Dose-escalating Trial With UniCAR02-T Cells and CD123 Target Module (TM123) in Patients With Hematologic and Lymphatic Malignancies

Acute Myeloid Leukemia (AML) Clinical Trial

Official title:

Multicenter, Open-label, Adaptive Design Phase I Trial With Genetically Modified T-cells Carrying Universal Chimeric Antigen Receptors (UniCAR02-T) in Combination With CD123 Target Module (TM123) for the Treatment of Patients With Hematologic and Lymphatic Malignancies Positive for CD123

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04230265
• Other study ID #: UC02-123-01
• Secondary ID: 2019-001339-30
• Status: Recruiting
• Phase: Phase 1
• Start date: January 28, 2020
• Est. completion date: September 2025

Study information

• Verified date: May 2024
• Source: AvenCell Europe GmbH
• Contact: Martin Lorkowski, Dr.
• Phone: +493514466450
• Email: UC02-123-01[@]avencell.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: September 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. Permanent 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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Cyclophosphamide (Non-IMP)
Intravenous infusion over 3 days
• Fludarabine (Non-IMP)
Intravenous infusion over 3 days
• TM123 (IMP)
Intravenous Infusion for 20 days
• UniCAR02-T (IMP)
Intravenous infusion of single dose

Locations

Country	Name	City	State
Germany	Uniklinik RWTH Aachen	Aachen	NRW
Germany	Universitätsklinikum Dresden	Dresden	Sachsen
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Philipps-Universität Marburg	Marburg	Hessen
Germany	Klinikum der Universität München	Munich	Bavaria
Germany	Universitätsklinikum Ulm	Ulm	Baden-Württemberg
Germany	Universitätsklinikum Würzburg	Würzburg	Bayern
Netherlands	Erasmus University Medical Center	Rotterdam	GD

Sponsors (2)

Lead Sponsor	Collaborator
AvenCell Europe GmbH	PHARMALOG Institut für klinische Forschung GmbH

Countries where clinical trial is conducted

Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability	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	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)
Primary	Recommended phase 2 dose (RP2D)	Establishing recommended phase 2 dose (RP2D) and schedule	Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Primary	Response	Complete remission (CR, CRh, CRi, CRMRDneg, CRMRDpos) and partial remission (PR) at any time point and duration of responses	Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Secondary	Establishing recommended phase 2 dose (RP2D)	The RP2D will be determined based on MTD, all available efficacy data, and all available safety data, including information derived from additional treatment cycles.	DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Secondary	Complete (CR, CRh, CRi ) and partial remission (PR)	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 %.	until fifteen years after last UniCAR02-T administration
Secondary	Disease stabilization (DS)	Reduction of blast percentage by 25% compared to baseline without normalization of peripheral blood counts to levels not qualifying for PR or CR.	until fifteen years after last UniCAR02-T administration
Secondary	Best response rate	The best observed response during observational period. Response states are ordered descending as follows: CR > CRi > PR > DS > refractory disease.	until fifteen years after last UniCAR02-T administration
Secondary	Progression free survival (PFS)	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.	until fifteen years after last UniCAR02-T administration
Secondary	Overall survival (OS)	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.	until fifteen years after last UniCAR02-T administration
Secondary	Toxicity and efficacy in repeated cycles of TM123 administration	Patients who tolerate TM123 and UniCAR02-T without DLT and achieve a clinical benefit are candidates for consolidation cycles	duration of consolidation cycle treatment