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: August 2023
• 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 AML or BPDCN (according to standard of care testing) and CD123 positivity of =20 % of blasts. In the case of MRD+ AML, if there are insufficient blasts at screening for CD123 testing, the most recent available sample with sufficient blasts should be used.

• Relapsed or refractory AML/BPDCN

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; routinely using a highly effective method of birth control

Exclusion Criteria:

1. Acute promyelocytic leukemia (t15;17)

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

3. Manifestation of AML or BPDCN in central nervous system

4. Bone marrow failure syndromes

5. 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 6 months prior to study entry

6. Patients undergoing renal dialysis

7. Pulmonary disease with clinical relevant hypoxia

8. Parkinson, epilepsy and, stroke or presence or history of seizures, paresis, aphasia or intracranial hemorrhage

9. Presence of disseminated intravascular coagulation (DIC) or thromboembolism, or history of such within 3 months prior to start of treatment

10. Hemolytic anemia

11. Multiple sclerosis

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

13. Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow obstruction

14. Allogeneic stem cell transplantation within last two months or Graft versus host disease (GvHD) requiring immunosuppressive therapy

15. Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy

16. Major surgery within 28 days

17. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed

18. 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

19. Prior treatment with gene therapy products

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

21. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants

22. Pregnant or breastfeeding women

23. Psychologic disorders, drug and/or significant active alcohol abuse

24. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

25. Presence of autoantibodies against La/Sjögren syndrome (SS)-B or presence or history of autoimmune diseases

26. Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting module (TM123) excipients or to compounds of the lymphodepletion therapy or tocilizumab or corticosteroids

27. Evidence suggesting that the patient is not likely to follow the study protocol

28. Incapability of understanding purpose and possible consequences of the trial

29. Patients who should not be included according to the opinion of the investigator

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
• 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

Sponsors (2)

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

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1a Dose Escalationand Re-initiated Dose Escalation in 3+3 design: Safety and tolerability	Incidence and intensity of adverse events graded according to CTCAE V5.0 with the exception of CRS and ICANS	DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) until Safety Follow-up 1 (infusion period of TM123 + 28 days + 3 months)
Primary	Phase 1a Dose Escalation and Re-initiated Dose Escalation in 3+3 design: Incidence of dose limiting toxicity (DLT)	DLT is defined as any adverse Event at least possible related to TM123 and/or UniCAR02-T	DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Primary	Phase 1a Dose Escalation and Re-initiated Dose Escalation in 3+3 design: Maximum tolerated dose (MTD)	The dose for which the isotonic estimate of the DLT probability is closest to the target DLT probability of 0.2.	DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Primary	Ph1b Dose Expansion: Safety and tolerability	Incidence and intensity of adverse events graded according to CTCAE V5.0 with the exception of CRS and ICANS	Infusion period of TM123 (up to 20 days)
Primary	Ph1b Dose Expansion: Establishing recommended phase 2 dose (RP2D)		Infusion period of TM123 (up to 20 days)
Primary	Ph1b Dose Expansion: Response evaluation	Complete and partial remission at any time point and durability of response	Infusion period of TM123 (up to 20 days)
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