Phase 1 Study of Allo-RevCAR01-T-CD123 in Patients With Selected CD123 Positive Hematologic Malignancies

Inclusion criteria

• Male or female participants, age ≥18 years. 2. HLA type of participant must match at HLA B and C loci 3.

• For Phase 1a escalation part of the trial Participants with CD123+ AML (defined as ≥20% of leukemic cells expressing CD123 at any point in the course of disease)

(1) for whom all standard or life-extending therapies have failed and for whom no potentially curative therapies are available or who are intolerant to such therapies.

• For Phase 1b expansion part of the trial (Phase 1b) Participants with CD123+ AML (defined as ≥20% of leukemic cells expressing CD123 at any point in the course of disease)

• up to 3rd relapse for whom all standard or life-extending therapies have failed and for whom no potentially curative therapies are available or who are intolerant to such therapies
• having up to 30% blasts in a bone marrow assessment at either screening or prescreening, or having between 30% and 40% blasts for two consecutive bone marrow assessments with a minimum of one month and no more than two months apart,
• without hyperproliferative disease requiring cytoreductive treatment,
• 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. Exceptions to minimum CD123 expression are not allowed.
• For Phase 1a escalation and Phase 1b expansion part of the trial

Participants with MRD+ AML are potentially eligible but must meet the following criteria:

• MRD positivity must be based on assays and markers supported by consensus guidelines [Heuser2021] and in the judgment of the investigator must confer negative prognostic risk highly likely to result in relapse.
• must have received or be ineligible for allogeneic stem cell transplant.
• must be approved by the Sponsor for inclusion in the study. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 5. Life expectancy of at least 3 months in the judgment of the investigator. 6. Adequate renal and hepatic laboratory assessments: 7. Adequate cardiac function 8. Long-term central venous access existing (e.g., port-system) or willing to have such a device inserted.

• Able to give written informed consent. 10. Weight ≥45 kg. 11. Negative pregnancy; routinely using a highly effective method of birth control

Exclusion criteria

• Acute promyelocytic leukemia (t15;17).
• AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma)
• Acute manifestationof AML in the central nervous system.
• Bone marrow failure syndromes
• Cardiac disease: heart failure (New York Heart Association 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.
• Active pulmonary disease with clinically relevant hypoxia
• Parkinson's disease or epilepsy with clinical symptoms in the previous 12 months .
• Stroke, seizure, or intracranial hemorrhage in the past 12 months.
• History or presence of disseminated intravascular coagulation (DIC), deep vein thrombosis or thromboembolism within 3 months prior to start of treatment.
• Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
• Presence of hemorrhagic cystitis
• Other toxicity from prior anticancer treatment has not resolved to Grade ≤1 or baseline.
• Allogeneic stem cell transplantation within last 2 months or GvHD requiring systemic immunosuppressive therapy.
• Vaccination with live viruses < 2 weeks prior to lymphodepletion therapy.
• Major surgery within 28 days prior to start of R-TM123 infusion.
• Prior malignancy in the past 3 years or any malignancy requiring ongoing active therapy other than adjuvant endocrine therapy. Participants with resected or ablated tumors, such as basal cell carcinoma of skin, carcinoma-in-situ of the cervix, or other tumors considered cured may be considered for the study with Sponsor approval.
• Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whichever is shorter) of the substance prior to lymphodepletion.
• Treatment with anti-leukemic therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to lymphodepletion.
• Prior treatment with gene modified cell products.
• Use of checkpoint inhibitors within 5 half-lives of the specific drug.
• Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants.
• Pregnant or breastfeeding women.
• Psychologic disorders with treatment modifications required within the last 3 months, drug and/or significant active alcohol abuse as per investigator's medical judgement. Depression or anxiety due to presence of the underlying malignancy may be exempted with Sponsor approval.
• 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).
• Presence of autoantibodies against lupus La protein (La)/ Sjögren syndrome type B antigen (SS-B) or presence or history of autoimmune diseases associated with such antibodies
• Known hypersensitivity to cellular component (Allo-RevCAR01-T) and/or TM (R-TM123) excipients or to compounds of the lymphodepletion therapy, tocilizumab, or corticosteroids.
• Evidence that the participant is not likely or able to follow the study protocol (e.g., lacking compliance) in the judgment of the investigator.
• Participant unable to understand the informed consent and possible consequences of the participation in the clinical trial in the judgement of the investigator.