Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer

Department of Hematology, M54, Karolinska University Hospital, 141 86 Stockholm, Sweden
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2012; 30(29):3633-9. DOI: 10.1200/JCO.2011.40.7783
Source: PubMed

ABSTRACT 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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Available from: Klas G Wiman, Aug 20, 2015
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    • "These have included antibodies (Hupp et al., 1995), peptides (Selivanova et al., 1999) and small molecules identified via structure-guided design (Boeckler et al., 2008) and screening approaches (Bykov et al., 2002). The most advanced of these is the small molecule PRIMA-1MET (APR-246) that has successfully completed Phase I/II clinical trials, where it was observed that it could induce p53-dependent biological effects in tumour cells in vivo (Lehmann et al., 2012). "
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