title: Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.
authors.affiliation: Division of Hematology & Medical Oncology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ, 85259, USA, tibes.raoul@mayo.edu.
authors.forename: R
authors.initials: R
authors.lastname: Tibes
authors.forename: K T
authors.initials: KT
authors.lastname: McDonagh
authors.forename: L
authors.initials: L
authors.lastname: Lekakis
authors.forename: J M
authors.initials: JM
authors.lastname: Bogenberger
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Frazer
authors.forename: S
authors.initials: S
authors.lastname: Mohrland
authors.forename: D
authors.initials: D
authors.lastname: Bassett
authors.forename: R
authors.initials: R
authors.lastname: Garcia
authors.forename: K
authors.initials: K
authors.lastname: Schroeder
authors.forename: V
authors.initials: V
authors.lastname: Shanmugam
authors.forename: J
authors.initials: J
authors.lastname: Carpten
authors.forename: R T
authors.initials: RT
authors.lastname: Hagelstrom
authors.forename: C
authors.initials: C
authors.lastname: Beaudry
authors.forename: D
authors.initials: D
authors.lastname: Von Hoff
authors.forename: T C
authors.initials: TC
authors.lastname: Shea
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008111:Liver Function Tests; D008297:Male; D009637:Masoprocol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000737:chemistry; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C076852:terameprocol; D009637:Masoprocol; D016203:CDC2 Protein Kinase