5 Questions with Adil I. Daud, MD, on Chemotherapy Prescription Drug, LEUKINE®

Dr. Daud is a clinical physician and medical researcher, certified by the American Board of Internal Medicine in both Oncology and Hematology. He serves as associate professor and director of Melanoma Clinical Research at the University of California, San Francisco, and is a member of the National Comprehensive Cancer Network’s Melanoma Panel Committee, the American Society of Clinical Oncology and the American Association for Cancer Research.

Please explain how Leukine works to extend the lives of patients with high-risk melanoma. What is the efficacy when used in combination therapy?

The study findings published in the July 1st issue of the Journal of Clinical Oncology provide early signals that Leukine may offer clinical benefits in high-risk melanoma patients by increasing and differentiating dendritic cells.

Dendritic cells are special antigen-presenting cells that help the immune system recognize cancer cells and are the most effective antigen-presenting cells known. These study results indicate that an increase in dendritic cell counts may correlate with delayed recurrence of disease in high-risk melanoma patients.

In addition to these data published in the Journal of Clinical Oncology, further findings of Leukine in melanoma were released at the 44th annual meeting of the American Society of Clinical Oncology (ASCO). According to these data, adjuvant therapy with Leukine and a synergistic cytokine, IL-2, was generally well-tolerated in patients with high-risk melanoma following potentially curative surgery. Each patient received two years of adjuvant therapy: year one with Leukine and IL-2 and year two with only Leukine. Results showed that 60 percent of the 45 high-risk patients enrolled in the trial experienced disease-free survival and 64 percent of patients achieved overall survival at 21 months.

What is the median overall survival time in patients? How long has the study been conducted, what patients were tested, and when do you anticipate moving into a Phase III trial?

Data from the Phase II trial of 42 high-risk melanoma patients published in the Journal of Clinical Oncology showed that Leukine demonstrated a median overall survival of 65 months (95 percent, CI 43-67 months) and a median recurrence-free survival of 5.6 months (95 percent, CI 3.7-11 months).

Patients were treated with Leukine at 125 g/m2/day for 14 consecutive days followed by 14 days of no treatment. This regimen was repeated for 13 cycles, or a total of one year, unless patients had unacceptable toxicity or showed evidence of disease recurrence. Patients had no evidence of the disease at the start of the trial as measured by imaging. Patients underwent restaging every four months.

Additionally, 11 patients who relapsed within three months of starting Leukine had lower dendritic cell counts at two weeks compared to those who relapsed after three months and those who remained in remission throughout the course of the study.

However, the ability of Leukine to induce mature dendritic cells appeared to be confined to those patients who had low dendritic cell count before the start of treatment.

In regards to a Phase III trial, there is currently an ongoing fully accrued cooperative group trial, E4697, that randomizes patients to one of six arms depending on whether they are HLA A2+ or not and includes vaccine in some arms. Results from this trial are expected next year. A concern about this trial is that splitting a relatively small number of patients into multiple arms could reduce the power to tell us if GM-CSF truly was better or not. As of now, I don’t know of any other ongoing or planned Phase III trials in high-risk melanoma.

Are any other treatment options available to patients with melanoma at this time that demonstrate comparable results?

This is currently a very difficult area for patients. We know melanoma recurrence is highly associated with death form this disease, yet there aren’t many options. The most commonly used agent that is FDA approved for this indication is Interferon Alpha-2B. However, it is much more toxic. It has been shown in randomized trials to reduce the risk of melanoma recurrence and its effect on overall survival is of borderline statistical significance in a metanalysis looking at all randomized interferon clinical trials done to date. So Interferon is an option for young, healthy patients.

Vaccines have been tested for more than three decades and to date no study has shown a benefit in terms of survival or disease free survival. Some studies presented at the ASCO 2008 and 2007 meetings have even shown that they may reduce survival so we have to carefully evaluate them in the future. Chemotherapy has been tested and found to not help and probably should not be considered an option here.

What additional research is, or will be, conducted with regard to Leukine?

Leukine is being evaluated in clinical trials in combination with other drugs as a potential treatment for a number of conditions, including melanoma and B-cell non-Hodgkin's lymphoma.

Can Leukine be used in any related or additional oncology treatments?

Leukine is currently FDA approved for several indications for oncology related treatments:

• Use following induction chemotherapy in older adults with acute myelogenous leukemia (AML) to shorten the time to neutrophil recovery and reduce the incidence of severe and lifethreatening infections and infections resulting in death

• Use in myeloid reconstitution following allogeneic and autologous bone marrow transplantation (BMT)

• Use in peripheral blood stem cell (PBSC) mobilization and subsequent myeloid reconstitution in patients undergoing PBSC transplantation

• Use in bone marrow transplantation failure or engraftment delay.