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Fall 2005 Volume 6, Issue 6:
MOZOBIL™, a potential new agent for Stem Cell Harvesting
By An interview with Neal Flomenberg, MD
Colony-stimulating factors such as G-CSF (filgrastim) induce the marrow to grow, while MOZOBIL is a new agent that aids in releasing stem cells into circulating blood where they can be collected by a process called apheresis.

What is the idea behind stem cell transplantation for multiple myeloma?

A peripheral blood stem cell (PBSC) transplant is commonly employed in the treatment of myeloma. It is a procedure used to restore the immune system of myeloma patients who have had high-dose chemotherapy treatments that previously destroyed their immune cells. The idea behind transplant is that it allows one to treat more intensively than one could in the absence of a transplant. Many chemotherapy drugs suppress some of the faster-growing cells in the body, of which the bone marrow is one. When the bone marrow is suppressed, you cannot make certain blood components because the marrow is the "blood factory." A low white count puts you at risk for infection; a low platelet count puts you at risk for bleeding. Most people can tolerate low blood counts for short period of time, but the longer such conditions last, the more vulnerable one becomes to these side effects. So, after high doses of chemotherapy completely destroy the marrow and, hopefully, the myeloma cells as well, the re-infusion of these "baby cells" restarts the marrow growth and function. In order to perform a PBSC transplant, one must collect stem cells that will be used to restart the marrow after the transplant. The more stem cells you transplant, the faster you restart the marrow, and the shorter the period of vulnerability.

How would you compare the colony-stimulating factors that are currently used and MOZOBIL™ (AMD3100)?

Colony-stimulating factors such as G-CSF (filgrastim) induce the marrow to grow, while MOZOBIL is a new agent that aids in releasing stem cells into circulating blood where they can be collected by a process called apheresis.

What is MOZOBIL's mechanism of action?

MOZOBIL inhibits the chemokine receptors that act as "anchors" holding these baby cells to the marrow. Alternatively, you can think of this "anchoring" as two sides of a piece of Velcro, or a lock and key. MOZOBIL disrupts this action, and it does so directly, as opposed to the indirect effects of G-CSF. The effects of G-CSF are not seen for 4 or 5 days. The effects of MOZOBIL are seen much more quickly, in 4 to 6 hours, reflecting the fact that the cells aren't just growing, but also being released. It may be that these complementary effects are why the combination seems to be more effective than either of the drugs alone.

Has MOZOBIL been studied as a single agent?

It is currently being studied as a single agent in a Phase II clinical trial. Also, it is being used in addition to one of the current standards of care. In Europe, Phase II trials are ongoing to evaluate MOZOBIL in combination with different stem cell mobilizing regimens, including chemotherapy.

Can you tell us about MOZOBIL's clinical development?

In Phase I clinical trials, researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In Phase II clinical trials, the study drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety. In Phase III clinical trials, the study drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. MOZOBIL's clinical program is designed to evaluate its ability to improve overall transplantation procedure by increasing stem cells available for transplant.

Can you describe the study design and how each patient was able to be his or her own control?

Each patient got mobilized twice, first either with G-CSF alone followed by G-CSF and MOZOBIL combined, or vise versa. There were approximately 2 weeks of rest between the two mobilizing approaches. Who got mobilized with which approach first was decided by a "computer coin toss." That way, the results were not biased in favor of either approach. Scientifically, we thought that this was a more precise way to do the study. Controlled trials are more convincing than studies that do not use a control, and allow investigators to get a better handle on the effectiveness of the drug when studying a smaller group of patients. While a Phase II trial is not as definitive as a randomized Phase III trial with hundreds of patients, I do think that it gave us far more information than we would have had if we only mobilized with a combination and not studied how these same patients did with G-CSF alone.

What did the data from your Phase II trial show?

A combination of MOZOBIL and G-CSF is better than G-CSF alone to mobilize and collect the optimal number of stem cells for autologous transplantation. The combination has shown potential to help more patients collect more cells and improve the transplant procedure.T he use of MOZOBIL increased the number of stem cells in peripheral blood and also reduced the number of apheresis sessions required for patients to reach the target number of stem cells collected.

Five of the patients who received G-CSF alone and failed to collect, were then successfully able to mobilize enough stem cells with a combination of G-CSF and MOZOBIL. Four of the patients who were successfully given a combination of G-CSF and MOZOBIL initially, afterwards failed to collect with G-CSF alone.

