APR-548 in Combination With Azacitidine for the Treatment of TP53 Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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Phase 1 study evaluating the safety and efficacy of APR-548 in combination with Azacitidine for the treatment of TP53-Mutant Myelodysplastic Syndromes.

Detailed Description
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Open-label first-in-human (FIH) phase 1 clinical trial assessing the safety, pharmacokinetics (PK), and clinical activity of orally (p.o.) administered APR-548 alone and in combination with azacitidine for the treatment of TP53-mutant myelodysplastic syndromes (MDS).

Official Title
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Phase 1 Study to Evaluate Safety and Efficacy of APR-548 in Combination With Azacitidine for the Treatment of TP53-Mutant Myelodysplastic Syndromes

Conditions
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MDS, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: APR-548 + Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures. Documented diagnosis of TP53-mutant MDS, according to WHO criteria that is relapsed/refractory or previously untreated MDS. Adequate organ function as defined by the following laboratory values: Creatinine clearance ≥60 mL/min (by Cockcroft-Gault method, Appendix I), Total serum bilirubin ≤1.5 × upper limit of normal (ULN) unless due to Gilbert's syndrome or MDS organ involvement, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN, unless due to MDS organ involvement. Age ≥18 years at the time of signing the informed consent form. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix II). Projected life expectancy of ≥12 weeks. Clear ocular media and adequate pupil dilation to permit fundus examination and retinal imaging. Exclusion Criteria: Cardiac abnormalities, which includes, but not limited to: Myocardial infarction within six months prior to enrollment New York Heart Association Class III or IV heart failure or known LVEF <40% Concomitant malignancies or previous malignancies with less than a 1 year disease-free interval at the time of signing informed consent. Use of cytotoxic chemotherapeutic agents, or experimental agents for the treatment of MDS within 14 days or 5 half-lives of the product (whichever is shorter) of the first day of study drug treatment. Prior exposure to eprenetapopt (APR-246). A female subject who is pregnant or breast-feeding. Known history of human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection. Malabsorption syndrome or other condition likely to affect gastrointestinal absorption of APR-548. Known history or current evidence of ocular disease in either eye

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Dose level 1 | Drug: APR-548 + Azacitidine<br>* APR-548 monotherapy period followed by APR-548 in combination with Azacitidine<br>|
| Experimental: Cohort 2<br>Dose level 2 | Drug: APR-548 + Azacitidine<br>* APR-548 monotherapy period followed by APR-548 in combination with Azacitidine<br>|
| Experimental: Cohort 3<br>Dose level 3 | Drug: APR-548 + Azacitidine<br>* APR-548 monotherapy period followed by APR-548 in combination with Azacitidine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the safety and tolerability of APR-548 as monotherapy and in combination with azacitidine. | Occurence of dose limiting toxicities (DLTs) and frequency of treatment emergent and serious adverse events. | Through study completion, approximately 1 year |