business decision by sponsor

This dose-escalating phase I trial assesses for the first time the safety, the side effects and the harmlessness, as well as the therapeutical benefit of the new study drug UniCAR02-T-CD123 in patients with hematologic and lymphatic malignancies positive for CD123 marker. The UniCAR02-T-CD123 drug is a combination of a cellular component (UniCAR02-T) with a recombinant antibody derivative (TM123) which together forms the active drug.

Phase 1a Dose Escalation:

Inclusion Criteria:

1. Male or female patients, age ≥ 18 years
2. Documented definitive diagnosis of Relapsed or refractory AML (according to standard of care testing) and CD123 positivity of ≥20 % of blasts. MRD+ AML without morphological relapse or refractoriness may be included with the sponsor's approval
3. Eastern Cooperative Oncology Group (ECOG) of 0 to 1
4. Life expectancy of at least 2 months
5. Adequate renal and hepatic laboratory assessments
6. Adequate cardiac function
7. Long-term venous access existing (e.g. port-system) resp. acceptance of implantation of a device
8. Able to give written informed consent
9. Weight ≥ 45 kg
10. Negative pregnancy test; routinely using a highly effective method of birth control

Exclusion Criteria:

1. Acute promyelocytic leukemia
2. AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma).
3. Refractory disease under anti-leukemic treatment lasting longer than 6 months
4. Current manifestation of AML in central nervous system
5. Bone marrow failure syndromes (e.g. Fanconi anemia, Kostman syndrome, Shwachman syndrome)
6. Significant cardiac disease: i.e., heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 12 months prior to study entry that may in the Investigator's opinion interfere with participation in the trial.
7. Patients undergoing renal dialysis
8. Pulmonary disease with clinically relevant hypoxia
9. Parkinson's disease, epilepsy, stroke, seizures, significant paresis or aphasia with clinical symptoms in the previous 12 months that may in the Investigator's opinion interfere with participation in the trial.
10. Disseminated intravascular coagulation (DIC) within 3 months prior to the planned start of the study treatment.
11. Hemorrhagic cystitis
12. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
13. Allogeneic stem cell transplantation within last two months or GvHD requiring systemic immunosuppressive therapy
14. Vaccination with live viruses within 2 weeks prior to lymphodepletion therapy
15. Major surgery within 28 days (prior to start of TM123 infusion)
16. Other malignancy requiring active therapy, but adjuvant endocrine therapy is allowed
17. Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whatever is shorter) of the substance prior to the day of apheresis
18. Prior treatment with gene therapy products unless approved by the sponsor
19. Use of checkpoint inhibitors within 5 half-lives of the respective substance
20. Pregnant or breastfeeding women
21. Currently significant psychologic disorder, including substance abuse
22. Known history of human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
23. Any significant autoimmune disease requiring systemic immunosuppressive therapy or that may otherwise, in the Investigator's opinion, interfere with participation in the trial, or documented presence of autoantibodies against La/SS-B.

Phase 1b Dose Expansion:

Inclusion Criteria:

1. Male or female patients, age ≥ 18 years

2. Relapsed or refractory AML (according to standard of care testing), having up to 30% blasts in a bone marrow assessment at either screening or prescreening, or patients having between 30% and 40% blasts for 2 consecutive bone marrow assessments with a minimum of 1 months and no more than 2 months apart, and without hyperproliferative disease requiring cytoreductive treatment, up to 3rd relapse, without further approved curative or life-extending treatment options, and documented CD123 positivity of ≥ 20 % of blasts. Exceptions to BM blast criterion are only possible in minor deviations in timing and/or blast count in clinically stable patients, and only with written sponsor approval. Exemptions to CD123 expression are not allowed. MRD+ AML without morphological relapse or refractoriness may be included with the sponsor's approval.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

4. Life expectancy of at least 2 months

5. Adequate renal and hepatic laboratory assessments:

   1. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤ 2.5× upper limit of normal (ULN)
   2. Total bilirubin ≤ 1.5× ULN
   3. Serum creatinine clearance at least 70 mL/min)

6. Adequate cardiac function, i.e., left ventricular ejection fraction (LVEF) of ≥ 50 %.

7. Long-term venous acces existing (e.g., port-system) resp. acceptance of implantation of a device

8. Able to give written informed consent

9. Weight ≥ 45kg

10. Negative pregnancy test; routinely using a highly effective method of birth control

    Exclusion criteria:

11. Acute promyelocytic leukemia (t15;17)

12. AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma)

13. Refractory disease under anti-leukemic treatment lasting longer than 6 months

14. Current manifestion of AML in central nervous system

15. Bone marrow failure syndromes (e.g. Fanconi anemia, Kostman syndrome, Schwachman syndrome)

16. Significant cardiac disease: i.e., heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 12 months prior to study entry that may in the Investigator''s opinion interfere with participation in the trial.

17. Patients undergoing renal dialysis

18. Pulmonary disease with clinically relevant hypoxia

19. Parkinson's disease, epilepsy, stroke, seizures, significant paresis or aphasia with clinical symptoms in the previous 12 months that may in the Investigator's opinion interfere with participation in the trial.

20. Disseminated intravascular coagulation (DIC) within 3 months prior to the planned start of the study treatment.

21. Hemorrhagic cystitis

22. Active infections disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy.

23. Allogenic stem cell transplantation within last two months or GvHD requiering systemic immunosuppressive therapy.

24. Vaccination with live viruses within 2 weeks prior to lymphodepletion therapy.

25. Major surgery within 28 days (prior to start of TM123 infusion)

26. Other malignancy requiring active therapy, but adjuvant endocrine therapy is allowed.

27. Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whatever is shorter) of the substance prior to the day of apheresis

28. Prior treatment with gene therapy products unless approved by the sponsor.

29. Use of checkpoint inhibitors within 5 half-lives of the respective substance.

30. Pregnatn or breastfeeding women.

31. Currently significant psychologic disorder, including substance abuse.

32. Known history of human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).

33. Any significant autoimmune disease requiring systemic immunosuppressive therapy or that may otherwise, in the Investigator''s opinion, interfere with participation in the trial, or documented presence of autoantibodies against La/SS-B.

In the expansion cohort 2 different TM123 dose levels shall be compared descriptively.