Preclinical Evaluation and Phase Ib Study of Prexasertib, a CHK1 Inhibitor, and Samotolisib (LY3023414), a Dual PI3K/mTOR Inhibitor

Clin Cancer Res. 2021 Apr 1;27(7):1864-1874. doi: 10.1158/1078-0432.CCR-20-3242. Epub 2021 Jan 25.

Abstract

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib + samotolisib, a PI3K/mTOR inhibitor.

Patients and methods: Prexasertib + samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient-derived xenograft (PDX) mouse models. In the phase Ib trial, following dose escalation, the initial expansion arm (E1, solid tumors) explored prexasertib 105 mg/m2 intravenously every 14 days + samotolisib 200 mg orally twice daily. Subsequent expansion arms evaluated samotolisib 150 mg twice daily in patients carrying PIK3CA mutations (E2, solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed.

Results: Prexasertib + samotolisib inhibited cell proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib + samotolisib exhibited synergistic or additive effects in 30 of 38 PDX single-mouse ("n = 1") models, and provided rationale for clinical evaluation. In the phase Ib study, 53 patients were enrolled (escalation, n = 13; E1, n = 9; E2, n = 15; and E3, n = 16). No dose-limiting toxicities (DLT) were observed during escalation; however, DLT-equivalent toxicities were observed in E1, leading to samotolisib dose reduction (150 mg twice daily) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 (PIK3CA) and 25% for E3 (TNBC).

Conclusions: Prexasertib + samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.

Trial registration: ClinicalTrials.gov NCT02124148.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / antagonists & inhibitors
  • Female
  • Humans
  • MTOR Inhibitors / administration & dosage
  • Male
  • Mice
  • Middle Aged
  • Phosphoinositide-3 Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / administration & dosage*
  • Pyrazines / administration & dosage*
  • Pyrazines / adverse effects
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Quinolones / administration & dosage*
  • Quinolones / adverse effects
  • Triple Negative Breast Neoplasms / drug therapy*

Substances

  • LY3023414
  • MTOR Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrazoles
  • Pyridines
  • Quinolones
  • prexasertib
  • Checkpoint Kinase 1

Associated data

  • ClinicalTrials.gov/NCT02124148