Cisplatin/Epinephrine Shows Positive Phase III Results: Next Step, NDA

Based on the positive results of two independent, corroborative, placebo-controlled phase III clinical studies in head and neck cancer, Matrix Pharmaceuticals, Inc, has announced plans to submit a new drug application for a cisplatin/epinephrine injectable gel (IntraDose) by the end of this year. The results of these clinical studies were presented at the 36th annual meeting of the American Society of Clinical Oncology (ASCO).

Both phase III trials showed cisplatin/epinephrine therapy to be effective in reducing the size of tumors in late-stage recurrent or refractory head and neck cancer patients. Moreover, the tumor response proved beneficial to the patient in both studies.

“These results are impressive for this disease and the stage and type of patients who were treated,” said Michael D. Casey, chairman and CEO of Matrix. “All of the patients had refractory or recurrent disease, had been heavily pretreated with other therapies, and were very late in the course of their disease. Over 85% of these patients were previously treated with surgery and radiation therapy, and half of those had also been treated with systemic chemotherapy.”

The protocols for the two trials were identical except for geographic location, allowing assessment on both a combined and individual basis. Objective tumor response was evaluated for the primary target tumor identified by the clinical investigator prior to treatment. Patient benefit was determined using treatment goals (eg, pain control, mobility, ability to hear) that were selected beforehand by both the clinical investigator and the patient. A total of 178 patients were evaluated.

Combined Results

On an intent-to-treat basis, 29% of patients treated with cisplatin/epinephrine achieved an objective tumor response, vs 2% for the placebo, a statistically significant result (P < .001). Approximately twice as many patients (19%) achieved complete responses as partial responses (10%).

The preselected patient benefit goal was attained in 27% of the cisplatin/epinephrine-treated patients vs 12% of the placebo-treated patients (P = .046). The association of objective tumor response with attainment of the preselected patient goal was also statistically significant

(P = .006). In addition, 47% of patients with a tumor response achieved their predetermined benefit goal, compared to only 15% of nonresponders. These measurements are based exclusively on the preselected goal and do not reflect other benefits that patients may have received from treatment.

Side Effects

Side effects of cisplatin/epinephrine therapy were generally limited to injection-site reactions—the most common was pain. The systemic side effects normally associated with systemic cisplatin (Platinol) therapy were infrequent.

During early stages of the trials, four patients experienced cerebrovascular side effects. However, none occurred after the protocols were modified to exclude patients with tumors invading or in close proximity to the carotid artery.

Individual Study Results

In the first study in 86 patients, conducted in North America, the objective tumor response rate was 34% for cisplatin/epinephrine-treated patients vs 0% for placebo (P = .001). The preselected patient benefit was attained in 34% of the cisplatin/epinephrine-treated patients vs 17% of the placebo-treated patients.

In the second study, which was conducted in 92 patients outside North America, the objective tumor response rate was 25% for cisplatin/epinephrine-treated patients vs 3% for placebo-treated patients (P = .007). The preselected patient benefit was attained in 19% of the cisplatin/epinephrine-treated patients vs 9% of the placebo-treated patients.

“In recent years, the FDA has increasingly looked at patient benefit or quality-of-life measurements in addition to tumor response rates in evaluating products,” said Richard D. Leavitt, md, senior vice president of Matrix. The combined results of these studies showed statistically significant patient benefit attainment with IntraDose therapy vs placebo, and the individual studies each had “a much higher proportion of patients who achieved the treatment benefit goal in the IntraDose group than in the placebo group.”

Dr. Leavitt added, “Importantly, patients who exhibited a tumor response were three times as likely to achieve their preselected benefit goal as those who did not have a tumor response. These results will strongly support an NDA filing for an indication in recurrent or refractory head and neck cancer.”