An open-label phase I dose-finding study of APR-246 in hematological malignancies

Mutations in the TP53 tumor suppressor gene occur at different frequencies in a variety of human malignancies. 1 TP53 encodes a DNA-binding transcription factor that induces cell growth arrest, senescence and cell death by apoptosis upon cellular stress, including oncogenic stress and DNA damage. In hematological malignancies TP53 mutations are common in relapsed/refractory disease and confers a dismal prognosis. 2 PRIMA-1 and the analog APR-246 (PRIMA-1 MET ) can restore wild-type conformation of mutant p53 and induce apoptosis in tumor cells of various origin. 3 , 4 , 5 APR-246 is the first compound targeting mutant p53 to enter into a clinical trial. In the first in-man study APR-246 was given daily as a 2 h intravenous infusion for 4 consecutive days. The maximum tolerable dose using this schedule was defined as 60 mg/kg daily and the most common adverse effects were neurological. 3 This is an extension of the first in-man study aiming at optimizing the dose regimen to obtain better antitumor response with less toxicity.