GTB-3650 TriKE® for the Treatment of Patients with High Risk Myelodysplastic Syndromes and Refractory/Relapsed Acute Myeloid Leukemia

Inclusion Criteria

• DISEASE SPECIFIC CRITERIA: Diagnosis of a high risk myelodysplastic syndromes (MDS), treatment related MDS, or relapsed/refractory acute myelogenous leukemia (AML) as defined by World Health Organization (WHO) Classification (5th edition Khoury, et al. 2023)
• DISEASE SPECIFIC CRITERIA: Tumor expresses >= 50% CD33+ target cells
• DISEASE SPECIFIC CRITERIA: Refractory to, intolerant of, or ineligible for therapy options that are known to provide clinical benefit
• DISEASE SPECIFIC CRITERIA: Persons who relapse after hematopoietic stem cell transplant (HSCT) must have received one form of post-transplant therapy and have residual disease (defined as > 5% morphologically detected blasts on the bone marrow aspirate) plus meet each of the following: * At least 6 months post-transplant, * Off immunosuppression for a minimum of 4 weeks, * Without active acute or chronic graft versus host disease (GVHD) requiring systemic therapy. Topical GVHD directed therapy such as eye drops, skin creams, inhalers, or oral swish and spit agents are allowed
• DISEASE SPECIFIC CRITERIA: Meets the disease specific criteria for previous treatment: * High Risk MDS: ** Progression or failure of at least 4 cycles of a hypomethylating agent (azacitidine or decitabine) ** Ineligible for hematopoietic stem cell transplantation (HCST) due to age > 75, Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) > 5, or frail according to the Fried Frailty index * Therapy Related MDS: ** Progression after or failure of at least 4 cycles of a hypomethylating agent (azacitidine or decitabine) * Relapsed AML: ** Failure of at least 2 cycles of induction that includes an anthracycline with cytarabine (including Vyxeos) or a hypomethylation agent and venetoclax in any combination (e.g. two cycles Vyxeos, or two cycles of hypomethylation agent/venetoclax [HMA/ven] are acceptable) * Refractory AML: ** Failure to achieve remission after: *** Age 18-60 years of age at consent signing: After at least 3 induction attempts that included at least 1 cycle of an anthracycline with cytarabine (including Vyxeos) AND a hypomethylating agent and venetoclax *** Age > 60 years of age at consent signing: After at least 2 induction attempts that included at least 1 cycle of an anthracycline with cytarabine (including Vyxeos) AND a hypomethylating agent and venetoclax AND a hypomethylating agent and venetoclax *** Age > 70 and ineligible to receive intense induction: at least 4 cycles of a hypomethylation agent and venetoclax
• Absolute lymphocyte count (ALC) >= 200 cells/µL OR absolute circulating CD56+/CD3- NK cell count > 25 cells/uL within the 14 days prior to cycle 1 day 1
• Peripheral blasts =< 20,000 at the time of treatment start. Hydroxyurea may be used up to day 1 of the 1st cycle to achieve this threshold and continued for the 1st two weeks of cycle 1 to maintain it.
• Age >= 18 years of age at time of consent
• Karnofsky performance status >= 70%
• Renal: a patient body surface area (BSA) corrected glomerular filtration rate >= 60 ml/min as calculated using the laboratory estimated glomerular filtration rate (eGFR) result x (patient’s BSA m^2/1.73 m^2)(Korhonen 2023) (within 14 days of cycle 1 day 1)
• Hepatic: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase =< 3 times the upper limit of normal (ULN) (within 14 days of cycle 1 day 1)
• Hepatic: Total bilirubin =< 1.5 times the ULN (within 14 days of cycle 1 day 1)
• Cardiac: New York Heart Association (NYHA) class I or II (within 30 days of cycle 1 day 1)
• Cardiac: Left ventricular ejection fraction >= 50% by echocardiogram, MUGA or cardiac MRI (within 30 days of cycle 1 day 1)
• Pulmonary: Room air oxygen (02) saturation at >= 95% (within 14 days of cycle 1 day 1)
• Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the last dose of GTB-3650. Non-childbearing is defined as > 1 year post-menopausal or surgically sterilized. Examples of highly effective birth control methods include but are not limited to the following: * Double-barrier contraception by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam * Oral contraceptive pills * Injectable contraception (i.e., Depo Provera) * Intrauterine device (IUD) * Transdermal contraceptive patch * Vaginal contraceptive ring * Contraceptive implants * Abstinence ** Note: Rhythm method alone is not considered an adequate method of contraception
• DOSE FINDING COMPONENT: Must agree to stay within a 60-minute drive of the study center through the cycle 1 day 29 visit (end of the dose limiting toxicity period)
• Provides voluntary written consent prior to the performance of any research related activity

