This Phase 1 study will evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and clinical activity of KT-253 in adult patients with relapsed or refractory (R/R) high grade myeloid malignancies, acute lymphocytic leukemia (ALL), R/R lymphoma, myelofibrosis, and R/R solid tumors. The study will identify the pharmacologically optimal dose(s) (MTD) of KT-253 as the recommended Phase 2 dose (RP2D), based on all safety, PK, PD, and efficacy data.

This is an open-label Phase 1 (dose escalation) first-in-human study (FIH) of KT-253 in adult patients. This study will be initiated in patients with lymphomas, and solid tumors and then subsequently in patients with advanced high grade myeloid malignancies and ALL. Therefore, the study is comprised of two arms to characterize the safety and tolerability of ascending doses of KT-253 in each arm. Arm A will consist of patients with lymphomas and advanced solid tumors and Arm B will consist of patients with high grade myeloid malignancies and ALL.

Inclusion Criteria:

1. All Participants:

   • Eastern Cooperative Oncology Group performance status: 0-2.
   • Resolved acute effects of any prior therapy except for alopecia to baseline severity or Grade ≤1 NCI CTCAE and Grade ≤2 neuropathy
   • Adequate organ function at screening

2. Solid Tumors and Lymphoma (Arm A) ONLY

   • Histologically or pathologically confirmed solid tumor or lymphoma.
   • Relapsed and/or refractory (R/R) disease to at least two prior standard-of-care treatments or tumors for whom standard therapies are not available.

3. Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (Arm B) ONLY • Primary diagnosis of AML, ALL, High/Very High-risk MDS, MDS/MPN. Must be relapsed/refractory to standard therapies.

Exclusion Criteria:

1. All Participants:

   • Ongoing unstable cardiovascular function.
   • Major surgery requiring general anesthesia within 4 weeks prior to first dose of study drug.
   • History of or active concurrent malignancy unless disease-free for ≥ 2 years.
   • Known presence of p53 mutations in tumor tissue or blood, which are known to completely inactivate p53 transcriptional activity

2. Solid Tumors and Lymphoma (Arm A) ONLY

   • Known active uncontrolled or symptomatic central nervous system (CNS) metastases.
   • Autologous or allogenic hematopoietic stem cell transplant (HSCT) within six months prior to first dose of study drug or participant has progressed within six months from the day of stem cell infusion (for lymphoma participants only).
   • Exposures to anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of study drug.
   • Received immunotherapy/biologic treatment or investigational therapy within 4 weeks prior to first dose of KT-253, including tumor vaccines and checkpoint inhibitors.

3. Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (Arm B) ONLY

   • Active CNS leukemia. Participants with symptoms suggestive of CNS disease will require a lumbar puncture to rule out CNS disease.
   • Prior chemotherapy/radiation (including craniospinal radiation) within 2 weeks prior to the first dose of study drug.
   • Received allogeneic hematopoietic cell transplantation (HCT) <12 weeks prior to first dose or donor lymphocyte infusion (DLI) without conditioning <4 weeks prior to first dose.
   • Received autologous stem cell transplant (ASCT) < 4 weeks prior to first dose or the patient has not recovered from transplant associated toxicities to ≤ grade 1 prior to the first dose of study drug.
   • Received chimeric antigen receptor therapy or other modified T cell therapy <3 weeks prior to the first dose.
   • Patients with signs or symptoms of Grade ≥ 2 acute or chronic graft versus host disease (GVHD) within 2 weeks of enrollment.