxicities are assessed during either 28 days or 42 days if patient experiences bone marrow aplasia at Day 28, after the initial UCART123 administration. ]
    Adverse events and toxicity assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 for adverse events; cytokine release syndrome (CRS); tumor lysis syndrome (TLS); acute graft vs. host disease (GvHD)

Secondary Outcome Measures :
  1. Assessment of Antileukemic activity following initial UCART123 administration. [ Time Frame: Day 14, Day 28, Day 56 and Day 84 then every 3 months until the end of the Follow-up Period (2 years). Patients will remain on study (Long-Term Follow-Up) for a total of 15 years, unless patient consent is withdrawn or death, whichever comes first. ]
    Antileukemic activity, as measured by European Leukemia Net (ELN) Response Criteria in AML.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03190278

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Contact: Gabrielle Gosciniak (646) 962-9359
Contact: Aaron Logue, MBA 513-579-9911 ext 12889

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United States, New York
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
Contact: Gail Roboz, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Cellectis S.A.
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Study Director: Stephane Depil, MD,PhD Cellectis S.A.

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Responsible Party: Cellectis S.A. Identifier: NCT03190278     History of Changes
Other Study ID Numbers: UCART123_01
First Posted: June 16, 2017    Key Record Dates
Last Update Posted: December 28, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cellectis S.A.:
Acute Myeloid Leukemia
Relapsed/Refractory Acute Myeloid Leukemia
Newly diagnosed AML
ELN adverse genetic risk group
Chimeric Antigen Receptor T-Cell (CAR-T) therapy

Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type