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.

In these single-agent studies, he emphasized, no grade 3-4 hematologic toxicity occurred, and nonhematologic toxicity was mostly grade 1-2 fatigue, nausea, and vomiting, with the latter well controlled by standard antiemetics.

Combination Therapy

First-line phase II combination therapy trials of TLK286 with platinums are ongoing. A multicenter phase I-IIa trial of first-line triplet therapy every 3 weeks for four to six cycles with TLK286, paclitaxel, and carboplatin in advanced NSCLC has produced encouraging interim results, Dr. Burris said. At the 11th World Conference on Lung Cancer in Barcelona, principal investigator Thomas J. Lynch, MD, of Dana-Farber Cancer Institute, reported an objective response rate (ORR) of 58% in 26 patients who received at least four cycles of therapy (1 complete response and 14 partial responses) and an overall disease stabilization rate of 92% (15 responses plus 9 patients with stable disease).

Commenting on Dr. Lynch's results with TLK286, Dr. Burris said "survival is the ultimate endpoint in NSCLC, but this agent is active as first-line therapy in stage IIIB and IV, and [these findings] certainly represent a step up, compared with response rates reported in other phase II studies of this [taxane-platinum] combination."

Toxicity was comparable to that typical of a platinum-based regimen, Dr. Burris added. The most common possibly treatment-related hematologic toxicities were anemia, neutropenia, and thrombocytopenia; these events were managed by dose reduction and/or growth factor support.

There were no additive nonhematologic toxicities; the most common events observed were fatigue, alopecia, and nausea, with the latter being well controlled by standard antiemetic therapy, he said. The trial is being expanded to include 100 patients, as a prelude to a phase III study, he said, and patient follow-up for efficacy and safety is ongoing.

Dr. Burris also reviewed findings he reported at the 2005 American Society of Clinical Oncology (ASCO) meeting, of a multi-center phase II doublet trial. Results showed a clinical benefit with TLK286 added to every-3-week cisplatin (abstract 7126). At interim analysis, 8 of 25 evalu-able patients (32%) had an objective response and 14 (56%) had stable disease, for an overall disease stabilization rate of 88%. Responses were durable and associated with symptom and performance status improvement.

"These responses are very different from the rate seen with single-agent cisplatin trials, which historically has been around 10%," he said. "Our overall take from the data was that TLK286 is a very important addition to cisplatin as a single agent." Treatment-related hematologic toxicities were mild-to-moderate anemia and neutropenia. Patients experienced no alopecia, mucositis, or diarrhea, though some required dose reductions because of thrombocytopenia.

Phase III ASSIST-2

The primary goal of the phase III registration trial, known as ASSIST-2 (Assessment of Survival in Solid Tumors-2), is to assess whether TLK286 increases survival compared with gefitinib (Iressa) as third-line therapy in NSCLC patients who failed to respond to first-line therapy with carboplatin or cisplatin, and to a second-line regimen. Secondary endpoints include time to tumor progression, ORR, and tolerability. ASSIST-2 completed enrollment with 520 patients in May 2005, Dr. Burris said, and results are expected in 2006. In addition, enrollment has been completed on ASSIST-1, a phase III trial of TLK286 as a single agent in third-line ovarian cancer, and enrollment is nearing completion on ASSIST-3, a phase III trial of TLK286 in combination with carboplatin in the second-line setting in platinum-resistant ovarian cancer.