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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic
Sören Lehmann1, Vladimir J N Bykov, Dina Ali
1Department of Hematology, M54, Karolinska University Hospital, 141 86 Stockholm, Sweden. Soren.Lehmann@ki.se
Purpose:
APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.
Patients And Methods:
APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.
Results:
MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.
Conclusion:
We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
Insights
APR-246 is a novel drug that restores p53 activity. This first-in-human trial found it safe and well-tolerated, with a favorable pharmacokinetic profile, supporting its potential in cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- APR-246 (PRIMA-1MET) is a novel therapeutic agent designed to restore the transcriptional activity of wild-type or mutant p53.
- The p53 tumor suppressor pathway is frequently inactivated in human cancers, making it a critical target for novel therapies.
Purpose of the Study:
- To evaluate the safety, tolerability, and pharmacokinetic profile of APR-246 in a first-in-human clinical trial.
- To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of APR-246.
- To assess the preliminary efficacy and biological effects of APR-246 in patients with hematologic malignancies and prostate cancer.
Main Methods:
- A Phase I, dose-escalation study of APR-246 administered intravenously over 4 consecutive days.
- 22 patients with hematologic malignancies (including AML) and prostate cancer were enrolled.
- Doses ranged from 2 mg/kg to 90 mg/kg, with MTD and DLTs identified.
Main Results:
- The MTD of APR-246 was determined to be 60 mg/kg.
- APR-246 was generally well-tolerated, with common adverse events including fatigue, dizziness, headache, and confusion.
- Pharmacokinetic analysis revealed minimal interindividual variation and no dose or time dependency, with a terminal half-life of 4-5 hours.
- Biologic effects observed included cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in tumor cells.
- One patient with AML and a p53 mutation showed a reduction in bone marrow blast percentage, and another with lymphoma showed a minor response.
Conclusions:
- APR-246 is safe and well-tolerated at predicted therapeutic plasma concentrations.
- The drug exhibits a favorable pharmacokinetic profile.
- APR-246 demonstrates the ability to induce p53-dependent biological effects in tumor cells in vivo, suggesting therapeutic potential.
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