Up to 65% of transplant patients have poor or sub-optimal mobilization using G-CSF alone, and there are no medical guidelines to predict which patients will respond poorly to G-CSF mobilization. These patients may require additional mobilization sessions to achieve a sufficient collection for transplantation. Patients transplanted with a sub-optimal number of cells can experience a delayed recovery of their immune system, and are at greater risk for infection and may require additional days of antibiotics, blood transfusions, and extended hospitalization. MOZOBIL possibly allows for a more rapid collection of a larger number of stem cells from the peripheral blood. Larger stem cell doses for transplantation are correlated to faster recovery times.

At this time, I am very upbeat that MOZOBIL has the potential to become part of the standard of care for myeloma. Of the 25 patients treated, 9 could not have been transplanted with G-CSF mobilization alone. Other patients in the study were able to save one or more days of apheresis due to the use of the G-CSF and MOZOBIL combination. Approximately 84% of patients treated derived benefit form the combination, and that's a very substantial improvement.

Blood published Phase II data in September 2005, and we will report new Phase II data at the American Society of Hematology (ASH) conference in December 2005. Based on Phase II results, as well as historical data from standard stem cell mobilization regimens using G-CSF alone, a Phase III clinical trial initiated patient enrollment in January 2005.

What about side effects?

The side effects profile is very good. There have been very few serious side effects, and none of them could be related to MOZOBIL Ð they occurred during or after transplant, well after MOZOBIL was administered, or they occurred during mobilization with G-CSF alone, before MOZOBIL was ever administered. The fairly mild and brief side effects we've seen include discomfort at the site of the injection, pins and needles in the fingers and toes, and GI upset.

What can you tell us about the Phase III trial?

This study is intended to determine whether the combination of MOZOBIL plus G-CSF is better than placebo plus G-CSF. One of the Phase III studies being conducted is exclusively enrolling several hundred myeloma patients (see list of U.S. centers below). This study is randomized, double-blind, placebo controlled, comparative. To be as scientifically rigorous as possible, and to avoid any bias, the Phase III study is only enrolling patients undergoing the stem cell collection process for a transplant for the first time.

What about patients who have previously failed to collect enough stem cells for a transplant?

AnorMED, the pharmaceutical company developing MOZOBIL, has a compassionate use program that might be available to patients who have already attempted mobilization and were not successful.

What are your thoughts about PBSC transplant for myeloma as opposed to standard therapy?

There have been some randomized studies, which have suggested that there are more patients disease-free at later time points in their illness with PBSC transplant than with non-transplant therapies. But this is a moving target because new agents continue to become available for treatment within and outside the transplant setting. Fortunately, there is much progress being made in the field of myeloma.

Phase III study sites in the U.S.

  • City of Hope, Phoenix, Arizona
  • Myeloma Institute for Research and Therapy, Little Rock, Arkansas
  • Rocky Mountain Cancer Center, Denver, Colorado
  • Yale University School of Medicine, New Haven, Connecticut
  • H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
  • Loyola University Medical Center, Maywood, Illinois
  • Indiana Blood and Marrow Transplantation Center, Beech Grove, Indiana
  • University of Iowa, Iowa City, Iowa
  • Fairview-University Medical Center, University of Minnesota, Minneapolis, Minnesota
  • Mayo Clinic, Rochester, Minnesota
  • Washington University School of Medicine, Saint Louis, Missouri
  • Kansas City Cancer Center, Kansas City, Missouri
  • The Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey
  • University of Rochester Medical Center, Rochester, New York
  • Roswell Park Cancer Institute, Buffalo, New York
  • Duke University Medical Center, Durham, North Carolina
  • Cleveland Clinic Foundation, Cleveland, Ohio
  • Oregon Health & Science University, Portland, Oregon
  • Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
  • University of Texas Health Science Center, San Antonio, Texas
  • Texas Transplant Institute, San Antonio, Texas
  • Utah Blood and Marrow Transplant Program, Salt Lake City, Utah
  • Virginia Commonwealth University, Richmond, Virginia
  • Fred Hutchinson Cancer Research Center, Seattle, Washington
  • Thomas Jefferson University, Philadelphia, Pennsylvania

Editor's Note: For additional MOZOBIL Phase III study information, please visit www.ClinicalTrials.gov and use identifier NCT00103662.

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