title: A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer.
abstract: OBJECTIVE
  Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA).
  
  
  METHODS
  We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response.
  
  
  RESULTS
  Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy.
  
  
  CONCLUSIONS
  The combination of triapine at 72 mg/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.
authors: Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Ludmila Katherine
authors: LK
authors: Martin
authors: John
authors: J
authors: Grecula
authors: Guang
authors: G
authors: Jia
authors: Lai
authors: L
authors: Wei
authors: Xiangyu
authors: X
authors: Yang
authors: Gregory A
authors: GA
authors: Otterson
authors: Xin
authors: X
authors: Wu
authors: Erica
authors: E
authors: Harper
authors: Cheryl
authors: C
authors: Kefauver
authors: Bing-Sen
authors: BS
authors: Zhou
authors: Yun
authors: Y
authors: Yen
authors: Mark
authors: M
authors: Bloomston
authors: Michael
authors: M
authors: Knopp
authors: S Percy
authors: SP
authors: Ivy
authors: Michael
authors: M
authors: Grever
authors: Tanios
authors: T
authors: Bekaii-Saab
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy / Q000379:methods; D003287:Contrast Media; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011879:Radiotherapy Dosage; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors / Q000097:blood; D013882:Thiosemicarbazones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D025521:Tumor Suppressor Proteins / Q000097:blood
chemical_list: D003287:Contrast Media; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; D013882:Thiosemicarbazones; D025521:Tumor Suppressor Proteins; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C093713:ribonucleotide reductase M2; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase