BETHESDA, MdThe FDA’s Oncologic Drugs Advisory Committee
(ODAC) declined in a unanimous vote to recommend that the agency approve
histamine hydrochloride injections (Maxim Pharmaceuticals) for adjuvant use
with interleukin-2 (IL-2) in the treatment of adult patients with advanced
melanoma that has metastasized to the liver.
Maxim sought approval based on a subgroup of 129 patients
enrolled in a 305-patient randomized, multicenter, open-label study designed to
show the benefit to metastatic melanoma patents of adding histamine to IL-2
therapy. The rationale for the study was that monocytes and macrophages inhibit
the IL-2-induced activation of lymphocyte functions, and that histamine can
restore the responsiveness of natural-killer cells and T cells to IL-2.
Patients received either IL-2 alone or with histamine.
According to the FDA analysis of the trial, median survival among all study
participants was 8.0 months in the IL-2 group and 8.9 in the combination arm, a
difference that was not statistically significant.
Among patients whose melanoma had metastasized to the liver,
however, median survival was statistically significant: 5.0 months in the IL-2
treatment arm and 9.2 among patients receiving both IL-2 and histamine,
according to the company’s analysis.
FDA medical reviewer Judy Chiao, MD, challenged several aspects
of the study protocol and changes that were made to it during the course of the
conduct of the study. Dr. Chiao and a number of ODAC members also expressed
concerns about some safety data that emerged in both FDA’s and the company’s
analyses of the study.
According to the FDA, "There were many imbalances in known
prognostic factors and other patient characteristics between the two treatment
arms in the subgroup of patients with liver metastases, perhaps because there
was no stratified randomization. These included performance status, albumin,
disease-free interval, and the number of metastatic sites. When the data are
adjusted for imbalances, the result becomes less favorable, losing statistical