Hypoxia-Targeting Agent in Phase III Lung Cancer

NEW YORK—Two large phase III trials using tirapazamine (investigational, also known as tirazone) in triplet regimens for non-small-cell lung cancer (NSCLC) are rapidly accruing patients, according to a report presented at the Chemotherapy Foundation Symposium XIX (abstract 60).

A novel drug that targets hypoxic tumor cells, tirapazamine is being tried in conjunction with cisplatin (Platinol) and vinorelbine (Navelbine) in an international trial, reported Joseph A. Treat, MD, vice chairman, Fox Chase Temple University Cancer Center. In a US trial, it is being combined with paclitaxel (Taxol) and carboplatin (Paraplatin).

The International Tirazone Triple Trial (i3T), Dr. Treat said, may finish slightly ahead of schedule early in 2002, having accrued 575 of the projected 800 patients by the end of October at 100 sites in 13 countries. Under the protocol, all patients receive cisplatin every 4 weeks at 100 mg/m² and vinorelbine 25 mg/m² weekly. In one arm, patients also receive 330 mg/m² of tirapazamine every 4 weeks.

The Southwest Oncology Group has accrued 175 of the projected 500 patients for its trial comparing a standard pacli-taxel-carboplatin regimen with one that adds tirapazamine, Dr. Treat said. In this trial, the tirapazamine dose starts at 260 mg/m² but may be escalated to 330 mg/m² for patients who tolerate the lower amount. The carboplatin dose is AUC 6, and the paclitaxel dose is 225 mg/m².

Preclinical trials in mice, Dr. Treat said, showed that tirapazamine given as a single agent produced relatively little cell kill or antitumor activity. These studies also showed that the synergistic effect of tirapazamine with platinum agents is induced only if the drug is given either 2 hours before or after the platinum.

"This is a schedule-dependent drug, at least in the preclinical models," Dr. Treat said, "and we have taken this time reference into account in the clinic."

Tumor-cell hypoxia confers resistance to chemotherapy and radiation, he noted. "Tirapazamine is novel," he said, "in that it very selectively goes after these hypoxic cells, and prior exposure of cells to the agent sensitizes the kill by cisplatin." Preclinical studies, he added, showed a synergistic effect of tirapazamine with cisplatin, paclitaxel, gemcitabine (Gemzar), and radiation therapy.

An earlier phase III trial (CATAPULT I) provided proof of principle that adding tirapazamine to a then-standard single-agent cisplatin regimen for NSCLC was effective, Dr. Treat reported. The combination increased median and 1-year survival rates.

However, in CATAPULT II, when cisplatin/tirapazamine was tested against cisplatin/etoposide (VePesid), there was a trend toward better 1-year survival with the cisplatin/etoposide arm. These results led to the design of the ongoing phase III trials in which tirapazamine is added to a standard doublet rather than replacing an effective agent in a doublet.

Toxicities related to tirapazamine identified in earlier clinical trials included transient minor skin rashes, visual abnormalities, and acute hearing loss, Dr. Treat said. Hearing problems, initially of concern, turned out to be insignificant, with the rate of grade 3-4 episodes being 1%. Fatigue and hematologic toxicities, he noted, were not different from those seen with cisplatin alone.

Leg cramps and muscle contractions occur in about 30% of patients, he reported, but are generally mild and of short duration. The gastrointestinal toxicity of cisplatin was enhanced with the addition of tirapazamine, he said, with a larger percentage of grade 3-4 complaints than with cisplatin alone.

Lowering the Dose

In these early trials, the tirapazamine dose was 390 mg/m² every 3 weeks. In the two large ongoing phase III studies of triplet regimens, dosages are lower. In the international trial with cisplatin and vinorelbine, the dose is 330 mg/m² every 4 weeks. "I’ve had access to early safety data from this trial," Dr. Treat said. No difference in grade 3 or 4 toxicities is apparent in the study’s two arms, he indicated. "Certainly with more cycles being given that could change," he said, "but at this moment, the two arms appear to have the same safety profile."