Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer
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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.
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Adverse events with eprenetapopt plus azacitidine were similar to those reported for azacitidine or eprenetapopt monotherapy.
“Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [25]
The Safety and Tolerability section (page not provided) reports adverse events during APR-246 (eprenetapopt) monotherapy, so this paper supplies one monotherapy safety profile. It does not assess eprenetapopt plus azacitidine, compare the combination with either monotherapy, or report the cited grade ≥3 event rates. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn a phase I study including patients with AML, eprenetapopt monotherapy demonstrated clinical activity with corresponding activation of p53-dependent pathways.
“In a phase I study including patients with AML, eprenetapopt monotherapy demonstrated clinical activity with corresponding activation of p53-dependent pathways.25,26”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [25]
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Targeting p53 by small molecules in hematological malignancies
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Acute Myeloid Leukemia: The Good, the Bad, and the Ugly
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Current status and new treatment approaches in TP53 mutated AML
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Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?
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- Authors
- Lehmann, S., Bykov, V. J. N., Ali, D., Andrén, O., Cherif, H., Tidefelt, U., Uggla, B., Yachnin, J., Juliusson, G., Moshfegh, A., Paul, C., Wiman, K. G., & Andersson, P.-O.
- Affiliations
- Karolinska University Hospital (SE)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2012-10-10
- Volume
- 30
- Issue
- 29
- Pages
- 3633-3639
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2142765738
- Cited by
- 406
- References
- 21
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 14 · 2023: 27 · 2022: 27 · 2021: 42 · 2020: 38 · 2019: 43 · 2018: 38 · 2017: 30 · 2016: 36 · 2015: 26 · 2014: 37 · 2013: 17 · 2012: 2
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- APR-246, PRIMA-1MET, p53 reactivation, mutant p53, acute myeloid leukemia, non-Hodgkin lymphoma, prostate cancer, hematologic malignancies, maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, cell cycle arrest, apoptosis, global gene expression
- MeSH terms
- Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Pharmacogenetics, Prospective Studies, Prostatic Neoplasms, Quinuclidines, Risk Factors, Sensitivity and Specificity, Tumor Cells, Cultured, Genes, p53, Treatment Outcome, Hematologic Neoplasms, Maximum Tolerated Dose, Molecular Targeted Therapy, Patient Safety
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