title: A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study.
abstract: BACKGROUND
  3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.
  
  
  METHODS
  Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated.
  
  
  RESULTS
  Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route.
  
  
  CONCLUSIONS
  Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.
authors: City of Hope Medical Center, Building room 4117, 1500 East Duarte Road, 91010, Duarte, CA, USA.
authors: Joseph
authors: J
authors: Chao
authors: Timothy W
authors: TW
authors: Synold
authors: Robert J
authors: RJ
authors: Morgan
authors: Charles
authors: C
authors: Kunos
authors: Jeff
authors: J
authors: Longmate
authors: Heinz-Josef
authors: HJ
authors: Lenz
authors: Dean
authors: D
authors: Lim
authors: Stephen
authors: S
authors: Shibata
authors: Vincent
authors: V
authors: Chung
authors: Ronald G
authors: RG
authors: Stoller
authors: Chandra P
authors: CP
authors: Belani
authors: David R
authors: DR
authors: Gandara
authors: Mark
authors: M
authors: McNamara
authors: Barbara J
authors: BJ
authors: Gitlitz
authors: Derick H
authors: DH
authors: Lau
authors: Suresh S
authors: SS
authors: Ramalingam
authors: Angela
authors: A
authors: Davies
authors: Igor
authors: I
authors: Espinoza-Delgado
authors: Edward M
authors: EM
authors: Newman
authors: Yun
authors: Y
authors: Yen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002140:California; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone