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
Journal
Investigational New Drugs
Journal Volume
32
Journal Issue
3
Pages
445-451
Date Issued
2014
Author(s)
Ghamande S.
Cho D.C.
Shapiro G.I.
Kwak E.L.
Silverman M.H.
Tseng Y.
Kuo M.-W.
Mach W.B.
Hsu S.-C.
Coleman T.
Ghalib M.H.
Chuadhary I.
Goel S.
Abstract
Purpose: 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. Experimental design: 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/m2 over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m2 developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m2, 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/m2 for S,R and 996 (1333) L/m2 for S,S, and 2174 (2526) L/h-m2 for S,R and 2670 (2988) L/h-m2 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/m2 on the current treatment schedule is generally safe and well tolerated. ? 2013 Springer Science+Business Media.
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; camptothecin; tlc 388; unclassified drug; antineoplastic agent; camptothecin; TLC 388; adult; advanced cancer; aged; alanine aminotransferase blood level; anemia; antineoplastic activity; area under the curve; article; aspartate aminotransferase blood level; bile duct carcinoma; cardiopulmonary insufficiency; cerebrovascular accident; cohort analysis; colon tumor; constipation; diarrhea; dose limiting toxicity; drug clearance; drug distribution; drug dose escalation; drug dose reduction; drug half life; drug safety; drug structure; drug tolerability; drug withdrawal; esophagus tumor; fatigue; febrile neutropenia; female; human; hyperbilirubinemia; hyponatremia; kidney carcinoma; leukopenia; major clinical study; male; maximum plasma concentration; maximum tolerated dose; multiple cycle treatment; nausea; neutropenia; open study; pancreas tumor; phase 1 clinical trial; pleura effusion; priority journal; prostate tumor; solid tumor; thrombocytopenia; time to maximum plasma concentration; toxicological parameters; transitional cell carcinoma; urinary tract infection; uterine cervix tumor; vomiting; analogs and derivatives; blood; chemically induced; clinical trial; leukopenia; middle aged; multicenter study; Neoplasms; thrombocytopenia; urine; very elderly; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Camptothecin; Female; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Thrombocytopenia
Publisher
Springer New York LLC
Type
journal article