title: Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies.
abstract: OBJECTIVE
  Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells--G1, S, and G2/M.
  
  
  METHODS
  Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.
  
  
  RESULTS
  Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m(2) IV D1, 8; and bortezomib 0.6 mg/m2 IV D1, 4, 8, 11 [DOSAGE ERROR CORRECTED] of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9).
  
  
  CONCLUSIONS
  Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation.
authors.affiliation: a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Rajul K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.affiliation: a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Helgason
authors.affiliation: a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Nai-Yi
authors.initials: NY
authors.lastname: Shi
authors.affiliation: b SimVivo ; Houston , TX USA.
authors.forename: Yash
authors.initials: Y
authors.lastname: Gad
authors.affiliation: c Moores Cancer Center; University of California San Diego ; La Jolla , CA USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib / Q000008:administration & dosage; D003198:Computer Simulation; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013781:Texas; D013997:Time Factors; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C401859:temsirolimus; D000069286:Bortezomib; D019772:Topotecan; D020123:Sirolimus
keywords: bortezomib; cell cycle; oncology; pharmacodynamics; phase I; temsirolimus; topotecan