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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.

In English

Författare

  • Sören Lehmann
  • Vladimir J N Bykov
  • Dina Ali
  • Ove Andrén
  • Honar Cherif
  • Ulf Tidefelt
  • Bertil Uggla
  • Jeffrey Yachnin
  • Gunnar Juliusson
  • Ali Moshfegh
  • Christer Paul
  • Klas G Wiman
  • Per-Ola Andersson
Visa allt

Summary, in English

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.

Publiceringsår

2012

Språk

Engelska

Sidor

3633-3639

Publikation/Tidskrift/Serie

Journal of Clinical Oncology

Volym

30

Issue

29

Dokumenttyp

Artikel i tidskrift

Förlag

American Society of Clinical Oncology

Ämne

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1527-7755