Safety and Efficacy of GYA01 (CART84) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Acute Lymphoblastic T Leukemia Patients (T-ALL).

AML and T-ALL are aggressive cancers, with poor prognosis with currently available therapies and significant unmet medical needs. Despite advancements in conventional therapies, relapse and refractory disease remain major challenges, necessitating innovative therapeutic approaches.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of certain hematological malignancies and achieved excellent results in some cases and thus, there is robust rationale for expanding this therapeutic modality to R/R AML and T-ALL patients.

CD84 antigen is an immunoreceptor whose expression has been reported in certain immune cells and in B-cell malignancies. CD84 is overexpressed in AML and has been identified as a promising target for immunotherapy approaches, particularly CAR T-cell therapy. Although CD84 has been more extensively studied in the context of AML, it is a promising CAR T target for the treatment of several hematological malignancies.

Recently, CART84 cells were successfully expanded in vitro and exerted high cytotoxicity towards cell lines from different hematological malignancies, including AML and T-ALL. These findings suggest that CART84 cells may be a promising therapeutic option for patients with these diseases.

As such, this study is planned as a Phase I and Phase IIa trial, where the primary objective of Phase I is to evaluate the safety of CART84 cell therapy in patients with R/R AML and to determine the candidate dose for Phase II, where the clinical efficacy of CART84 at the recommended phase II dose (RP2D) level will be evaluated in AML and T-ALL patients.

Inclusion criteria

• Age 18 years or older at the time of signing the informed consent.
• Willing and able to give written, informed consent to the current study.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Diagnosed with AML or T-ALL with ≥5% blasts in BM and/or PB at screening, without any approved therapeutic alternative and one of the following:

• Primary refractory disease (not achieving CR/CRi after more than two cycles of induction chemotherapy).
• Second relapse or beyond.
• Refractory relapse after at least 1 line of salvage therapy.
• Relapsed or refractory disease after allogeneic transplant provided the CART84 infusion occurs at least 3 months after the stem cell transplant.
• Documentation of CD84 expression on leukemic blasts in the BM and in peripheral blood, or other tissues if blasts are present, as assessed by flow cytometry at screening.
• For T-ALL patients: diagnosed with T-ALL exhibiting a double-negative (CD4- CD8-) immunophenotype, or patients with CD4+ and/or CD8+ T-ALL with no detectable blasts in peripheral blood.
• Availability of an appropriate HSCT donor, either related (haploidentical HLA matching or HLA identical sibling donor) or unrelated, if available within the required timeframe (days 30-90 post-CART84 infusion). If an unrelated donor is selected, it is highly recommended to have an haploidentical HLA matched donor identified and evaluated as a backup.
• For females of childbearing potential (defined as <24 months after last menstruation or not surgically sterile), a negative serum or urine pregnancy test must be documented at screening, prior to pre-conditioning and confirmed before receiving the first dose of study treatment.
• For females who are not postmenopausal (<24 months of amenorrhea) or who are not surgically sterile (absence of ovaries and/or uterus), commitment to the use of 2 methods of contraception, comprising of one highly effective method of contraception together with a barrier method, during the treatment period and for at least 12 months after the last dose of study treatment.
• Male participants must agree to use 2 acceptable methods of contraception (one by the patient - usually a barrier method), and one highly effective method by the patient's partner during the treatment period and for at least 12 months after the last dose of study treatment.
• Adequate renal, hepatic, pulmonary, and cardiac function defined as:

• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x ULN (upper limit of normal).
• Creatinine clearance (as estimated by the Cockcroft Gault formula) ≥50 mL/min.
• Total bilirubin ≤2 x ULN, except in patients with Gilbert's syndrome, who must have normal direct bilirubin.
• Left ventricular ejection fraction (LVEF) ≥45% (or ≥institution's lower limit of normal) confirmed by ECHO or MUGA.
• Baseline oxygen saturation >92% on room air.

Exclusion criteria

• Isolated extramedullary (EM) disease.
• Females who are pregnant or lactating.
• For T-ALL patients: Patients with T-ALL exhibiting CD4+ and/or CD8+ immunophenotypes with detectable blasts in peripheral blood.
• History or presence of clinically relevant CNS pathology, such as epilepsy, paresis, aphasia, stroke within 3 months prior to enrollment, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis.
• Clinically significant, uncontrolled heart disease (New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, sick-sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities, unless the patient has a pacemaker) or a recent (within 12 months) cardiac event.
• Patients with active, life-threatening bleeding.
• Presence of uncontrolled fungal, bacterial, viral, or other infection requiring systemic antimicrobials for management.
• Positive serological testing for human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody (anti-HBc), and hepatitis C virus antibody. Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR test within 6 weeks prior to initial IMP administration.
• History of autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months, or any autoimmune disease with CNS involvement.
• History of other malignant neoplasms unless disease-free for at least 12 months (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal therapy allowed).
• Known history of concomitant genetic syndromes such as Fanconi anemia, Schwachman-Diamond syndrome, Kostmann syndrome, or any other known BM failure syndrome.
• Patients who have received a prior stem cell transplant less than 3 months prior to CART84 infusion.
• Active significant (overall Grade ≥II, Seattle criteria) acute graft-versus-host disease (GvHD) or moderate/severe chronic GvHD (NIH consensus criteria) requiring systemic steroids or other immunosuppressants within 4 weeks of consent.
• The following medications are excluded:

• Steroids: Therapeutic doses of corticosteroids (greater than 10 mg daily of prednisone or its equivalent) within 7 days of leukapheresis or 72 hours prior to CART84 administration. However, physiological replacement, topical, and inhaled steroids are permitted.
• Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis and CART84 infusion.
• Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >2 weeks prior to leukapheresis and not repeated thereafter.
• Graft-versus-host disease therapies: Any drug used for the treatment of GvHD must be stopped >2 weeks prior to leukapheresis and not repeated thereafter.
• Treatment with any T cell-lytic or toxic antibody (e.g. alemtuzumab) within 6 months prior to leukapheresis.
• Intrathecal therapy within 2 weeks prior to starting pre-conditioning chemotherapy.
• If the patient participated in another experimental clinical trial within 1 month prior to CART84 infusion.
• Inability to tolerate leukapheresis.
• Patients who, in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study or unlikely to complete all protocol-required study visits or procedures, including follow-up visits.