By Debbie Strickland
Stage IV melanoma patients who received once-a-week double shots of an experimental vaccine therapy may not have survived any longer than a control group of chemotherapy-treated patients, but they were significantly happier.
"What we have at the close of this study is this: There is no difference in survival, but there is a very highly significant difference in quality of life," said Ken Von Eschen, vice president for clinical regulatory affairs at Ribi ImmunoChem Research Inc. "All things considered, Melacine presents a very reasonable, relatively safe treatment."
The company's stock closed Tuesday at $4.50, up $0.125.
With the backing of the Phase III data, the Hamilton, Mont.-based company this year plans to submit applications for marketing approval in North America, Europe and Australia.
The Canadian application is likely to be completed during the current quarter. Biomira Inc., of Edmonton, Alberta, has licensed exclusive Canadian marketing rights, but Ribi has exclusive rights everywhere else through a licensing agreement with the University of Southern California.
Melacine melanoma theraccine (therapeutic vaccine) consists of lysed cells from two human melanoma cell lines with a broad array of melanoma antigens, combined with Ribi's proprietary Detox adjuvant. Detox adjuvant contains MPL immuno-stimulant (monophosphoryl lipid A) and mycobacterial cell wall skeleton, both of which stimulate the human immune system.
The Phase III study consisted of two groups of 70 patients, with 54 evaluable patients in the Melacine group and 52 evaluable patients in the chemotherapy group.
Melacine is administered as a two-shot vaccination once a week for five weeks, with a two-week respite and then a repeat of the weekly vaccinations for five weeks. Patients who respond may receive a second course of therapy, as well as maintenance therapy of one vaccination a month.
The chemotherapy treatment employed in the study was an investigational four-drug treatment called the Dartmouth Protocol that has been recommended as a first-line therapy for advanced melanoma. The Dartmouth Protocol calls for intravenous administration of two drugs, decarbazine and cisplatin, for three days, a cycle that is repeated after 28 days, and intravenous administration of a third drug, carmustine, for one day, repeated after 56 days. The fourth drug, tamoxifen, is taken orally twice a day for the duration of the therapy. Patients who respond may receive additional therapy.
The Phase III data indicate Melacine provides a statistically significant advantage in quality of life compared to the chemotherapy regimen. Researchers measured symptom distress, physical function and mental health.
In a key quality-of-life measure, 70 percent of the Melacine patients rated their lives normal to slightly inconvenient, while 68 percent of the chemotherapy patients described their days as uncomfortable to miserable. Moreover, only one serious adverse event was associated with the Melacine treatment; the chemotherapy group reported 86.
The quality-of-life comparison achieved a p-value of 0.011, a "highly significant" result, the company noted, since the standard for statistical significance is a p-value of 0.05 or less.
"Most of the patients said they could do everything they usually do and that they didn't feel bad," said Robert Ivy, president, chairman and CEO of the company.
However, as announced in 1994 preliminary findings, Melacine failed to outperform chemotherapy in the trial's primary endpoint, survival length. The company had aimed for a 50 percent increase in median survival.
Instead, the median survival for combination chemotherapy patients was 12.4 months, 1.4 months longer than the Melacine group. With a p-value of 0.37, this result was not statistically significant.
Melacine did hit its survival target, Ivy noted, but better-than-expected chemotherapy results foiled the comparison.
He also pointed out that a sub-analysis of the data showed that median survival exceeded 18 months among Melacine patients who experienced complete or partial tumor responses or stabilization of disease; the median survival for similar chemotherapy patients was 15 months. The difference was not statistically significant.
To supplement its Phase III study, Ribi has performed a meta-analysis of 74 late-stage melanoma studies conducted since the mid-1970s. The meta-analysis found a median survival of 7.9 months for 5,392 evaluable patients. Median survival was 8.5 months for the 2,827 patients included in 52 studies published since 1985.
When compared to the meta-analysis results, the Melacine trial did achieve a statistically significant improvement in survival.
In addition to clinical benefits, Melacine offers a potential bottom-line boon as well: With fewer doctor's visits and reduced hospital stays, the vaccine will probably cost much less than combination chemotherapy, according to the company.
"Melacine will be considerably cheaper," Ivy said, "perhaps one-third to one-fourth as expensive as chemotherapy. And it's certainly easier to take."
While moving forward on the regulatory approval front, Ribi is continuing related trials of Melacine:
* A Phase II trial is under way to determine whether the vaccine prevents recurrence of melanoma in Stage II patients who have had their melanoma lesions surgically removed. The National Cancer Institute is sponsoring the study.
* A Phase III clinical trial is investigating the efficacy of combination therapy consisting of Melacine and Intron A (interferon alfa-2B). Results of the combination therapy administered to Stage IV melanoma patients will be compared to an Intron A-only control group. Ribi is conducting the study with Schering-Plough Corp., the Madison, N.J.-based developer of Intron A, which also is in Phase III trials. *