An Open-Label Phase 1a/1b Dose Escalation and Expansion Cohort Study of SL-172154 (SIRPα-Fc-CD40L) in Combination With Azacitidine or With Azacitidine and Venetoclax for the Treatment of Subjects With Higher-Risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

This Phase 1a/1b study is an open label, multicenter trial in subjects with higher-risk (i.e., intermediate, high or very high risk by IPSS-R) MDS or AML. The study is designed to evaluate the safety, PK, pharmacodynamic effects, and preliminary anti tumor activity of SL-172154 monotherapy and SL-1712154 administered with either Azacitidine or Azacitidine and Venetoclax. Subjects will receive SL-172154 as monotherapy or administered with Azacitidine with or without Venetoclax until documented disease progression, unacceptable toxicity or intolerance, withdrawal of consent, or the subject meets other criteria for discontinuation (whichever occurs first).

Inclusion Criteria:

1. Subject has voluntarily agreed to participate by giving written informed consent in accordance with International Council for Harmonisation/Good Clinical Practice (ICH/GCP) guidelines and applicable local regulations.
2. Age ≥ 18 years.
3. For subjects with AML, confirmation of AML diagnosis by 2016 World Health Organization (WHO) criteria [Arber, 2016] classification, excluding acute promyelocytic leukemia (APL).
4. Subjects with MDS must have:
   1. morphologically confirmed diagnosis of MDS by 2016 WHO criteria [Arber, 2016] with <20% blasts in bone marrow per bone marrow biopsy/aspirate or peripheral blood.
   2. confirmation of intermediate, high or very high risk category by Revised International Prognostic Scoring System (IPSS-R)
5. Subjects with AML must have relapsed/refractory disease (>5% blasts by manual aspirate differential, flow cytometry, or immunohistochemistry) following at least 1 prior line of therapy but no more than 4 prior lines of therapy.
6. Subjects with relapsed/refractory disease (as defined in Inclusion criterion 5) following at least 1 prior line of therapy but no more than 4 prior lines of therapy for AML or MDS.
7. Subjects diagnosed with MDS must be previously untreated. Prior MDS therapy with lenalidomide or supportive care in the form of transfusions or growth factors is allowed.
8. All subjects must have documentation of at least one tumor protein 53 (TP53) gene mutation/deletion based on local test.
9. Subjects with previously untreated de novo AML or secondary AML with TP53 gene mutation or deletion and who are unlikely to benefit from standard intensive induction therapy or refuse intensive induction therapy at time of enrollment are eligible. All subjects must have documentation of at least one TP53 gene mutation/deletion based on local test. Subjects with secondary AML after MDS must not have received prior chemotherapy or no more than 2 cycles of prior hypomethylating agent for MDS.
10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2
11. Laboratory values must meet the criteria outlined in the protocol.
12. Willing to provide consent for bone marrow aspirate samples for exploratory research at baseline and on-treatment per schedule described in the Schedule of Assessments.
13. For subjects with relapsed/refractory disease, recovery from prior anti-cancer treatments including surgery, radiotherapy, chemotherapy or any other anti-cancer therapy to baseline or ≤ Grade 1.
14. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 72 hours of the first dose of study treatment.
15. Male subjects with female partners of childbearing potential must have azoospermia from a prior vasectomy or underlying medical condition or agree to use an acceptable method of contraception during treatment and for 30 days (which exceeds 5 half-lives) or for the duration required by local regulatory guidance, whichever is longer, after last dose of study treatment.