[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
201 TLK286: Phase I dose-escalation trial in patients with advanced malignancies. LS Rosen1, L Kadib1, B Laxa1, J Brown1, G Kilfoil2, R Gomez2, M Wick2, C Vollmer2, and G Brown2. 1UCLA Jonsson Cancer Center, Los Angeles, CA; 2Telik, Inc. South San Francisco, CA.
We report the results of the first clinical trial with the agent TLK286, a novel glutathione derivative of an alkylating agent that is preferentially activated by the enzyme glutathione S-transferase (GST P1-1). GSTs play a central role in drug detoxification and have been implicated in mediating cellular resistance to several classes of anticancer therapy. GST P1-1 mediates cellular resistance to several classes of cancer drugs, with levels of GST P1-1 elevated in tumor tissue and negatively correlated with prognosis. TLK286 exhibits antitumor activity in vitro and against a variety of xenograft models in vivo, particularly those that express high levels of GST P1-1 and are resistant to other agents. When metabolized by GST P1-1, the cytotoxic moiety of TLK286 is released. This phase I study, the first use of TLK286 in humans, was designed to examine the toxicity and pharmacokinetics of TLK286, given intravenously every three weeks in patients with advanced malignancies. To date, we have enrolled 14 patients [8M/6F, median age 54 years (range 36-75), median ECOG performance status 1 (range 0-2)] with a variety of malignancies (4 colorectal, 3 breast, 2 non-small cell lung, 5 miscellaneous). Patients have been treated thus far on 4 dose levels ranging from 60-300 mg/m2, with a range of from 2-5 cycles of drug. To date, a total of 33 cycles have been administered. Possible drug associated toxicities include minimal fatigue and nausea, but no moderate or dose-limiting toxicities have been seen. Importantly, no myelosuppression has been seen with this cytotoxic agent. One minor antitumor response (adenocarcinoma of unknown primary) and prolonged disease stabilization (1 colorectal, 1 sarcoma) were seen at 120 mg/m2. Pharmacokinetic analysis is ongoing and will be reported at the meeting. While enrollment continues rapidly, we are encouraged by the early indications of antitumor activity with TLK286, a drug taking advantage of TRAP-guided rational drug design methodology. |
