An open-label phase I dose-finding study of APR-246 in hematological malignancies
Open accessAbstract
Mutations in the TP53 tumor suppressor gene occur at different frequencies in a variety of human malignancies. 1 TP53 encodes a DNA-binding transcription factor that induces cell growth arrest, senescence and cell death by apoptosis upon cellular stress, including oncogenic stress and DNA damage. In hematological malignancies TP53 mutations are common in relapsed/refractory disease and confers a dismal prognosis. 2 PRIMA-1 and the analog APR-246 (PRIMA-1 MET ) can restore wild-type conformation of mutant p53 and induce apoptosis in tumor cells of various origin. 3 , 4 , 5 APR-246 is the first compound targeting mutant p53 to enter into a clinical trial. In the first in-man study APR-246 was given daily as a 2 h intravenous infusion for 4 consecutive days. The maximum tolerable dose using this schedule was defined as 60 mg/kg daily and the most common adverse effects were neurological. 3 This is an extension of the first in-man study aiming at optimizing the dose regimen to obtain better antitumor response with less toxicity.
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In 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 [26]
The unpaginated study text reports that eight participants had AML and that one AML patient met the response criterion after APR-246 treatment. It does not report corresponding activation of p53-dependent pathways in these patients; its discussion of p53 activity is background. A second AML patient's remission cannot be attributed to APR-246 monotherapy because the paper says the patient was also receiving hydroxyurea and sorafenib. (LLM, conf=0.87)
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Cites
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- Authors
- Deneberg, S., Cherif, H., Lazarevic, V, Andersson, P.-O., von Euler, M., Juliusson, G., & Lehmann, S.
- Affiliations
- Karolinska University Hospital (SE)
- Uppsala University (SE)
- Södra Älvsborg Hospital (SE)
- Skåne University Hospital (SE)
- Corresponding author
- Deneberg, S
- Venue
- Blood Cancer Journal
- Published
- 2016-07-15
- Volume
- 6
- Issue
- 7
- Pages
- e447-e447
- ISSN
- 2044-5385 (ISSN-L)
- PMC
- PMC5141349
- OpenAlex
- W2466299625
- Cited by
- 84
- References
- 5
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 6 · 2022: 12 · 2021: 12 · 2020: 17 · 2019: 13 · 2018: 9 · 2017: 6 · 2016: 1
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Blood Cancer Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Stockholms Läns Landsting
- 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 › Cell death mechanisms and regulation
- Keywords
- APR-246, TP53 mutation, hematologic malignancies, relapsed/refractory disease, dose-finding, maximum tolerated dose, dose optimization, neurological adverse effects, apoptosis induction
- MeSH terms
- Adult, Aged, Antineoplastic Agents, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Quinuclidines, Treatment Outcome, Hematologic Neoplasms, Maximum Tolerated Dose
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