∙ Participants are eligible to be included in the study only if all of the following criteria apply:

∙ Age

• Dose Escalation: Male or female participants aged ≥18 years.

• Backfill Cohorts: Male or female participants aged ≥12 years for whom no curative treatment options, including transplantation, are available.

• Diagnosis \& Disease Characteristics

• Participants with histological confirmation of advanced hematologic malignancy including:

∙ 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.

‣ 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).

‣ R/R CMML who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine).

• White blood cells must be below 25,000/µL at time of enrollment. Participants may receive cytoreduction prior to enrollment.

• Historical documented evidence of HLA-A\*02:01 allele positivity.

• Performance Level

• 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

• Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia.

• 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).

• 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.

⁃ 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.

⁃ 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.

⁃ 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.

⁃ 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.

⁃ 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

⁃ 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).

• Participants ≥18 years: glomerular filtration rate ≥45 mL/min

∙ 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

⁃ 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.

⁃ 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

⁃ Participant or participant's health care proxy is able and willing to provide written informed consent and able to follow study instructions.