Genzyme Corporation (Nasdaq: GENZ) announced today that a Phase 1/2 trial provided early clinical data suggesting that Mozobil® (plerixafor injection) in combination with chemotherapy may offer a therapeutic impact on leukemic cells protected in bone marrow. The investigational trial, partially supported by Genzyme, was the subject of an oral presentation at the 2009 annual meeting of the American Society of Hematology in New Orleans, LA. Genzyme has initiated two clinical trials to further explore this potential new strategy to attack blood cancers.
“If we can begin to impact leukemic cells protected in bone marrow, we may be able to reduce residual disease and therefore provide better potential outcomes for patients,” said John F. DiPersio, M.D., Ph.D., professor, Washington University, St. Louis, the senior author of the study that was presented at ASH. “Our initial work in humans has produced some encouraging results.”
In the clinical trial, study director Geoffrey Uy, M.D. and colleagues from Washington University School of Medicine gave Mozobil as a pre-conditioning strategy prior to chemotherapy in forty patients with relapsed or refractory acute myeloid leukemia (AML). Many of the trial participants were either unresponsive to, or had short remissions, following prior treatments. The patients were given Mozobil, and four hours later received the AML combination chemotherapy regimen mitoxantrone, etoposide, and cytarabine (MEC). The Mozobil plus MEC regimen was repeated daily for five days, following the standard MEC treatment protocol.
Of the 32 patients available for the first follow-up evaluation, researchers observed a complete remission (CR or CRi) in 50 percent of patients. Thirteen of these patients had a CR with normal platelet recovery, and three patients had complete remission with incomplete platelet recovery (CRi). In a larger patient population, Washington University’s historical CR and CRi rate in relapsed and refractory AML patients receiving MEC alone ranges from 25 to 35 percent.
The study, developed primarily to determine optimal dosing and safety of Mozobil as a tumor sensitization agent, found no evidence of hyperleukocytosis, excessive release of white blood cells into the bloodstream. There was also no observed delay in the recovery of neutrophils or platelets important to immune system protection and prevention of bleeding, respectively. Treatment failure was considered to be due to persistent disease in 14 patients (44 percent) and death during aplasia (not producing enough new blood cells) in two patients (6 percent). Grade three or higher adverse events consisted primarily of cytopenias and infections, commonly seen in patients treated with the MEC combination alone.
Increasing the ability of chemotherapy to destroy cancerous blood cells in patients’ bone marrow has long been a goal of clinicians. Within the bone marrow environment, some studies suggest that certain cellular communication pathways and adhesion molecules work together to promote leukemic cell survival and poor response to chemotherapy. The ability of these cells to withstand chemotherapy contributes to minimal residual disease, small numbers of leukemic cells that remain in a patient during or after treatment, which is a cause of relapse in cancer.
Preclinical studies suggest that Mozobil may sensitize leukemic cells in the bone marrow to chemotherapy in several ways, including the disruption of a key signaling pathway that promotes leukemia cell survival, affecting interactions between stroma cells and leukemic cells, or by moving the cells out of the bone marrow entirely. Either separately or in combination, these potential actions may make cancer cells more susceptible to chemotherapy.
“We are excited by the interest that physicians have expressed in studying Mozobil for this potential new use,” said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. “The preclinical and early clinical data continue to support the development of Mozobil in this important area that could transform the treatment paradigm for hematologic cancers.”
Genzyme has also initiated company sponsored Phase 1 and Phase 1/2 Mozobil tumor sensitization trials in patients with blood cancers. The Phase 1 trial includes relapsed and refractory patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and is designed to investigate Mozobil as a tumor sensitization agent in combination with the monoclonal antibody rituximab. The Phase 1/2 trial includes AML patients without prior treatment, and is evaluating Mozobil with the anti-cancer drug regimen cytarabine and daunorubicin (known as “7+3”). The primary objective of both trials is to evaluate safety and to define optimal dosing strategies. The company anticipates top-line data from these trials in 2011.
Mozobil is also being studied as a tumor sensitization agent in 10 additional investigator sponsored trials.