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

• ClinicalTrials.gov Identifier: NCT04230265
• Recruitment Status: Recruiting
• First Posted: January 18, 2020
• Last Update Posted: August 18, 2023
• Sponsor: AvenCell Europe GmbH
• Collaborator: PHARMALOG Institut für klinische Forschung GmbH
• Information provided by (Responsible Party): AvenCell Europe GmbH

Tracking Information

• First Submitted Date: January 10, 2020
• First Posted Date: January 18, 2020
• Last Update Posted Date: August 18, 2023
• Actual Study Start Date: January 28, 2020
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 9, 2023)

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

Original Primary Outcome Measures (submitted: January 14, 2020)

• Safety and tolerability [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 days in patients with complete blast clearance) 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
• Incidence of dose limiting toxicity (DLT) [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 days in patients with complete blast clearance) ]
  DLT is defined as any adverse Event at least possible related to TM123 and/or UniCAR02-T
• Maximum tolerated dose (MTD) [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 days in patients with complete blast clearance) ]
  The dose for which the isotonic estimate of the DLT probability is closest to the target DLT probability of 0.2.

Current Secondary Outcome Measures (submitted: June 9, 2023)

• Establishing recommended phase 2 dose (RP2D) [ Time Frame: 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.
• Complete (CR, CRh, CRi ) and partial remission (PR) [ Time Frame: 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 %.
• Disease stabilization (DS) [ Time Frame: 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.
• Best response rate [ Time Frame: 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.
• Progression free survival (PFS) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: duration of consolidation cycle treatment ]
  Patients who tolerate TM123 and UniCAR02-T without DLT and achieve a clinical benefit are candidates for consolidation cycles

Original Secondary Outcome Measures (submitted: January 14, 2020)

• Recommended phase 2 dose (RP2D) [ Time Frame: DLT period (infusion period of TM123 + 7 days or + 28 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.
• Complete remission (CR), incomplete remission (CRi) and partial remission (PR) [ Time Frame: 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 %.
• Disease stabilization (DS) [ Time Frame: 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.
• Best response rate [ Time Frame: 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.
• Progression free survival (PFS) [ Time Frame: 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) [ Time Frame: 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dose-escalating Trial With UniCAR02-T Cells and CD123 Target Module (TM123) in Patients With Hematologic and Lymphatic Malignancies
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

Phase 1a Dose Escalation: Initial dose escalation followed an adaptive design.

Phase 1a Re-initiated Dose Escalation in 3+3 design: Dose escalation includes 2 additional dose levels of TM123. Patients will be treated according to a classical 3+3 design.

Phase 1b Dose Expansion: Once the re-initiated dose escalation phase has been completed, an expansion cohort of up to 20 patients will be initiated.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

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

Intervention

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

Study Arms

Experimental: UniCAR02-T-CD123

Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with the recombinant antibody derivative TM123.

Interventions:

• Drug: Cyclophosphamide (Non-IMP)
• Drug: Fludarabine (Non-IMP)
• Drug: TM123 (IMP)
• Drug: UniCAR02-T (IMP)

• Publications *: Loff S, Dietrich J, Meyer JE, Riewaldt J, Spehr J, von Bonin M, Grunder C, Swayampakula M, Franke K, Feldmann A, Bachmann M, Ehninger G, Ehninger A, Cartellieri M. Rapidly Switchable Universal CAR-T Cells for Treatment of CD123-Positive Leukemia. Mol Ther Oncolytics. 2020 Apr 29;17:408-420. doi: 10.1016/j.omto.2020.04.009. eCollection 2020 Jun 26.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 9, 2023): 90
• Original Estimated Enrollment (submitted: January 14, 2020): 45
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Martin Lorkowski, Dr.; +493514466450 ext 0; UC02-123-01@avencell.com

Contact: Antje Schubert, Dr.; +493514466450 ext 0; UC02-123-01@avencell.com

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04230265
• Other Study ID Numbers: UC02-123-01; 2019-001339-30 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AvenCell Europe GmbH
• Original Responsible Party: Same as current
• Current Study Sponsor: AvenCell Europe GmbH
• Original Study Sponsor: Same as current
• Collaborators: PHARMALOG Institut für klinische Forschung GmbH

Investigators

• Principal Investigator: Martin Wermke, MD; Universitätsklinikum Carl Gustav Carus Dresden

• PRS Account: AvenCell Europe GmbH
• Verification Date: August 2023