Exclusion Criteria

• Pregnant or breast-feeding. The effect of GTB-3650 TriKE on the fetus is unknown. Persons of childbearing potential must have a negative serum or urine test within 7 days prior to cycle 1 day 1 to rule out pregnancy
• A candidate for hematopoietic stem cell transplant (HSCT) or newly relapsed after HSCT (e.g. no post-HSCT therapy given)
• Bi-phenotypic acute leukemia or mixed lineage leukemia
• Acute promyelocytic leukemia (APL)
• No anticancer therapy within 14 days of cycle 1 day 1; any AEs from therapy given prior must have resolved to grade 1 or baseline
• New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan unless cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving with associated clinical improvement after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections)
• Active systemic infection requiring parenteral antibiotic therapy. Any prior systemic infections must have resolved following optimal therapy
• Known history of HIV
• Active hepatitis B or hepatitis C (virus detectable by polymerase chain reaction [PCR]) - chronic asymptomatic viral hepatitis is allowed * Occult or prior hepatitis B infection (defined as positive hepatitis B virus core antibody [HBcAb] and negative hepatitis B virus surface antigen [HBsAg]) may be included if hepatitis B virus HBV deoxyribonucleic acid (DNA) is undetectable. These participants must be willing to undergo monthly polymerase chain reaction (PCR) HBV DNA testing
• Positive test results from chronic hepatitis B infection (defined as positive HBsAg serology) and/or positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology test) * Positive for HCV antibody are eligible only if PCR is negative for HCV ribonucleic acid (RNA)
• Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer currently in complete remission, or any other cancer from which the patient has been disease-free for 1 year
• Active central nervous system (CNS) malignancy or symptoms of CNS spread or administration of intrathecal (IT) chemotherapy within 14 days prior to day 1 * Persons with previously treated for CNS spread may be eligible provided no leukemic cells are present in the cerebrospinal fluid (CF) on lumbar puncture (LP) within 7 – 14 days prior to day 1 * If CNS spread is associated with the current relapse, CF must negative for leukemic cells on 2 separate LPs at least 1 week apart and the most recent within 7 – 14 days prior to day 1 and no ongoing need for steroids
• Extramedullary disease causing symptoms and/or involving the CNS or spinal canal - asymptomatic extramedullary disease outside the CNS and spinal canal is eligible provided the marrow has measurable disease
• Known autoimmune disease requiring active treatment with steroids or other immunosuppressive medications within 14 days before cycle 1 day 1. Inhaled or topical steroids, and adrenal replacement steroid doses =< 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Persons with a condition requiring systemic treatment with steroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days before cycle 1 day 1
• The potential risk of QT/corrected QT interval (QTc) prolongation is unknown in humans receiving TriKE therefore either of the following is an exclusion criterion: * QTc interval > 480 msec at screening * A family history of long QT syndrome
• Psychiatric illness/social situations that, in the judgement of the enrolling investigator, would limit compliance with study requirements
• Other illness or a medical issue that, in the judgement of the enrolling investigator, would exclude the patient from participating in this study