Novel Glutathione Leads to Longer Ovarian Cancer Survival

NEW YORK—Previously treated patients with ovarian cancer who received a novel glutathione (TLK286, Telik, Inc., San Francisco) have thus far survived a median of more than 56 weeks, according to preliminary results from an ongoing multicenter phase II trial. John J. Kavanagh, MD, presented the results at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.

Final median survival has not yet been reached in the trial, which includes patients who are receiving TLK286 as second-, third- or fourth-line therapy. Historically, ovarian cancer patients receiving second-line liposomal doxorubicin (Doxil) or topotecan (Hycamtin) in clinical trials had median survival rates of 36 and 41 weeks, respectively, said Dr. Kavanagh, professor of medicine, Department of Gynecologic Medical Oncology, M.D. Anderson Cancer Center.

"Median survival with TLK286 is strikingly longer" and increasing, Dr. Kavanagh said. "Response rate is similar, with complete responses seen in this study, and a toxicity profile and dosage reduction very favorable, compared to those therapies."

Responses in the 36-patient trial include one complete remission of more than 14 months’ duration, Dr. Kavanagh said. In addition, there have been four partial responses associated with improvement of symptoms.

The novel cytotoxic agent is given intravenously in an inactive form. In cancer cells, it is activated by an enzyme (glutathione S-transferase P1-1) expressed in ovarian cancer and other solid tumors.

Phase I data are "extensive" for TLK-286, with a large number of patients receiving multiple courses, Dr. Kava-nagh said. There is a safety database representing approximately 1,500 courses in at least 320 previously treated patients who received the new agent on an every-3-week or weekly schedule. Side effects have been mild and reversible.

Investigators have noticed durable responses in multiple bulky tumors, he said. The overall response rate was about 15% (1 complete response and 4 partial responses), and the disease control rate was 50% (the 5 responders plus 12 with stable disease). Likelihood of response did not seem to vary according to number of prior regimens or by whether their disease was platinum resistant or platinum refractory. "Responses were seen in all subgroups and at all centers," Dr. Kavanagh said.

The complete responder was a 42-year-old woman who developed bulky, progressive disease on platinum/taxane therapy; she had a complete response on the glutathione agent and has remained disease free for 14 months, including 7 months off treatment, Dr. Kavanagh said.

Dosage reduction was not frequent (six cases) and was usually due to mild thrombocytopenia or neutropenia. Overall, there were no grade 4 events, only 6% of events were grade 3, and there were no cumulative toxicities. Of 14 hematologic events, only one was grade 3-4 (a grade 3 anemia). Nonhematologic adverse events were mostly grade 1-2 and included nausea, vomiting, fatigue, and dysuria.

Further studies of TLK286 in advanced ovarian cancer are underway, Dr. Kava-nagh said. In addition, investigators are planning a phase III registration trial of this novel agent vs standard therapy.