The high-affinity CXCR4 antagonist BKT140 is safe and induces a robust mobilization of human CD34+ cells in patients with multiple myeloma.

Abstract

PURPOSE:

CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.

EXPERIMENTAL DESIGN:

Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m(2) cyclophosphamide (day 0), followed by granulocyte colony-stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.

RESULTS:

BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34(+) cells (20.6 ± 6.9 × 10(6)/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 10(6) CD34(+) cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).

CONCLUSIONS:

When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34(+) cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment.

• Authors: Amnon Peled, Michal Abraham, Irit Avivi, Jacob M Rowe, Katia Beider, Hanna Wald, Lena Tiomkin, Lena Ribakovsky, Yossi Riback, Yaron Ramati, Sigal Aviel, Eithan Galun, Howard Laurence Shaw, Orly Eizenberg, Izhar Hardan, Avichai Shimoni, Arnon Nagler
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 2 Pg. 469-79 (Jan 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24246358 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• BKT140
• Oligopeptides
• Receptors, CXCR4
• Granulocyte Colony-Stimulating Factor

Topics

• Adult
• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology)
• Blood Cell Count
• Cell Line, Tumor
• Disease Models, Animal
• Drug Synergism
• Female
• Granulocyte Colony-Stimulating Factor (administration & dosage, adverse effects, pharmacology)
• Hematopoietic Stem Cell Mobilization
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells (drug effects, metabolism)
• Humans
• Male
• Mice
• Middle Aged
• Multiple Myeloma (metabolism, therapy)
• Oligopeptides (administration & dosage, adverse effects, pharmacology)
• Protein Binding
• Receptors, CXCR4 (antagonists & inhibitors, metabolism)
• Treatment Outcome