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

Multicenter, Open-label, Phase 1 Study of Allo-RevCAR01-T-CD123 Consisting of Genetically Modified T Cells Carrying Reverse Chimeric Antigen Receptors (Allo RevCAR01 T) in Combination With CD123 Target Module (R-TM123) for the Treatment of Patients With Selected Hematologic Malignancies Positive for CD123

The Allo-RevCAR01-T-CD123 drug is a combination of a cellular component (Allo-RevCAR01-T) with a recombinant antibody derivative (R-TM123), which together form the active drug. The cellular component Allo-RevCAR01-T consists of an allogeneic human T-cell genetically multi-edited and expressing a reversed, universal chimeric antigen receptor (RevCAR) presenting an extracellular peptide epitope (RevCAR epitope). R-TM123 functions as a bridging module between Allo-RevCAR01-T and a CD123-expressing target cancer cell by selectively binding the RevCAR epitope and CD123.

Inclusion Criteria:

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

1. 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.

2. 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)

   1. 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
   2. 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,
   3. without hyperproliferative disease requiring cytoreductive treatment,
   4. 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.

3. 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:

1. 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.
2. must have received or be ineligible for allogeneic stem cell transplant.
3. 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.

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

Exclusion Criteria:

1. Acute promyelocytic leukemia (t15;17).
2. AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma)
3. Acute manifestationof AML in the central nervous system.
4. Bone marrow failure syndromes
5. 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.
6. Active pulmonary disease with clinically relevant hypoxia
7. Parkinson's disease or epilepsy with clinical symptoms in the previous 12 months .
8. Stroke, seizure, or intracranial hemorrhage in the past 12 months.
9. History or presence of disseminated intravascular coagulation (DIC), deep vein thrombosis or thromboembolism within 3 months prior to start of treatment.
10. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
11. Presence of hemorrhagic cystitis
12. Other toxicity from prior anticancer treatment has not resolved to Grade ≤1 or baseline.
13. Allogeneic stem cell transplantation within last 2 months or GvHD requiring systemic immunosuppressive therapy.
14. Vaccination with live viruses < 2 weeks prior to lymphodepletion therapy.
15. Major surgery within 28 days prior to start of R-TM123 infusion.
16. 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.
17. 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.
18. Treatment with anti-leukemic therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to lymphodepletion.
19. Prior treatment with gene modified cell products.
20. Use of checkpoint inhibitors within 5 half-lives of the specific drug.
21. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants.
22. Pregnant or breastfeeding women.
23. 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.
24. 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).
25. 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
26. Known hypersensitivity to cellular component (Allo-RevCAR01-T) and/or TM (R-TM123) excipients or to compounds of the lymphodepletion therapy, tocilizumab, or corticosteroids.
27. Evidence that the participant is not likely or able to follow the study protocol (e.g., lacking compliance) in the judgment of the investigator.
28. Participant unable to understand the informed consent and possible consequences of the participation in the clinical trial in the judgement of the investigator.