BKT140 Is a Novel CXCR4 Antagonist with Stem Cell Mobilization and Antimyeloma Effects: An Open-Label First Human Trial In Patients with Multiple Myeloma Undergoing Stem Cell Mobilization for Autologous Transplantation

• Published in: Blood 2010-11, Vol.116 (21), p.2260-2260
• Main Authors: Nagler, Arnon, Shimoni, Avichai, Avivi, Irit, Rowe, Jacob M., Beider, Katia, Hardan, Izhar, Abraham, Michal, Wald, Hanna, Galun, Eithan, Shaw, Howard Laurence, Eizenberg, Orly, Peled, Amnon
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.2260.2260

Abstract 2260 BKT140 is a high affinity CXCR4 inhibitor with an extended K off-rate. Pre-clinical studies in animal models with BKT140 showed a robust mobilization of white blood cells (WBC) and hematopoietic stem cells (HSC). Furthermore, BKT140 also showed a direct anti-tumor effect against human-derived multiple myeloma (MM), lymphoma and primary leukemia cells and cell lines in vitro and in vivo, causing significant apoptosis. To assess BKT140 toxicity (primary endpoints), the mobilization capacity of CD34+ hematopoietic progenitors and CD138 MM cells, and pharmacokinetic (PK) and pharmacodynamic (PD) (secondary endpoints). 16 MM patients in first CR/PR were included in a phase I/IIa study, in which escalating doses of BKT140 (30, 100,300,900 μg/kg) were administered together with a high-dose cyclophosphamide (Cy) (2 g/m2) and G-CSF (5 μg/Kg) for stem cell mobilization. G-CSF was started on day 5 post Cy and BKT140 was injected subcutaneously (SC) once on day 10. Toxicity, PK, and mobilization capacity (assessed by serial measurements of number of WBC and CD34+ and CD138+ cells) were measured pre- and post BKT140 administration. BKT140 was well tolerated at all doses and none of the patients developed grade II-IV toxicity. BKT140 was rapidly absorbed with no observed lag time, with peak plasma concentrations occurring 0.5h after administration. Clearance was rapid, with a median terminal half-life of 0.69h. BKT140 administration resulted in a significant dose-dependent increase in the number of peripheral blood neutrophils, monocytes, lymphocytes, and CD34+ cells compared to the G-CSF/Cy individual patient baseline. The maximum increase in the number of WBC from baseline was observed within 8h following BKT140 injection, 2.5-, and 3.0-, 4.1- and 4.8-fold, for the 4 BKT140 doses, respectively. Furthermore, BKT140 administration resulted in a significant increase in the mean absolute PB CD34+ cells mobilized (6.6, 7.5, 11.2 and 20.6 ×106/kg) for the 4 BKT140 administered doses, respectively. Moreover, the number of aphaeresis was reduced from 2.25 procedures at the first two BKT140 doses to 1.25 and 1 aphaeresis at the highest BKT140 doses, respectively. An increase in the number of CD138+ cells was observed in 6 out of 6 pts that had CD138+ cells in their blood and were treated with lower doses of BKT140 (30 and 100 μg/kg). Interestingly, in pts that were treated with the highest doses of BKT140 (300 and 900 μg/kg) a reduced number of CD138+ cells was o