Acute Myeloid Leukemia (AML)
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-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.
Interventions
Intravenous infusion over 3 days
Intravenous infusion over 3 days
DRUGTM123 (IMP)
Intravenous Infusion for 20 days
DRUGUniCAR02-T (IMP)
Intravenous infusion of single dose
Sponsors
AvenCell Europe GmbH
PHARMALOG Institut für klinische Forschung GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
In the expansion cohort 2 different TM123 dose levels shall be compared descriptively.
Intervention model description
Phase 1b Dose Expansion: An expansion cohort of up to 20 patients was initiated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase 1a Dose Escalation: Inclusion Criteria: 1. Male or female patients, age ≥ 18 years 2. Documented definitive diagnosis of Relapsed or refractory AML (according to standard of care testing) and CD123 positivity of ≥20 % of blasts. MRD+ AML without morphological relapse or refractoriness may be included with the sponsor's approval 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. Long-term 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 test; routinely using a highly effective method of birth control
Exclusion criteria
1. Acute promyelocytic leukemia 2. AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma). 3. Refractory disease under anti-leukemic treatment lasting longer than 6 months 4. Current manifestation of AML in central nervous system 5. Bone marrow failure syndromes (e.g. Fanconi anemia, Kostman syndrome, Shwachman syndrome) 6. Significant 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 12 months prior to study entry that may in the Investigator's opinion interfere with participation in the trial. 7. Patients undergoing renal dialysis 8. Pulmonary disease with clinically relevant hypoxia 9. Parkinson's disease, epilepsy, stroke, seizures, significant paresis or aphasia with clinical symptoms in the previous 12 months that may in the Investigator's opinion interfere with participation in the trial. 10. Disseminated intravascular coagulation (DIC) within 3 months prior to the planned start of the study treatment. 11. Hemorrhagic cystitis 12. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy 13. Allogeneic stem cell transplantation within last two months or GvHD requiring systemic immunosuppressive therapy 14. Vaccination with live viruses within 2 weeks prior to lymphodepletion therapy 15. Major surgery within 28 days (prior to start of TM123 infusion) 16. Other malignancy requiring active therapy, but adjuvant endocrine therapy is allowed 17. 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 18. Prior treatment with gene therapy products unless approved by the sponsor 19. Use of checkpoint inhibitors within 5 half-lives of the respective substance 20. Pregnant or breastfeeding women 21. Currently significant psychologic disorder, including substance abuse 22. Known history of human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) 23. Any significant autoimmune disease requiring systemic immunosuppressive therapy or that may otherwise, in the Investigator's opinion, interfere with participation in the trial, or documented presence of autoantibodies against La/SS-B. Phase 1b Dose Expansion: Inclusion Criteria: 1. Male or female patients, age ≥ 18 years 2. Relapsed or refractory AML (according to standard of care testing), having up to 30% blasts in a bone marrow assessment at either screening or prescreening, or patients having between 30% and 40% blasts for 2 consecutive bone marrow assessments with a minimum of 1 months and no more than 2 months apart, and without hyperproliferative disease requiring cytoreductive treatment, up to 3rd relapse, without further approved curative or life-extending treatment options, and documented CD123 positivity of ≥ 20 % of blasts. Exceptions to BM blast criterion are only possible in minor deviations in timing and/or blast count in clinically stable patients, and only with written sponsor approval. Exemptions to CD123 expression are not allowed. MRD+ AML without morphological relapse or refractoriness may be included with the sponsor's approval. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 4. Life expectancy of at least 2 months 5. Adequate renal and hepatic laboratory assessments: 1. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤ 2.5× upper limit of normal (ULN) 2. Total bilirubin ≤ 1.5× ULN 3. Serum creatinine clearance at least 70 mL/min) 6. Adequate cardiac function, i.e., left ventricular ejection fraction (LVEF) of ≥ 50 %. 7. Long-term venous acces existing (e.g., port-system) resp. acceptance of implantation of a device 8. Able to give written informed consent 9. Weight ≥ 45kg 10. Negative pregnancy test; routinely using a highly effective method of birth control
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability | Infusion period of TM123 (up to 20 days) + 7 days resp. 14 days in patients with complete blast clearance during the IC or 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 graded according to Lee et al. 2014 and Lee et al. 2019 respectively |
| Recommended phase 2 dose (RP2D) | Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) | Establishing recommended phase 2 dose (RP2D) and schedule |
| Response | Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance) | Complete remission (CR, CRh, CRi, CRMRDneg, CRMRDpos) and partial remission (PR) at any time point and duration of responses |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Establishing recommended phase 2 dose (RP2D) | 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) | 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) | 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 | 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) | 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) | 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 | duration of consolidation cycle treatment | Patients who tolerate TM123 and UniCAR02-T without DLT and achieve a clinical benefit are candidates for consolidation cycles |
Countries
Germany, Netherlands
Outcome results
None listed