title: A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors.
abstract: OBJECTIVE
  The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors.
  
  
  METHODS
  TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2.
  
  
  RESULTS
  Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients.
  
  
  CONCLUSIONS
  TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.
authors.affiliation: Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Sharad
authors.initials: S
authors.lastname: Ghamande
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Cho
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Michael H
authors.initials: MH
authors.lastname: Silverman
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Tseng
authors.forename: Min-Wen
authors.initials: MW
authors.lastname: Kuo
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Mach
authors.forename: Shu-Chi
authors.initials: SC
authors.lastname: Hsu
authors.forename: Teresa
authors.initials: T
authors.lastname: Coleman
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Ghalib
authors.forename: Imran
authors.initials: I
authors.lastname: Chuadhary
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; C549429:TLC 388; D002166:Camptothecin