Prostate Cancer
Conditions
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-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.
Interventions
Intravenous infusion for 3 days
Intravenous infusion for 3 days
DRUGUniCAR02-T-pPSMA
Intravenous Infusion for 21 days
DRUGUniCAR02-T (IMP)
Intravenous infusion of single dose
Sponsors
PHARMALOG Institut für klinische Forschung GmbH
AvenCell Europe GmbH
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Initial dose escalation followed an adaptive design. Further dose escalation includes 2 additional TMpPSMA dose levels and follows a 3+3 design.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Patients diagnosed with progressive castration-resistant prostate cancer refractory to standard treatments and with no other available standard or curative treatment 3. Measurable or non-measurable disease based on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) and positivity in PSMA Positron Emission Tomography (PET) 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 5. Life expectancy of at least 3 months 6. Adequate renal and hepatic laboratory assessments 7. Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) 8. Permanent venous access existing (e.g. port-system) resp. acceptance of implantation of a device 9. Able to give written informed consent 10. Weight ≥ 45kg 11. Using a highly effective method of birth control
Exclusion criteria
1. Central nervous system metastasis or meningeosis carcinomatosa 2. 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 3. Patients undergoing renal dialysis 4. Pulmonary disease with clinical relevant hypoxia (need for oxygen inhalation) 5. Parkinson, epilepsy and stroke or presence or history of seizures, paresis, aphasia, central nervous system (CNS) or intracranial hemorrhage 6. History or presence of disseminated intravascular coagulation (DIC) or thromboembolism within the last three months 7. Multiple sclerosis 8. Hemolytic anemia 9. Eye diseases with neovascularization 10. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy 11. Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow obstruction 12. Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy 13. Any disease requiring immunosuppressive therapy 14. Major surgery within 28 days (prior start of TMpPSMA infusion) 15. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed 16. 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 17. Prior treatment with gene therapy products 18. Use of checkpoint inhibitors within 5 half-lives of the respective substance prior to administration of TMpPSMA 19. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants (note that physiologic steroid replacement not exceeding 10 mg prednisolone equivalent per day is allowed) 20. Psychologic disorders, drug and/or significant active alcohol abuse 21. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) 22. 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) 23. 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 24. Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance) 25. Incapability of understanding purpose and possible consequences of the trial 26. Patients who should not be included according to the opinion of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 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 |
| Incidence of dose limiting toxicity (DLT) | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | DLT is defined as any adverse event at least possible related to TMpPSMA and/or UniCAR02-T |
| Maximum tolerated dose (MTD) | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | The dose for which the isotonic estimate of the DLT probability is closest to the target DLT probability of 0.2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Until fifteen years after last UniCAR02-T administration | — |
| Recommended phase 2 dose (RP2D) | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | The RP2D will be determined based on MTD, all available efficacy data, and all available safety data, including information derived from additional treatment cycles. |
| Influence on Circulating tumor cells (CTC) | Before start of lymphodepletion therapy until 6 resp. 12 months after start of last TMpPSMA application | — |
| Antitumor activity | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | 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) |
| Prostate specific antigen (PSA) response | DLT period (infusion period of TMpPSMA + 7 days or + 14 days in patients with with myelosuppression) | — |
Countries
Germany
Outcome results
None listed