Phase i study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias

R. Tibes, K. T. McDonagh, L. Lekakis, J. M. Bogenberger, S. Kim, N. Frazer, S. Mohrland, D. Bassett, R. Garcia, K. Schroeder, V. Shanmugam, J. Carpten, R. T. Hagelstrom, C. Beaudry, D. Von Hoff, T. C. Shea

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Purpose: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. Patients and methods: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. Results: Patients had AML (n=11), chronic myelogeneous leukemia in blast phase (CML-BP, n=2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. Conclusion: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.

Original languageEnglish (US)
Pages (from-to)389-396
Number of pages8
JournalInvestigational New Drugs
Volume33
Issue number2
DOIs
StatePublished - Apr 1 2015

Keywords

  • AKT
  • Acute leukemia
  • Inhibitor
  • Survivin
  • Terameprocol
  • cdc2/CDK1

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Tibes, R., McDonagh, K. T., Lekakis, L., Bogenberger, J. M., Kim, S., Frazer, N., Mohrland, S., Bassett, D., Garcia, R., Schroeder, K., Shanmugam, V., Carpten, J., Hagelstrom, R. T., Beaudry, C., Von Hoff, D., & Shea, T. C. (2015). Phase i study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias. Investigational New Drugs, 33(2), 389-396. https://doi.org/10.1007/s10637-014-0198-y