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

Lehmann, Sören; Bykov, Vladimir J N; Ali, Dina; Andrén, Ove; Cherif, Honar; Tidefelt, Ulf; Uggla, Bertil; Yachnin, Jeffrey; Juliusson, Gunnar LU and Moshfegh, Ali, et al. (2012) In Journal of Clinical Oncology 30(29). p.3633-3639
Abstract
PURPOSEAPR-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 METHODSAPR-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.ResultsMTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue,... (More)
PURPOSEAPR-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 METHODSAPR-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.ResultsMTD 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. CONCLUSIONWe 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. (Less)
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Journal of Clinical Oncology
volume
30
issue
29
pages
3633 - 3639
publisher
American Society of Clinical Oncology
external identifiers
  • wos:000309653600014
  • pmid:22965953
  • scopus:84867615093
ISSN
1527-7755
DOI
10.1200/JCO.2011.40.7783
language
English
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yes
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5599cae1-74c4-424e-a75b-b3777a7cf12c (old id 3124059)
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http://www.ncbi.nlm.nih.gov/pubmed/22965953?dopt=Abstract
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2012-10-03 21:15:44
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2017-11-19 04:18:01
@article{5599cae1-74c4-424e-a75b-b3777a7cf12c,
  abstract     = {PURPOSEAPR-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 METHODSAPR-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.ResultsMTD 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. CONCLUSIONWe 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.},
  author       = {Lehmann, Sören and Bykov, Vladimir J N and Ali, Dina and Andrén, Ove and Cherif, Honar and Tidefelt, Ulf and Uggla, Bertil and Yachnin, Jeffrey and Juliusson, Gunnar and Moshfegh, Ali and Paul, Christer and Wiman, Klas G and Andersson, Per-Ola},
  issn         = {1527-7755},
  language     = {eng},
  number       = {29},
  pages        = {3633--3639},
  publisher    = {American Society of Clinical Oncology},
  series       = {Journal of Clinical Oncology},
  title        = {Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer.},
  url          = {http://dx.doi.org/10.1200/JCO.2011.40.7783},
  volume       = {30},
  year         = {2012},
}