UAB - Center for Clinical and Translational Science

• Participants with cytologically/histologically confirmed MDS according to the 2016 World Health Organization (WHO) classification with the following: - Measurable disease per WHO MDS with excess blasts criteria as defined either: - 5%-9% blasts in the bone marrow or 2%-4% blasts in the peripheral blood or - 10%-19% blasts in the bone marrow or 5%-19% blasts in the peripheral blood - MDS that is relapsed or refractory and must not have other therapeutic options known to provide clinical benefit in MDS available. - Treatment failure after prior hypomethylating agent (HMA) therapy for MDS, defined as one of the following: - Progression (per 2006 International Working Group [IWG] criteria) at any time after initiation of HMA therapy. - Lack of response (failure to achieve complete remission [CR], partial response [PR], or hematologic improvement [HI] per 2006 IWG criteria) after at least 6 cycles of azacitidine (or equivalent HMA) or 4 cycles of decitabine (or equivalent HMA). - Relapse after achievement of CR, PR, or HI (per 2006 IWG criteria). - Intolerance of HMA (Grade 3 or higher non-hematologic toxicity leading to treatment discontinuation). - Participants with isolated 5q-/5q- syndrome must have progressed, failed, relapsed, or not tolerated lenalidomide in addition to HMA. - Must be off HMA therapy ≥ 2 weeks and must be off any other treatments for MDS for ≥ 4 weeks prior to first dose of SEA-CD70; growth factors and transfusions are allowed before and during the study as clinically indicated - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Part B Inclusion Criteria - Participants with cytologically/histologically confirmed MDS according to the WHO classification with the following: - Measurable disease per WHO MDS with excess blasts (MDS-EB) criteria as defined either: - 5%-9% blasts in the bone marrow or 2%-4% blasts in the peripheral blood, or - 10%-19% blasts in the bone marrow or 5%-19% blasts in the peripheral blood - MDS that is relapsed or refractory and must not have other therapeutic options known to provide clinical benefit in MDS available. - Treatment failure after prior HMA therapy for MDS defined as one of the following: - Progression (per 2006 IWG criteria) at any time after initiation of HMA therapy. - Lack of response (failure to achieve CR, PR, or HI per 2006 IWG criteria) after at least 6 cycles of azacitidine or 4 cycles of decitabine. - Relapse after achievement of CR, PR, or HI (per 2006 IWG criteria). - Intolerance of HMA (Grade 3 or higher non-hematologic toxicity leading to treatment discontinuation). - Participants with isolated 5q-/5q- syndrome must have progressed, failed, relapsed, or not tolerated lenalidomide in addition to HMA. - Must be off HMA therapy ≥ 2 weeks and must be off any other systemic treatments for MDS for ≥ 4 weeks prior to first dose of SEA-CD70; growth factors and transfusions are allowed before and during the study as clinically indicated. - ECOG Performance Status of 0-2 Part C Inclusion Criteria - Participants with relapsed or refractory AML according to International Consensus Classification (ICC) 2022 (except for acute promyelocytic leukemia [APL]): - Who have received either 2 or 3 previous regimens to treat active disease. Post-remission treatments, intrathecal chemotherapy, and radiotherapy are not considered previous regimens. - Who have received 1 previous regimen to treat active disease and have at least one of the following: - Age > 60 and ≤75 years. - Primary resistant AML (defined as failure to achieve CR after 1-2 courses of induction therapy) - First CR duration <6 months - Adverse-risk per European Leukemia Network genetic risk stratification - Secondary AML (prior history of MDS or therapy-related) - Age 18-75 years - ECOG performance status of 0-2 Parts D and F Inclusion Criteria - Participants with diagnosis of MDS or MDS/AML according to ICC 2022 criteria - Disease which has relapsed, failed to respond after minimum of 6 cycles, or progressed following an HMA in the immediately preceding line of therapy. - Eligible for continued therapy with azacitidine - Must be off any other systemic treatment for AML/MDS. Must be off HMA therapy ≥ (greater than or equal to) 2 weeks and any other systemic treatments for MDS for ≥ (greater than or equal to) 4 weeks prior to first dose of SEA-CD70 - ECOG Performance Status 0-2 Parts D and E Inclusion Criteria - Participants with diagnosis of MDS or MDS/AML according to ICC 2022 criteria, previously untreated. - Participants with MDS/AML should not have AML-defining cytogenetics. - Participants with higher-risk (Moderate High, High, or Very High) per Molecular International Prognostic Scoring System (IPSS-M) MDS and MDS/AML - ECOG Performance Status 0-2

(All Parts) - History of another malignancy within 3 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death. - Previous exposure to CD70-targeted agents - Prior allogeneic hematopoietic stem cell transplant, for any condition - Central nervous system leukemia based on imaging or documented positive cytology in cerebral spinal fluid - History of clinically significant sickle cell anemia, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura - Parts D and F only: Prior oral HMA or oral HMA-combinations