Clinical Trial 21778

• Overview

  Study Title:

  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)

  Summary:

  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).

  Objective:

  Primary- To evaluate the safety and tolerability of SL-172154 administered alone or with azacitidine OR azacitidine + venetoclax in subjects with higher-risk MDS or AML Secondary- To assess preliminary evidence of antitumor efficacy of SL-172154 administered alone or with azacitidine OR azacitidine + venetoclax in subjects with higher-risk MDS or AML

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy; Therapy (NOS)

  Medications:

  GDC-0199 (Venetoclax); SL-172154 (); Venetoclax (); azacitidine (5-azacitidine)

• Inclusion Criteria

  Inclusion Criteria:
  • Participant 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.
  • Age ≥ 18 years.
  • For participants with AML, confirmation of AML diagnosis by 2016 World Health Organization (WHO) criteria [Arber, 2016] classification, excluding acute promyelocytic leukemia (APL).
  • Participants with MDS must have: (a) morphologically confirmed diagnosis of MDS by 2016 WHO criteria [Arber, 2016] with > Participants 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.
  • Participants 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.
  • Participants 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.
  • All participants must have documentation of at least one tumor protein 53 (TP53) gene mutation/deletion based on local test.
  • Participants 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 participants must have documentation of at least one TP53 gene mutation/deletion based on local test. Participants with secondary AML after MDS must not have received prior chemotherapy or no more than 2 cycles of prior hypomethylating agent for MDS.
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2
  • Laboratory values must meet the criteria outlined in the protocol.
  • 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.
  • For participants 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.
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 72 hours of the first dose of study treatment.
  • Male participants 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.

• Exclusion Criteria

  Exclusion Criteria:
  • Participant with relapsed or refractory disease has received treatment for AML or MDS with any of the following: (a) Chimeric antigen receptor (CAR)-T cell therapy (b) Prior treatment with anti-cluster of differentiation 47 (CD47) targeting agent or cluster of differentiation 40 (CD40) agonist within 28 days prior to: (1) the first dose of study treatment. (2) Prior treatment with signal-regulatory protein alpha (SIRPα)-targeting antibody (3) Other experimental therapies for AML or MDS within 14 days or at least 5 half- lives (whichever is shorter) prior to the first dose of study treatment
  • Evidence of active central nervous system (CNS) involvement with leukemia
  • Participants requiring agents other than hydroxyurea to control blast counts within 14 days prior to the first dose of study treatment.
  • Evidence of active bleeding or bleeding diathesis or major coagulopathy (including familial)
  • [Only for Cohorts including Venetoclax in the regimen] Participant has received strong and/or moderate cytochrome P450, family 3, subfamily A (CYP3A) inducers within 7 days prior to the first dose of study treatment.
  • Use of corticosteroids or other immunosuppressive medication, current or within 14 days of the first dose of study treatment
  • Receipt of live attenuated vaccine within 30 days of first dose of SL-172154 treatment, the exception is that vaccines for coronavirus disease 19 (COVID-19) are permitted.
  • Participant has active, uncontrolled infection (e.g, viral, bacterial, or fungal). Participants are eligible if infection is controlled with antibiotics, antivirals and/or antifungals.
  • [Only for Cohorts including Venetoclax in the regimen] Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
  • Symptomatic peptic ulcer disease or gastritis, active diverticulitis, other serious gastrointestinal disease associated with diarrhea within 6 months of first dose of study treatment.
  • Clinically significant or uncontrolled cardiac disease including any of the following: Myocarditis, Unstable angina within 6 months from D1 of study treatment, Acute myocardial infarction within 6 months from D1 of study treatment, Uncontrolled hypertension, New York Heart Association (NYHA) Class III or IV congestive heart failure, Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, second- or third- degree atrioventricular (AV) block without a pacemaker, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia not stabilized on therapy).
  • Participant has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participation in the study.
  • Participants who have had any major surgical procedure within 14 days of first dose of study treatment.
  • Participant is a woman who is pregnant or breast feeding or planning to become pregnant or breast feed while enrolled in this study.
  • Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of adverse events (AEs) or compromised ability to provide written informed consent.
  • Presence of another malignancy that requires active therapy and that in the opinion of the investigator and Sponsor would interfere with the monitoring of disease assessments in this study.
  • Known hypersensitivity to any of the study medications including excipients of Azacitidine.
  • Has undergone solid organ transplantation.
  • Known or active human immunodeficiency virus (HIV) infection
  • Known or active infection with hepatitis B
  • Other exclusions apply

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