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

Study Overview
=================
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.

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

Conditions
-----------------
Acute Myeloid Leukemia (AML), Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide (Non-IMP)
* Drug: Fludarabine (Non-IMP)
* Drug: TM123 (IMP)
* Drug: UniCAR02-T (IMP)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients, age ≥ 18 years 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 Eastern Cooperative Oncology Group (ECOG) of 0 to 1 Life expectancy of at least 2 months Adequate renal and hepatic laboratory assessments Adequate cardiac function Permanent venous access existing (e.g. port-system) resp. acceptance of implantation of a device Able to give written informed consent Weight ≥ 45 kg Negative pregnancy; routinely using a highly effective method of birth control Exclusion Criteria: Acute promyelocytic leukemia (t15;17) Refractory disease under anti-leukemic treatment lasting longer than 6 months Manifestation of AML or BPDCN in central nervous system Bone marrow failure syndromes 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 Patients undergoing renal dialysis Pulmonary disease with clinical relevant hypoxia Parkinson, epilepsy and, stroke or presence or history of seizures, paresis, aphasia or intracranial hemorrhage Presence of disseminated intravascular coagulation (DIC) or thromboembolism, or history of such within 3 months prior to start of treatment Hemolytic anemia Multiple sclerosis Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow obstruction Allogeneic stem cell transplantation within last two months or Graft versus host disease (GvHD) requiring immunosuppressive therapy Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy Major surgery within 28 days Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed 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 Prior treatment with gene therapy products Use of checkpoint inhibitors within 5 half-lives of the respective substance Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants Pregnant or breastfeeding women Psychologic disorders, drug and/or significant active alcohol abuse Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) Presence of autoantibodies against La/Sjögren syndrome (SS)-B or presence or history of autoimmune diseases Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting module (TM123) excipients or to compounds of the lymphodepletion therapy or tocilizumab or corticosteroids Evidence suggesting that the patient is not likely to follow the study protocol Incapability of understanding purpose and possible consequences of the trial Patients who should not be included according to the opinion of the investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UniCAR02-T-CD123<br>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. | Drug: Cyclophosphamide (Non-IMP)<br>* Intravenous infusion over 3 days<br>Drug: Fludarabine (Non-IMP)<br>* Intravenous infusion over 3 days<br>Drug: TM123 (IMP)<br>* Intravenous Infusion for 20 days<br>Drug: UniCAR02-T (IMP)<br>* Intravenous infusion of single dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| Ph1b Dose Expansion: Establishing recommended phase 2 dose (RP2D) |  | Infusion period of TM123 (up to 20 days) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |