A Study of CBX-250 in Participants With Relapsed or Refractory Myeloid Leukemias

Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Age 1. Dose Escalation: Male or female participants aged ≥18 years. 2. Backfill Cohorts: Male or female participants aged ≥12 years for whom no curative treatment options, including transplantation, are available. Diagnosis \& Disease Characteristics 3. Participants with histological confirmation of advanced hematologic malignancy including: 1. R/R AML, as defined by standardized criteria (e.g., European LeukemiaNet criteria \[Dohner 2022\]; after standard of care therapy. Participants with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment (including HSCT) are eligible. 2. R/R HR-MDS or very high risk MDS as per the Revised International Prognostic Scoring System (IPSS-R; Greenberg 2012) or Molecular International Prognostic Scoring System (IPPS-M, Bernard 2022) who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine). 3. R/R CMML who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine). 4. White blood cells must be below 25,000/µL at time of enrollment. Participants may receive cytoreduction prior to enrollment. 5. Historical documented evidence of HLA-A\*02:01 allele positivity. Performance Level 6. ECOG PS score 0-1 (if aged ≥18 years); Karnofsky Performance Scale of ≥70 (if aged ≥16 years and \<18 years); Lansky PS of ≥70 (if aged \<16 years). Prior Therapy 7. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia. 8. Radiation Therapy: At least 60 days from prior total body irradiation, craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port). 9. Stem Cell Infusion: At least 60 days must have elapsed from HSCT and at least 4 weeks (from first dose) must have elapsed from donor lymphocyte infusion without conditioning. 10. Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy. 11. Anti-Leukemia Therapy: At least 14 days since the completion of anti-leukemic therapy (for example, but not limited to, small molecule or cytotoxic/myelosuppressive therapy), with the following exceptions: * Hydroxyurea for cytoreduction can be initiated without restriction related to timing of study entry. Hydroxyurea for cytoreduction can be continued concomitantly with CBX-250, with Study Responsible Physician approval. * Intrathecal chemotherapy at the time of diagnostic lumbar puncture at least 24 hours prior to the start of CBX-250 and may continue prophylactic intrathecal chemotherapy beginning in Cycle 2, at the treating physician's discretion. 12. Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors. 13. Biologics (e.g. monoclonal antibody therapy): At least 28 days or 5 half-lives, whichever is shorter, have elapsed since the completion of therapy with a biologic agent. Any AE related to prior biologic treatment must be resolved to baseline severity or ≤Grade 1. 14. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy. Cytoreductive therapy must have approval of the Study Responsible Physician. Adequate Organ Function Requirements within 10 Days of Treatment Initiation 15. Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 based on local institutional practice for age-appropriate determination (eg, Schwartz formula for pediatric participants or Cockcroft-Gault formula for adults). 1. Participants ≥18 years: glomerular filtration rate ≥45 mL/min 2. Participants \<18 years: ≥45 mL/min x (participant's body surface area m2/1.73) • Adequate liver function defined as: * Total bilirubin \<1.5 × the upper limit of normal (ULN) for age or normal conjugated bilirubin, or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in participants with well documented Gilbert's syndrome or hemolysis or who require regular blood transfusions. * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<3 × ULN (unless attributed to leukemic involvement with discussion with the Study Responsible Physician). Sex and Contraceptive/Barrier Requirements 16. If a female of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose. 17. If male of childbearing potential, agrees to use barrier contraception from the time of enrollment through 120 days following the last study drug dose. Informed Consent 18. Participant or participant's health care proxy is able and willing to provide written informed consent and able to follow study instructions. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Diagnosis 1. Previous CTSG targeted therapy or treatment with any pMHC T-cell engager. 2. Isolated extramedullary relapse. 3. Active central nervous system (CNS) disease. Participants with prior CNS history can be enrolled if the participant has a negative lumbar puncture following completion of intrathecal chemotherapy). Infection 4. Known HIV infection. 5. Active hepatitis B infection (participants with documented clearance following treatment are allowed). 6. Active hepatitis C infection (participants with documented clearance following treatment are allowed). Pregnancy and Breastfeeding 7. Pregnant or nursing women: Negative serum preg