Phase III Melanoma Trial Planned for Biochemotherapy

LOS ANGELES--A modified M.D. Anderson biochemotherapy regimen for metastatic melanoma that includes interleukin-2 (IL-2) has antitumor activity and is suitable for testing in a cooperative group setting, according to analysis of pilot trial data. The pilot study precedes the larger phase III ECOG/SWOG 3695 intergroup trial that will compare the regimen to CVD (cisplatin, vinblastine, and dacarbazine).

Speaking at the 34th Annual Meeting of the American Society of Clinical Oncology and in a subsequent interview, Michael Atkins, MD, associate professor of medicine, Harvard Medical School, said that ample data from multiple sites have shown that the combination of cisplatin-based chemotherapy and IL-2-based immunotherapy can produce tumor regression in upwards of 50% of patients with metastatic melanoma.

"At first blush, it is superior to what you see with either approach given separately," Dr. Atkins said. "The history of melanoma, however, is replete with promising phase II studies that turn out to offer no advantage when compared with standard therapy. So we feel that a phase III trial is called for."

The pilot trial was designed to test the feasibility of using the inpatient M.D. Anderson biochemotherapy regimen in a cooperative group-like setting. Investigators modified the regimen, however, because of concerns about the high incidence of infection in prior experience.

"We added prophylactic antibiotics and removed central lines at the end of every course of therapy, and used growth factor support to keep the blood counts up following each treatment," he said. Antiemetics were also increased, and strict care guidelines were established for managing nausea, vomiting, hydration status, low blood counts, low blood pressure, and kidney and electrolyte problems.

The Protocol

Patients received CVD concurrently with IL-2 (9 MIU/m² by continuous IV infusion on days 1-4) and interferon alfa-2b (Intron A) (5 MIU/m² on days 1-5, 8, 10, and 12). Routine G-CSF (Neupogen) and aggressive antiemetics were initiated after patients 7 and 14, respectively.

Forty-four patients were enrolled. None had received prior chemotherapy or IL-2. However, 23 had received prior interferon (53%), mostly in the adjuvant setting.

Responses were seen in 19 of 42 evaluable patients (45%), with 6 complete responses (14%). Response durations, Dr. Atkins said, ranged from 1 to more than 14 months, with 7 currently ongoing. Many responses, however, were of short duration, due largely to a high incidence of CNS relapse.

Significant toxicities leading to dose modification included hypotension requiring pressors; grade 3/4 vomiting (12 episodes, but only 6 episodes in 90 cycles after initiation of the modified antiemetic regimen); transient renal insufficiency; grade 4 thrombocytopenia (25 episodes, one associated with bleeding); neu-tropenia with or without fever (14 instances, but only 10 in 121 cycles following routine use of G-CSF); and catheter-related bacteremia. The most frequent side effects were myelosuppression and nausea/vomiting.

A recent report of the original M.D. Anderson trial of this regimen without the increased precautions demonstrated much higher toxicity than that seen in this pilot trial of the modified regimen, Dr. Atkins commented in an interview.

"We conclude that this modified concurrent biochemotherapy regimen is active and likely tolerable for use in a cooperative group setting," he said. Approaches need to be developed for dealing with CNS relapse, he noted.