title: Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Hematology, M54, Karolinska University Hospital, 141 86 Stockholm, Sweden. Soren.Lehmann@ki.se
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
authors.forename: Vladimir J N
authors.initials: VJ
authors.lastname: Bykov
authors.forename: Dina
authors.initials: D
authors.lastname: Ali
authors.forename: Ove
authors.initials: O
authors.lastname: Andrén
authors.forename: Honar
authors.initials: H
authors.lastname: Cherif
authors.forename: Ulf
authors.initials: U
authors.lastname: Tidefelt
authors.forename: Bertil
authors.initials: B
authors.lastname: Uggla
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Yachnin
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Ali
authors.initials: A
authors.lastname: Moshfegh
authors.forename: Christer
authors.initials: C
authors.lastname: Paul
authors.forename: Klas G
authors.initials: KG
authors.lastname: Wiman
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Andersson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016158:Genes, p53 / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D061214:Patient Safety; D010597:Pharmacogenetics; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011812:Quinuclidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D011812:Quinuclidines; C533410:eprenetapopt