title: Phase I pharmacokinetic and pharmacodynamic study of SJG-136, a novel DNA sequence selective minor groove cross-linking agent, in advanced solid tumors.
abstract: OBJECTIVE
  This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer.
  
  
  METHODS
  In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 μg/m(2)) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 μg/m(2)). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care.
  
  
  RESULTS
  Schedule A-dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3-4). PK analysis revealed dose-dependent increases in AUC and C(max). Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B-the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2.
  
  
  CONCLUSIONS
  The MTD of SJG-136 in this study was 30 μg/m(2) administered on a daily 3× basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232-6307, USA. igor.puzanov@vanderbilt.edu
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.forename: M Wade
authors.initials: MW
authors.lastname: Calcutt
authors.forename: David L
authors.initials: DL
authors.lastname: Hachey
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Vermeulen
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Spanswick
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Liao
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001570:Benzodiazepinones / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage; D004417:Dyspnea / Q000139:chemically induced; D004487:Edema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); D001570:Benzodiazepinones; D011758:Pyrroles; D003907:Dexamethasone