New 'combination therapy' improves survival for malignant melanoma patients

May 29, 2000

PITTSBURGH, MAY 30 -- Researchers at the University of Pittsburgh Cancer Institute announced that an immunomodulating agent, histamine dihydrochloride (Maxamine), used in combination with lower doses of interleukin-2 (IL-2), improved survival for stage-IV malignant melanoma patients compared with those treated with the same doses of IL-2 alone. The Phase III, multi-center study included 305 patients with this most deadly and serious form of skin cancer, randomized to receive either the histamine/IL-2 combination or IL-2 alone. The results of the study will be presented for the first time at the Perspectives in Melanoma meeting in Pittsburgh, June 1-2.

The combination therapy improved overall survival, increased survival rates at 12, 18 and 24 months, and improved time-to-disease-progression over treatment with IL-2 alone. Improvement in survival was statistically significant in patients having metastases of their melanoma to the liver, a patient population that historically has had a very poor prognosis.

Preliminary results also indicated that treatment with histamine dihydrochloride and IL-2 was safe and well-tolerated and had substantially less toxicity than the high-dose regimens under which IL-2 was originally approved. The tolerability of the histamine/IL-2 combination therapy allowed these advanced-stage malignant melanoma patients to take this treatment at home.

"The patients in this study represented a group with factors that are indicative of a poor prognosis for survival, including liver metastases," explained Sanjiv S. Agarwala, M.D., lead-enrolling investigator for the study and associate medical director of the Melanoma Center at the University of Pittsburgh Cancer Institute. "This is the first well-controlled, multi-center Phase III trial to show a significant increase in survival among patients with advanced metastatic melanoma."

Treatment of Malignant Melanoma
Malignant melanoma is one of the most rapidly increasing cancers in the world, with approximately 90,000 new cases of malignant melanoma and 15,000 deaths from the disease each year in the United States, Europe and Australia. At present, there is no effective treatment that has been proven to increase survival for advanced stage-IV melanoma.

"Treatment of stage-IV melanoma with chemotherapy, immunotherapy and combination biochemotherapy has provided varying tumor response rates without proof to date that any of these treatments prolong survival significantly," stated John M. Kirkwood, M.D., director of the Melanoma Center at the University of Pittsburgh Cancer Institute. "More effective treatments are required that can improve survival, ideally while maintaining patient quality of life."

Novel Therapeutic Approach
The therapeutic approach utilized in the study is designed to improve the immune system's ability to identify, disable and destroy malignant cells. Cytokines such as IL-2 are immunotherapeutic agents that stimulate certain of the body's immune cells, natural-killer (NK) and T cells, to detect and destroy tumor cells. Histamine dihydrochloride (Maxamine) enhances the effectiveness of cytokines by protecting these critical immune cells from immunosuppression. Because the combination helps cytokines to be more effective, lower and less toxic doses can be used effectively on an outpatient basis.

Survival Benefit, Patients with Liver Metastases
For all randomized patients entering the study with liver metastases (n=129), treatment with histamine dihydrochloride plus IL-2 resulted in a median survival of 283 days compared to 154 days for control patients treated with IL-2 alone (p=0.004 under the Log-Rank test).

Survival Benefit, All Randomized Patients
For all randomized patients entering the study (n=305), treatment with histamine dihydrochloride plus IL-2 resulted in a median survival of 272 days compared to 245 days for control patients treated with IL-2 alone (p greater than 0.05 under the Log-Rank test). Overall survival, adjusted for quality of life, was also significantly improved for patients treated with histamine dihydrochloride and IL-2 compared to IL-2 alone (p less than 0.0001 for the median quality-adjusted survival improvement). In addition, time-to-disease-progression was also significantly improved for those patients receiving histamine dihydrochloride and IL-2 (p=0.01).

Survival to 24 months occurred in a total of 25 percent of patients treated with histamine dihydrochloride and IL-2, compared with 17 percent in those treated with IL-2 alone. Published reports indicate that the 24-month survival for patients treated with high-dose IL-2 was 12 percent in prior studies.

Survival Benefit, Efficacy Evaluable Population
Patients treated at clinical centers that best followed the study protocol by treating all of their patients on average with two or more cycles of therapy were considered the "efficacy evaluable" population. For all patients in the efficacy evaluable population (n=219), treatment with histamine dihydrochloride plus IL-2 resulted in a median survival of 326 days compared to 251 days for patients treated with IL-2 alone (p=0.0336 under the Log-Rank test).

For all patients in the efficacy evaluable population who entered the study with baseline liver metastases (n=93), treatment with histamine dihydrochloride plus IL-2 resulted in a median survival of 363 days compared to 157 days for control patients treated with IL-2 alone (p=0.0007 under the Log-Rank test).
-end-
CONTACT: Heather Szafranski, szafranskihl@msx.upmc.edu
Lauren Ward, wardle@msx.upmc.edu
University of Pittsburgh
(412) 624-2607
or
Ed Stevens, ed.stevens@pr-euro.com
PResence Euro RSCG
(619) 293-7100

Histamine Dihydrochloride (Maxamine) The clinical trial was sponsored by Maxim Pharmaceuticals, Inc., a San Diego-based bio-pharmaceutical company that holds the patent rights associated with the therapeutic use of histamine.

University of Pittsburgh Cancer Institute Ranked 12th in NCI funding and the only NCI-designated comprehensive cancer center in western Pennsylvania, UPCI is widely recognized as a leader in translating laboratory findings into applications of potential clinical importance and for its commitment to developing new and effective approaches to cancer prevention, diagnosis, treatment and care. For more information about UPCI, please access http://www.upci.upmc.edu or call the UPCI's Cancer Information and Referral Service toll-free at 1 (800) 247-4724.

University of Pittsburgh Medical Center

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