Dose-escalating Trial With UniCAR02-T Cells and PSMA Target Module (TMpPSMA) in Patients With Progressive Disease After Standard Systemic Therapy in Cancers With Positive PSMA Marker

Study Overview
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Brief Summary
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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-pPSMA in patients with progressive disease after standard systemic therapy in castration-resistant prostate cancers with positive PSMA marker. The UniCAR02-T-pPSMA drug is a combination of a cellular component (UniCAR02-T) with a recombinant antibody derivative (TMpPSMA) which together forms the active drug.

Official Title
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Multicenter, Open-label, Adaptive Design Phase I Trial With Genetically Modified T-cells Carrying Universal Chimeric Antigen Receptors (UniCAR02-T) in Combination With PSMA Peptide Target Module (TMpPSMA) for the Treatment of Patients With Progressive Disease After Standard Systemic Therapy in Cancers With Positive PSMA Marker

Conditions
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Prostate Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Patients diagnosed with progressive castration-resistant prostate cancer refractory to standard treatments and with no other available standard or curative treatment Measurable or non-measurable disease based on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) and positivity in PSMA Positron Emission Tomography (PET) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Life expectancy of at least 3 months Adequate renal and hepatic laboratory assessments Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) Permanent venous access existing (e.g. port-system) resp. acceptance of implantation of a device Able to give written informed consent Weight ≥ 45kg Using a highly effective method of birth control Exclusion Criteria: Central nervous system metastasis or meningeosis carcinomatosa 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 (need for oxygen inhalation) Parkinson, epilepsy and stroke or presence or history of seizures, paresis, aphasia, central nervous system (CNS) or intracranial hemorrhage History or presence of disseminated intravascular coagulation (DIC) or thromboembolism within the last three months Multiple sclerosis Hemolytic anemia Eye diseases with neovascularization 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 Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy Any disease requiring immunosuppressive therapy Major surgery within 28 days (prior start of TMpPSMA infusion) 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 of the substance (whatever is shorter) prior to administration of TMpPSMA Prior treatment with gene therapy products Use of checkpoint inhibitors within 5 half-lives of the respective substance prior to administration of TMpPSMA Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants (note that physiologic steroid replacement not exceeding 10 mg prednisolone equivalent per day is allowed) 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/SS-B or presence or history of autoimmune diseases (e.g. systemic lupus erythematosus, SS/SLE overlap syndrome, subacute cutaneous lupus erythematosus, neonatal lupus, primary biliary cirrhosis, Sjögren's syndrome) Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting peptide module (TMpPSMA) excipients and/or contraindication to compounds of the lymphodepletion therapy (cyclophosphamide and fludarabine), and tocilizumab or corticosteroids as specified in the respective IB/SmPC Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance) 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
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Initial dose escalation followed an adaptive design. Further dose escalation includes 2 additional TMpPSMA dose levels and follows a 3+3 design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UniCAR02-T-pPSMA<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 peptide TMpPSMA. | Drug: Cyclophosphamide (Non-IMP)<br>* Intravenous infusion for 3 days<br>Drug: Fludarabine (Non-IMP)<br>* Intravenous infusion for 3 days<br>Drug: UniCAR02-T-pPSMA<br>* Intravenous Infusion for 21 days<br>Drug: UniCAR02-T (IMP)<br>* Intravenous infusion of single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 
| Incidence of dose limiting toxicity (DLT) | DLT is defined as any adverse event at least possible related to TMpPSMA and/or UniCAR02-T | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 
| 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 TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 
| Antitumor activity | Antitumor activity of UniCAR02-T-pPSMA at any time point according to irRECIST (immune-related) Response Evaluation Criteria in Solid Tumors): Complete remission (CR) and partial remission (PR), Objective response rate (ORR), Disease control rate (DCR), Best response rate, Duration of response (DOR),Progression free survival (PFS) | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 
| Prostate specific antigen (PSA) response |  | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 
| Overall Survival (OS) |  | Until fifteen years after last UniCAR02-T administration | 
| Influence on Circulating tumor cells (CTC) |  | Before start of lymphodepletion therapy until 6 resp. 12 months after start of last TMpPSMA application |