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

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/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: Sharad Ghamande, Chia-Chi Lin, Daniel C Cho, Geoffrey I Shapiro, Eunice L Kwak, Michael H Silverman, Yunlong Tseng, Min-Wen Kuo, Wendy B Mach, Shu-Chi Hsu, Teresa Coleman, James Chih-Hsin Yang, Ann-Lii Cheng, Mohammad H Ghalib, Imran Chuadhary, Sanjay Goel
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 3 Pg. 445-51 (Jun 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24271274 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antineoplastic Agents
• TLC 388
• Camptothecin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Female
• Humans
• Leukopenia (chemically induced)
• Male
• Middle Aged
• Neoplasms (blood, drug therapy, urine)
• Thrombocytopenia (chemically induced)