Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer.

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 29 Pg. 3633-9 (Oct 10 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 22965953 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Quinuclidines
• eprenetapopt

Topics

• Aged
• Aged, 80 and over
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Genes, p53 (drug effects)
• Hematologic Neoplasms (drug therapy, genetics, pathology)
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Molecular Targeted Therapy (methods)
• Patient Safety
• Pharmacogenetics
• Prospective Studies
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Quinuclidines (adverse effects, pharmacology, therapeutic use)
• Risk Factors
• Sensitivity and Specificity
• Treatment Outcome
• Tumor Cells, Cultured (drug effects)