Phase 1 Study of UniCAR02-T-CD123 in Patients With Selected CD123 Positive Hematologic Malignancies

Phase 1

Active, not recruiting

• Conditions: Acute Myeloid Leukemia (AML)
• Interventions: Drug: Cyclophosphamide (Non-IMP); Drug: Fludarabine (Non-IMP); Drug: TM123 (IMP); Drug: UniCAR02-T (IMP)

• Registration Number: NCT04230265
• Lead Sponsor: AvenCell Europe GmbH

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-01-10
• Study First Submitted QC: 2020-01-14
• Study First Posted: 2020-01-18
• Study Start: 2020-01-28
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-24
• Last Update Posted: 2025-03-25
• Primary Completion: 2025-05
• Study Completion: 2025-09

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 90

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
UniCAR02-T-CD123 (4 mg/day TM123)	Cyclophosphamide (Non-IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (8 mg/day TM123)	TM123 (IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (8 mg/day TM123)	UniCAR02-T (IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (4 mg/day TM123)	TM123 (IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (4 mg/day TM123)	UniCAR02-T (IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (8 mg/day TM123)	Cyclophosphamide (Non-IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (8 mg/day TM123)	Fludarabine (Non-IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
UniCAR02-T-CD123 (4 mg/day TM123)	Fludarabine (Non-IMP)	Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.

Primary Outcome Measures

Name	Time	Method
Safety and tolerability	Infusion period of TM123 (up to 20 days) + 7 days resp. 14 days in patients with complete blast clearance during the IC or until Safety Follow-up 1 (infusion period of TM123 + 28 days + 3 months)	Incidence and intensity of adverse events graded according to CTCAE V5.0 with the exception of CRS and ICANS graded according to Lee et al. 2014 and Lee et al. 2019 respectively
Recommended phase 2 dose (RP2D)	Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)	Establishing recommended phase 2 dose (RP2D) and schedule
Response	Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)	Complete remission (CR, CRh, CRi, CRMRDneg, CRMRDpos) and partial remission (PR) at any time point and duration of responses

Secondary Outcome Measures

Name	Time	Method
Best response rate	until fifteen years after last UniCAR02-T administration	The best observed response during observational period. Response states are ordered descending as follows: CR \> CRi \> PR \> DS \> refractory disease.
Establishing recommended phase 2 dose (RP2D)	DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)	The RP2D will be determined based on MTD, all available efficacy data, and all available safety data, including information derived from additional treatment cycles.
Disease stabilization (DS)	until fifteen years after last UniCAR02-T administration	Reduction of blast percentage by 25% compared to baseline without normalization of peripheral blood counts to levels not qualifying for PR or CR.
Complete (CR, CRh, CRi ) and partial remission (PR)	until fifteen years after last UniCAR02-T administration	CR: Bone marrow blasts \< 5%, absence of extramedullary disease, absolute neutrophil count \> 1 Gpt/L and platelet count \> 100 Gpt/L. Level of MRD should be measured in patients achieving CR in case as suitable marker exists.; CRi: All criteria for CR except residual thrombocytopenia (platelets \< 100 Gpt/L) and/or neutropenia (absolute neutrophil count \< 1 Gpt/L).; PR: All hematological criteria for CR with bone marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50 %.
Progression free survival (PFS)	until fifteen years after last UniCAR02-T administration	The time from first treatment with TM123 and UniCAR02-T until disease progression or death. If no progress of death was observed during the observational period, the patient's progression free survival time will be censored on the date the patient was last seen progression-free and alive.
Overall survival (OS)	until fifteen years after last UniCAR02-T administration	The number of days between the first study drug administration and death from any cause. If death was not observed during the observational period, the patient's overall survival time will be censored on the date the patient was last seen alive.
Toxicity and efficacy in repeated cycles of TM123 administration	duration of consolidation cycle treatment	Patients who tolerate TM123 and UniCAR02-T without DLT and achieve a clinical benefit are candidates for consolidation cycles

Trial Locations

Locations (10)

Universitätsklinikum Ulm; 🇩🇪 Ulm, Baden-Württemberg, Germany

Klinikum der Universität München; 🇩🇪 Munich, Bavaria, Germany

Universitätsklinikum Würzburg; 🇩🇪 Würzburg, Bayern, Germany

Philipps-Universität Marburg; 🇩🇪 Marburg, Hessen, Germany

Uniklinik RWTH Aachen; 🇩🇪 Aachen, NRW, Germany

Universitätsklinikum Dresden; 🇩🇪 Dresden, Sachsen, Germany

Universitätsklinikum Leipzig; 🇩🇪 Leipzig, Sachsen, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Erasmus University Medical Center; 🇳🇱 Rotterdam, GD, Netherlands

Universitair Medisch Centrum Groningen; 🇳🇱 Groningen, GZ, Netherlands