Clinical trial NCT04014881: Safety and Efficacy of Anti-CD123 CAR-T Therapy in Patients With Refractory/ Relapsed CD123+ Acute Myeloid Leukemia.
Official title: Single-center, Open-label, Single-arm Clinical Study of Efficacy and Safety of Anti-CD123 CAR-T Therapy in Patients With Refractory/Relapsed CD123+ Acute Myeloid Leukemia.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: CD123+ Acute Myeloid Leukemia
Lead sponsor: Wuhan Union Hospital, China
Sponsor class: OTHER
Collaborators: name: Wuhan Bio-Raid Biotechnology Co., Ltd.
First posted: 2019-07-10
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This study was a single-center, open-label, single-arm, non-randomized,3+3 dose escalation clinical trial.Each dose group has 3 patients.If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level. The maximum dose could be extended.
Primary purpose: TREATMENT

Brief summary: This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia.

Detailed description: CD123 is a transmembrane subunit of the IL-3 receptor expressed on AML blasts. The investigators have conducted a third generationCD123-targeted CAR containing CD137 and CD28 costimulatory domains.This study aims to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with relapsed/refractory CD123+ Acute Myeloid Leukemia.

Eligibility criteria: Inclusion Criteria:

1. Pathological and histological examination confirmed CD123+ refractory or relapsed Acute Myeloid Leukemia.

   A. Diagnostic criteria for recurrent AML: After complete remission (CR), leukemia cells or bone marrow primordial cells \> 0.050 (except for bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemia cell infiltration appears again in peripheral blood.

   B．Diagnostic criteria for refractory AML(Meeting one of the following)

   i. ineffectiveness after the first standard regimen treatment of 2 courses.

   ii. patients relapse within 12 months after consolidation and intensive treatment after CR.

   iii. Patients relapse 12 months later and fail to respond to conventional chemotherapy.

   iv. Patients with two or more recurrences.

   v. Patients with persistent extramedullary leukemia.

   vi. Patients with recurrence after CR and unsuitable for HSCT (auto/allo-HSCT).
2. Aged 18 to 70 years (including 18 and 70 years old).
3. At least one measurable or evaluable lesion：AML patients with positive or relapsed positive bone marrow MRD.
4. ECOG≤ 2 and expected lifetime ≥3 months.
5. Adequate organ function:

   A. Liver function: ALT/AST≤3 ULN. Total bilirubin≤2 ULN.

   B. Renal function: eGFR\> 60 mL/min/1.73 m2, or creatinine clearance ≥45mL/min.

   C. Lung function: Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1) \> 45% predicted.

   D. Cardiac function: LVEF ≥ 50%.
6. The patients did not receive any anticancer treatments such as chemotherapy, radiotherapy and immunotherapy (such as immunosuppressive drugs) within 4 weeks before admission, and the toxicity related to previous treatments had returned to \< 1 level at admission (except for low toxicity such as alopecia).
7. Women of child-bearing potential and all male participants must use effective methods of contraception for at least 12 months after infusion.
8. Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

1. Women who are pregnant (urine/blood pregnancy test positive) or lactating.
2. Male or female with a conception plan in the past 1 years.
3. Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 1 years after enrollment.
4. Uncontrolled infectious disease within 4 weeks prior to enrollment.
5. Active hepatitis B/C virus.
6. HIV infected patients.
7. Suffering from a serious autoimmune disease or immunodeficiency disease.
8. The patient is allergic and is allergic to macromolecular biopharmaceuticals such as antibodies or cytokines.
9. The patient participated in other clinical trials within 6 weeks prior to enrollment.
10. Systemic use of hormones within 4 weeks prior to enrollment (except for patients with inhaled corticosteroids).
11. Suffering from mental illness.
12. Patient has drug abuse/addiction.
13. Central nervous system involvement.
14. According to the investigator's judgment, the patient has other unsuitable grouping conditions.

Primary outcomes:
measure: Incidence of Treatment-related Adverse Events
timeFrame: 3 years
Secondary outcomes:
measure: Overall remission rate(ORR) of anti-CD123 CAR-T Therapy in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia
timeFrame: 3 years
measure: Overall survival(OS) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia
timeFrame: 3 years
measure: Duration of Response(DOR) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia
timeFrame: 3 years
measure: Progress-free survival(PFS) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia
timeFrame: 3 years
measure: Rate of anti-CD123 CAR-T cells in bone marrow cells and peripheral blood cells
timeFrame: 3 years
measure: Quantity of anti-CD123 CAR copies in bone marrow cells and peripheral blood cells
timeFrame: 3 years
Other outcomes:
Locations:
city: Wuhan
country: China
facility: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
Study officials:
affiliation: Wuhan Union Hospital, China
name: Heng Mei, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hansrivijit P, Gale RP, Barrett J, Ciurea SO. Cellular therapy for acute myeloid Leukemia - Current status and future prospects. Blood Rev. 2019 Sep;37:100578. doi: 10.1016/j.blre.2019.05.002. Epub 2019 May 11.
citation: Arcangeli S, Rotiroti MC, Bardelli M, Simonelli L, Magnani CF, Biondi A, Biagi E, Tettamanti S, Varani L. Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia. Mol Ther. 2017 Aug 2;25(8):1933-1945. doi: 10.1016/j.ymthe.2017.04.017. Epub 2017 May 4.
citation: Cartellieri M, Feldmann A, Koristka S, Arndt C, Loff S, Ehninger A, von Bonin M, Bejestani EP, Ehninger G, Bachmann MP. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 2016 Aug 12;6(8):e458. doi: 10.1038/bcj.2016.61.
citation: Tettamanti S, Biondi A, Biagi E, Bonnet D. CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics? Oncoimmunology. 2014 May 14;3:e28835. doi: 10.4161/onci.28835. eCollection 2014.
citation: Tasian SK, Kenderian SS, Shen F, Ruella M, Shestova O, Kozlowski M, Li Y, Schrank-Hacker A, Morrissette JJD, Carroll M, June CH, Grupp SA, Gill S. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood. 2017 Apr 27;129(17):2395-2407. doi: 10.1182/blood-2016-08-736041. Epub 2017 Feb 28.
citation: Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, Hoffman L, Aguilar B, Chang WC, Bretzlaff W, Chang B, Jonnalagadda M, Starr R, Ostberg JR, Jensen MC, Bhatia R, Forman SJ. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood. 2013 Oct 31;122(18):3138-48. doi: 10.1182/blood-2012-12-474056. Epub 2013 Sep 12.