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TLK286 Effective, Well Tolerated in NSCLC, Early Clinical Trials Show

TLK286 Effective, Well Tolerated in NSCLC, Early Clinical Trials Show

NEW YORK-In both chemonaive and heavily pretreated patients with non-small-cell lung cancer (NSCLC), investigations of canfosfamide (TLK286, Telcyta) are yielding "exciting" findings, Howard A. Burris III, MD, reported at the Chemotherapy Foundation Symposium XXIII (abstract 7). Dr. Burris, director of drug development at the Sarah Cannon Cancer Center, Nashville, commented that in studies of the drug, "response rates are going up and patients are living longer . . . in the setting of better-tolerated therapy."

Telcyta is a novel glutathione analog prodrug rationally designed to exploit cytosolic enzyme glutathione S-transferase P1-1 (GST P1-1) overexpression, which is common in NSCLC and many other cancers (see image on page 1).

When the agent is metabolized by GST P1-1, it releases two fragments: a glutathione analog fragment and a cytotoxic fragment. The cytotoxic fragment reacts with important cell components, including RNA, DNA, and proteins, leading to apoptosis. The glutathione analog fragment may remain bound to GST P1-1, which may limit the enzyme's ability to inactivate other cancer drugs.

Phase II Trials

TLK286 has been well tolerated and has shown single-agent activity in several phase II trials in NSCLC, as well as in ovarian, breast, and colorectal cancer, Dr. Burris said, and it has demonstrated synergy with standard chemotherapy, without significantly increased toxicity.

Two recent phase II trials have investigated the agent given alone at a dose of 1,000 mg/m2 weekly or every 3 weeks, in patients with advanced NSCLC who did not respond to platinum therapy. These studies by Dr. Burris's group showed good responses, he reported. The every-3-week trial, he said, yielded a median survival time of 37 weeks among the 51 enrolled patients, who had metastatic stage IV disease and were receiving TLK286 as second- to fifth-line therapy. Although no responses were seen by RECIST, 51% of patients had disease stabilization, without grade 4 toxicity.

The trial of weekly TLK286 in 33 patients with metastatic stage IV disease who had received up to three prior treatment regimens showed an 11% response rate by RECIST, and 69% of patients had disease stabilization at interim analysis, with no grade 4 toxicity. Survival data are not yet mature, he said.


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