Safety Study of a Chemokine Receptor (CXCR4) Antagonist in Multiple Myeloma Patients
BKT-140 drug substance is a highly selective chemokine receptor (CXCR4) antagonist, which is developed by Biokine as a novel therapy for Multiple Myeloma (MM, a type of blood cancer). The unique combination of activities of BKT140, i.e., the induction of the exit of blood cells such as stem cells and mature cells from the bone marrow to the peripheral blood, coupled with specific induction of MM cell death by BKT-140, represents a novel therapeutic strategy against MM.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/IIA, Non-Randomized, Open Label, Single Dose, Dose-Escalation, Safety Study of BKT140, a CXCR4 Antagonist in Patients With Multiple Myeloma|
- White blood cell (WBC) count [ Time Frame: 24 hour ] [ Designated as safety issue: No ]
- CD34+ cells [ Time Frame: 24 hour ] [ Designated as safety issue: No ]
|Study Start Date:||October 2008|
|Study Completion Date:||July 2010|
|Primary Completion Date:||July 2010 (Final data collection date for primary outcome measure)|
The chemokine CXCL12 (also called SDF-1 - stromal-derived-factor-1) and its receptor, CXCR4 ((CXC Chemokine Receptor 4), a molecule endowed with potent chemotactic activity for hematopoietic cells, together play a pivotal role in the trafficking of hematopoietic stem cells to the bone marrow 10,11. The CXCL12/CXCR4 axis is also critically involved in the retention of hematopoietic cells within the BM microenvironment. Following chemotherapy and irradiation, the CXCL12/CXCR4 axis delays the recovery of the BM progenitor cells and the exit of mature cells such as neutrophils and monocytes to the periphery. Consequently, disruption of the CXCL12/CXCR4 interaction results in mobilization of hematopoietic cells including stem cells and a faster recovery of the treated BM.
BKT140 (4F-benzoyl-TN14003) is a highly selective and unique CXCR4 antagonist. Pre-clinical studies showed that BKT140 binds CXCR4 with high affinity (1nM) 13. Biokine has demonstrated the ability of the CXCR4 antagonist, BKT140, to mobilize various WBC such as neutrophils and monocytes as well as progenitor and stem cells, from the BM. The ability of BKT140 to stimulate the mobilization of these cells is superior to that of AMD3100, a CXCR4 antagonist that is in clinical development for mobilization of stem cells in MM and lymphoma patients, both qualitatively and quantitatively. BKT140 synergizes much more efficiently with G-CSF when compared to AMD3100. Moreover, Biokine has shown that BKT140, in synergism with G-CSF (NEUPOGEN®), is much more efficient in increasing the numbers of neutrophils and activated monocytes in the blood, by several folds as compared to G-CSF alone. BKT140 also shortens the neutropenic period due to an early release of neutrophils and monocytes from the BM. More importantly, BKT140, in synergism with G-CSF, reduces the anemic period caused by chemotherapy, due to a RBC production, which does not occur when G-CSF is given as a sole treatment. More importantly, BKT140, but not G-CSF or AMD3100, is also capable of shortening the period of cytopenia by boosting both the recovery of all hematopoietic cells in the BM and their exit to the periphery, and therefore shortening the period of cytopenia following chemotherapy or irradiation and BM transplantation. Importantly, Biokine has shown that upon interaction with CXCR4, BKT140, but not AMD3100, selectively, specifically and rapidly stimulates human leukemia and myeloma cell death in vitro and in vivo. Furthermore, BKT140 synergizes with other chemotherapeutic agents such as rapamycine to induce MM cell death.
|Department of Hematology and Bone Marrow Transplantation,Rambam Medical Center|
|Haifa, Israel, 31096|
|Chaim Sheba Medical Center,Tel-Hashomer|
|Ramat Gan, Israel, 52621|
|Principal Investigator:||Arnon Nagler, MD||Chaim Sheba Medical Center|