Dose-escalating Trial With Allo-RevCAR01-T Cells in Combination With CD123 Target Module (R-TM123) for Participants With Selected Hematologic Malignancies Positive for CD123

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia Refractory

Intervention / Treatment
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* Other: Cyclophosphamide (Non-IMP, Lymphodepletion)
* Other: Fludarabine (Non-IMP, Lymphodepletion)
* Drug: R-TM123
* Drug: Allo-RevCAR01-T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants, age ≥18 years. HLA type of participant must match at HLA B and C loci Participants with CD123+ AML (defined as ≥20% of leukemic cells expressing CD123 at any point in the course of disease) - Participants with MRD+ AML are eligible but must meet specific criteria Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy of at least 3 months in the judgment of the investigator. Adequate renal and hepatic laboratory assessments: Adequate cardiac function Permanent venous access existing (e.g., port-system) or willing to have such a device inserted. Able to give written informed consent. Weight ≥45 kg. Negative pregnancy; routinely using a highly effective method of birth control Exclusion Criteria: Acute promyelocytic leukemia (t15;17). History of 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. Stroke, seizure, or intracranial hemorrhage in the past 12 months. History or presence of disseminated intravascular coagulation (DIC) 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 Toxicity from prior anticancer treatment has not resolved to Grade ≤1 or baseline. Allogeneic stem cell transplantation within last 2 months or GvHD requiring 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 by local treatment 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Dose escalation follows a BOIN comb design with 3 dose levels of 100, 250, and 500 million Allo-RevCAR01-T and 3 dose levels of R-TM123 resulting in a maximum of 9 dose levels. Given 1 participant dose level cohorts, there will be an inherent stagger between each participant equivalent to the DLT window of 28 days
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allo-RevCAR01-T-CD123 treatment<br>Following lymphodepleting therapy, R-TM123 will be administered as continuous infusion from Cycle 1 Day 1 and then will continue for 20 days. After 4 hours (±30 minutes) of R TM123 start on Day 1, a single dose of Allo-RevCAR01-T will be administered as IV infusion | Other: Cyclophosphamide (Non-IMP, Lymphodepletion)<br>* Intravenous infusion over 3 days (d-5 to d-3)<br>Other: Fludarabine (Non-IMP, Lymphodepletion)<br>* Intravenous infusion over 3 days (d-5 to d-3)<br>Drug: R-TM123<br>* Intravenous infusion over 20 days<br>* Other names: R-TM123 is one component of the Allo-RevCAR01-T-CD123 treatment;Drug: Allo-RevCAR01-T<br>* A single dose of Allo-RevCAR01-T will be administered as IV infusion on Treatment day 1. Allo-RevCAR01-T will not be administered again within this study.<br>* Other names: Allo-RevCAR01-T is one component of the Allo-RevCAR01-T-CD123 treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety profile of the treatment | Incidence and intensity of adverse events (AEs) graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), tumor lysis syndrome, and graft versus host disease (GvHD), which will be graded according to widely accepted specialized criteria | At the end of cycle 1 (in total 28 days, given no treatment interruptions) | 
| To determine the incidence of dose-limiting toxicities (DLT) | Incidence of DLTs | At the end of cycle 1 (in total 28 days, given no treatment interruptions) | 
| To determine the maximum tolerated dose (MTD) | MTD | At the End of Cycle 1 (in total 28 days, given no treatment interruptions) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evidence of biological and clinical activity including best response rate | Complete remission (CR, CRh, CRi, CRMRDneg, CRMRDpos) Partial remission (PR) Overall response rate (ORR) Stable disease (SD) Best response rate Duration of response | At any timepoint until end of study (6 months after the end of last R-TM123 administration) | 
| Survival rates | Progression free survival Overall survival | At end of study visit (6 months after the end of last R-TM123 administration) | 
| Response rate to cycles 2 to 4 | Complete remission (CR, CRh, CRi, CRMRDneg, CRMRDpos), Partial remission (PR) Overall response rate (ORR) Stable disease (SD) Best response rate Duration of response | At any timepoint until end of study (6 months after the end of last R-TM123 administration) | 
| Establishing recommended Phase 2 dose (RP2D) | Based on assessments of MTD and DLTs | At any timepoint until end of study (6 months after the end of last R-TM123 administration) |