title: A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors.
abstract: OBJECTIVE
  Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G.
  
  
  METHODS
  Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured.
  
  
  RESULTS
  Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome.
  
  
  CONCLUSIONS
  This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.
authors: Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH, 43210, USA.
authors: Amir
authors: A
authors: Mortazavi
authors: Yonghua
authors: Y
authors: Ling
authors: Ludmila Katherine
authors: LK
authors: Martin
authors: Lai
authors: L
authors: Wei
authors: Mitch A
authors: MA
authors: Phelps
authors: Zhongfa
authors: Z
authors: Liu
authors: Erica J
authors: EJ
authors: Harper
authors: S Percy
authors: SP
authors: Ivy
authors: Xin
authors: X
authors: Wu
authors: Bing-Sen
authors: BS
authors: Zhou
authors: Xiyong
authors: X
authors: Liu
authors: Deidre
authors: D
authors: Deam
authors: J Paul
authors: JP
authors: Monk
authors: William J
authors: WJ
authors: Hicks
authors: Yun
authors: Y
authors: Yen
authors: Gregory A
authors: GA
authors: Otterson
authors: Michael R
authors: MR
authors: Grever
authors: Tanios
authors: T
authors: Bekaii-Saab
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012262:Ribonucleoside Diphosphate Reductase / Q000097:blood; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D013882:Thiosemicarbazones; D003841:Deoxycytidine; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine