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Clinical Trial 19481

Cancer Type: Malignant Hematology
Study Type: Treatment
NCT#: NCT03190278

Phase: Phase I
Principal Investigator: Sallman, David

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Overview

Study 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

Summary

Phase I, first-in-human, open-label, dose-escalation and dose-expansion study evaluating the safety and efficacy of UCART targeting CD123 in patients with relapsed/refractory acute myeloid leukemia (AML). The purpose of this study is to evaluate the safety and clinical activity of one infusion of UCART123 and determine the Maximum Tolerated Dose (MTD).

Objective

Primary:  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 highrisk acute myeloid leukemia (AML), and  To determine the Recommended Phase 2 Dose (RP2D) of UCART123. Secondary:  To assess the efficacy of UCART123 in relapsed or refractory AML patients and in patients with newly diagnosed, untreated AML (as defined by World Health Organization [WHO] criteria, [Arber et al., 2016]) who meet criteria for the European Leukemia Net (ELN) adverse genetics prognostic group (Döhner et al., 2016; Röllig et al., 2011). Exploratory:  To characterize the expansion, trafficking, and persistence of UCART123 after infusion by assessing the kinetics and characteristics of UCART123 at different time-points, in blood and bone marrow;  To assess cytokine, growth factor, and C-reactive protein levels after UCART123 infusion;  To investigate the development of an UCART123 generated immune response;  To investigate the potential relationship between baseline levels of CD123 expression and clinical outcome;  To assess the impact of UCART123 on leukemia stem cells, hematopoietic stem cells (HSCs), and progenitor cells;  To confirm the absence of replication competent lentivirus in blood;  To assess the impact of UCART123 on the tumor cell population by targeted sequencing; and  To monitor immune cell depletion and reconstitution post lymphodepletion and UCART123.

Treatments

Therapies

Chemotherapy (NOS); Immunotherapy

Medications

Alemtuzumab (); Campath (Alemtuzumab); Elitek (Rasburicase); Hydroxyurea (Droxia); Rasburicase (); Rituxan (rituximab); Tocilizumab (); UCART123v1 (); UCART123v1.2 (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate); rituximab ()

Inclusion Criteria

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

Between 18 and 65 years of age

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Adequate organ function, including renal and hepatic function based on the last assessment performed within the Screening Period, as defined in protocol.

Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to enrollment. Within the frame of this study, female patients of childbearing potential and male patients with partners of childbearing potential must use a highly effective method of birth control, as described in the protocol, as well as their partners, from the screening period for a duration of 12 months after UCART123v1 / UCART123v1.2 administration.

Patients with relapsed or primary refractory (i.e., never having achieved CR) AML with >5% bone marrow blasts: Patients who are considered primary refractory to treatment must have received induction therapy with at least two cycles of an anthracycline with ne, 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 single agent or in combination (note: one course is defined as at least 4 five-day cycles of either decitabine or azacitidine);

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

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, or haploidentical 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.

Exclusion Criteria

Patients with Acute Promyelocytic Leukemia (APL)

Previous treatment with investigational gene or CAR therapy, use of investigational cell therapy (excluding CAR therapy) within 60 days prior to start of the lymphodepletion (enrollment) is allowed;

More than one allogeneic stem cell transplant (SCT) received;

Donor Lymphocyte Infusion (DLI) received within 60 days prior to start of the lymphodepletion (enrollment);

Auto-immune disease requiring immunosuppressive treatment;

Use of other investigational products within five half-lives or within 14 days prior to start of the lymphodepletion (enrollment), whichever is longer; participation in non- interventional registries or epidemiological studies is allowed; In addition, treatment-related toxicities should have resolved to no more than Grade 1;

Previous chemotherapy including biologic/targeted therapy or immunological agents within 14 days prior to start of the lymphodepletion (enrollment);

Radioimmunotherapy or radiotherapy within 8 weeks (except for palliative radiotherapy at localized lesions not considered target lesions) before the start of lymphodepletion (enrollment);

Active or previous CNS leukemia involvement;

Presence of an active and clinically relevant CNS disorder such as epilepsy, generalized seizure disorder, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease, or organic brain syndrome;

Use of rituximab and other anti-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 UCART123v1 / UCART123v1.2 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 or human T-cell leukemia/lymphoma virus type 1;

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

Any known uncontrolled cardiovascular disease or any of the following within 3 months of enrollment: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure New York Heart Association class ≥II, cerebrovascular accident or transient ischemic attack, hypertension not adequately controlled by standard medications;

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

Macrophage activation syndrome as evidenced by laboratory abnormalities (eg: elevated ferritin, elevated triglycerides, hemophagocytosis on the bone marrow sample) and/or clinical indications;

Abnormal findings and/or clinically significant Grade ≥3 non-hematological toxicity during the Screening Period and any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient’s safety;

Any planned medical/surgical treatment that might interfere with the ability to comply with the study requirements; or

Evidence of another uncontrolled malignancy within 2 years prior to Screening (except in situ non-melanoma skin cell cancers and in situ cervical carcinoma).

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