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Targeting p53 in vivo: a first-in-man study with the p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
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2012 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 29, p. 3633-3639Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society of Clinical Oncology , 2012. Vol. 30, no 29, p. 3633-3639
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:oru:diva-27145DOI: 10.1200/JCO.2011.40.7783ISI: 000309653600014PubMedID: 22965953Scopus ID: 2-s2.0-84867615093OAI: oai:DiVA.org:oru-27145DiVA, id: diva2:601703
Note

Funding Agency:

Aprea, Stockholm, Sweden

Available from: 2013-01-30 Created: 2013-01-30 Last updated: 2017-12-06Bibliographically approved

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Andrén, OveTidefelt, UlfUggla, Bertil

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Andrén, OveTidefelt, UlfUggla, Bertil
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School of Health and Medical Sciences, Örebro University, SwedenSchool of Medicine, Örebro University, Sweden
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Journal of Clinical Oncology
Cancer and Oncology

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