CLL patients with del17p: in an extended phase I trial with a p53 inhibitor, APR-246 shows encouraging results

TP53 mutations are common in hematological malignancies and confer a dismal prognosis. APR-246 is the first compound targeting mutant p53 to enter into a clinical trial.

In this first in-man study, APR-246 was given daily as a 2h intravenous infusion for 4 consecutive days with a maximum tolerated dose of 60mg/kg daily. This trial was an extension of the first in-man study to determine the dose limiting toxicity (DLT), safety, pharmacokinetic profile, and anti-tumor effects of APR-246. The data was published by S. Deneberg, et al., in Blood Cancer Journal in July 2016. The trial was conducted in accordance to the Declaration of Helsinki and ICH-GCP guidelines and was registered at (NCT00900614).

The key findings were:

  • Two patients with Chronic Lymphocytic Leukemia (CLL) with a deletion of 17p, not eligible for other therapies, were included in this trial
  • One CLL patient (01-101), receiving a total infusion of 135mg/kg, showed a >25% reduction in lymphocyte count and a >25% reduction in lymph node size between day 1 and day 4. This patient received two additional treatment cycles at the 105 mg/kg dose, but no further responses were seen and the patient progressed during cycle 2

The take home messages are as follows:

  • APR-246 when administered to CLL patients with TP53 mutations, at a dose of 67.5mg/kg given as a 6h infusion on 4 consecutive days, was considered safe, well tolerated and showed some signs of clinical activity. However, sample size needs to be increased
  • The preliminary data shown by this trial lays the groundwork for exploring the potential of APR-246 in other hematological indications, preferentially in combination with standard chemotherapy

The full article can be found here.

  1. Deneberg S, et al. An open-label phase I dose-finding study of APR-246 in hematological malignancies. Blood Cancer J. 2016 Jul 15;6(7):e447. doi: 10.1038/bcj.2016.60.
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