CART123 T Cells in Relapsed or Refractory CD123+ Hematologic Malignancies: a Dose Escalation Phase I Trial

Adult patients with refractory or relapsed CD123+ hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or blastic plasmocytoid dentritic cell neoplasm will be recruited in the trial. CART123 cells will be manufatured from blood of each patient. During the production of CAR123 cells, patients may receive appropriate bridging therapy. After cells are produced, participants will undergo a single course of lymphodepleting chemotherapy and receive a single dose of CAR123 T cells. The trial will establish the recommended dose for further studies, either the Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD). Patients must be eligible for hematopoietic stem cell transplantation in order to participate in the trial.

This is an open-label, single arm study on up to 18 adult subjects with refractory or relapsed CD123+ AML, MDS, ALL or BPDCN. Following lymphodepleting conditioning regimen, the subjects will receive a single dose of autologous CAR123 T lymphocytes supplied by the sponsor´s manufacturing facility.

CART123 dose will be increased in three predefined steps using the accelerated Bayesian optimal interval (BOIN) design in order to establish recommended CART123 dose for further study, which will be either Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD), whichever is reached first.

Alternative dosing schedule will be adopted in case of dose limitation due to insufficient CART123 expansion during IMP manufacture.

Due to concern for potentially prolonged or irreversible hematologic toxicity of CART123, all patients recruited in the study must be eligible for hematopoietic stem cell transplantation (HSCT) and have a donor of allogeneic hematopoietic stem cells identified and cleared by the transplant center. Decision to perform HSCT will be made on a case-by-case basis.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with AML, MDS-IB2, BPDCN or ALL positive for CD123 antigen, who meet one of disease specific criteria below:

   a) Patients with AML will be eligible if they meet one of the following criteria:

   i) Patient with refractory AML defined as failure to achieve CR or CRi after at least 2 cycles of induction chemotherapy or 1 cycle of high dose salvage regimen or 4 cycles of venetoclax with azacytidine OR

   ii) Second or subsequent relapse of AML OR

   iii) Relapse after allogeneic HSCT.

   b) Patients with ALL will be eligible if they meet one of following criteria:

   i) disease refractory to or relapsed after CAR-19 cell therapy OR

   ii) CD19 negative relapse ineligible for treatment with TKI inhibitors and inotuzumab ozogamicin.

   c) Patients with BPDCN will be eligible if they meet following criteria:

   i) Refractory or relapsing after chemotherapy with or without allogeneic stem cell transplantation.

   d) Patients with MDS-IB2 will be eligible if they meet one of following criteria:

   i) Disease refractory to at least four cycles of azacytidine or progression on azacytidine-based therapy OR

   ii) Disease refractory to induction chemotherapy OR

   iii) Relapse after haematopoietic stem cell transplantation.
2. CD123 expression on malignant cells confirmed by flow cytometry or by immunohistochemistry.
3. Age between 18 and 70 years.
4. Patient has a suitable donor for allogeneic hematopoietic stem cell transplantation. Workup and clearance of the donor must be completed before IMP administration.
5. Patient able to understand and sign informed consent.
6. Women of child-bearing potential: negative pregnancy test at enrolment (PSV) and at Visit 1.
7. Patient for whom there are no standard-of-care treatments available or such treatment options have been exhausted.

Exclusion Criteria:

1. Known hypersensitivity to any component of the IMP.
2. Allogeneic HSCT within 3 months prior to IMP administration.
3. Severe, uncontrolled active infection.
4. Life expectancy \< 8 weeks.
5. Respiratory insufficiency (need for oxygen therapy).
6. Significant liver impairment: bilirubin \> 50 µmol/L, AST or ALT \> 4 times normal upper limit.
7. Acute kidney injury with serum creatinine \> 180 µmol/L, oliguria or need for acute dialysis.
8. Heart failure with LVEF \< 50% by echocardiography.
9. Presence of active grade 3 - 4 acute GvHD or severe chronic GvHD.
10. Serious uncontrolled neurological comorbidity.
11. Vaccination with live virus vaccines in the 4 weeks before IMP administration and within 90 days after the IMP dose.
12. Women: pregnancy or breast-feeding.
13. Subjects of fertile age, unless permanent sexual abstinence is their lifestyle choice:

    1. female patients of childbearing potential not willing to use a highly effective method of contraception during the study,
    2. male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception during the study.